Physiology

The Study of the normal functioning of a living organism and it's component parts including all its chemical and physical processes.

Environmental Conditions Required for Life

Cellular Physiology and The Body Fluid Compartments

Total Body Water

The relationships between volumes of the various body fluid compartments are shown for a normal young healthy male individual weighing 70 kg (2.2 lbs = 1 kg).

Extracellular Fluid

0.2 x BW = 14 L The watery internal environment of multicellular animals is called the extracellular fluid (also known as the interstitial fluid) which surrounds all the cells of the body. ECF includes the water contained within bones and dense connective tissue, as well as cerebrospinal fluid (CSF)FUNCTION: Extracellular fluid (ECF) serves as the transition between an organism’s external environment and the intracellular fluid inside cells. Because extracellular fluid is a buffer zone between the outside world and most cells of the body, elaborate physiological processes have evolved to keep its composition relatively stable. When the ECF composition varies outside its normal range of values, compensatory mechanisms activate and return the fluid to the normal state. If the body fails to maintain homeostasis, then normal function is disrupted and a disease state, or pathological condition may result.

Interstitial Fluid

Interstitial fluid urrounds the cells in the various tissues of the body and accounts for 75% of the ECF volume • this averages between about 10 L to 14 L (.75 of 0.2xBW) ♥ under some pathological conditions, additional fluid may accumulate in the interstitial space (referred to as a “third space”) and results in “pitting” edema

Plasma

blood plasma is the remaining 25% of the ECF volume (about 3.5 L) • the composition the interstitial fluid is almost in equilibrium with plasma except for a higher plasma protein concentrationalbumen is the predominant plasma protein (plasma osmotic pressure = 28 mm Hg, interstitial osmotic pressure = 8 mm Hg)

Intracellular Fluid

0.4 x BW = 28 L

Distribution of Solutes between compartments

osmolarity

osmolality

tonicity

isotoníc

hypotonic

hypertonic

changes when water is added

Cellular Membranes

Types

Plasma Membrane

Each cell is surrounded by a plasma membrane that separates it from the extracellular milieu.

Functions

The plasma membrane serves as a permeability barrier that allows the cell to maintain a cytoplasmic composition far different from the composition of the extracellular fluid.

Components

The plasma membrane contains enzymes, receptors, and antigens that play central roles in the interaction of the cell with other cells and with hormones and other regulatory agents in the extracellular fluid.

Lipids

Cholesterol

, which are mostly hydrophobic, insert themselves between the hydrophilic heads of phospholipids • cholesterol helps make the membranes impermeable to small water-soluble molecules and keeps membranes flexible over a wide range of temperatures

Phostophlipids

Components

Glycerol-Phosphate Head

- the glycerol-phosphate head of the molecule is polar and hydrophilic

Two Fatty Acid Tails

- the fatty acid tail is nonpolar and hydrophobicanother significant component of the membrane which have a fatty acid tail, but their heads may be either phospholipids or glycolipids

Products

Lipid Bilayer

. In an aqueous environment, phospholipids tend to form structures that allow the fatty acyl chains to be kept away from contact with water. One such structure is the lipid bilayer. An electron micrograph of a lipid membrane is shown on the right (PM = plasma membrane, M = mitochondria, ER = endoplasmic reticulum).

Fluid Mosaic Model

the phospholipids are arranged in a bilayer → creating a semi-permeable membrane

the hydrophilic phosphate heads face the aqueous solutions inside and outside the cell

the hydrophobic lipid tails are “hidden” in the center of the membrane

protein molecules of various kinds are inserted into and through the phospholipid bilayer

glycolipids and glycoproteins are formed when carbohydrates bind to proteins and lipids on the extracellular surface

Glycolipids

Sphngolipids

the major membrane lipid

Products

Lipid Rafts

Aggregates of sphingolipids and cholesterol can form stable microdomains that diffuse laterally in the phospholipid bilayer and form lipid rafts. It appears the lipid rafts may mediate the temporary assembly of complexes of intracellular signaling proteins, as well as the sorting of plasma membrane proteins for internalization. In the above image, sphingolipids (orange) are longer than phospholipids and stick up above the phospholipids of the membrane (black). A lipid-anchored enzyme, placental alkaline phosphatase (yellow), is almost always associated with a lipid raft.

Components

another significant component of the membrane which have a fatty acid tail, but their heads may be either phospholipids or glycolipids

Fatty Acid Tail

Phospho-lipid or GLycolipid Head

Carbohydrates

Glycoproteins

Membrane Proteins

According to some estimates, membrane proteins may make up nearly ⅓ of all proteins coded in human DNA. Each cell has between 10 and 50 different types of proteins inserted into its membranes. Anatomically, membrane proteins are classified into three categories:

Structural Classification

Found in-cell junctions-cytosketons

Integral Proteins

extend all the way across the cell membrane • they are tightly bound into the membrane because the 20-25 amino acids in the α-helix segments that pass through the bilayer are nonpolar • these amino acids create noncovalent interactions with the lipid tails of the phospholipids in the membrane • integral proteins are classified according to how many transmembrane segments they have • the amino acid chains protrude into the cytoplasm and the extracellular fluid

Extracellular Loops

Membrane-spanning integral proteins have loops of peptide chains that extend into the cytoplasm and extracellular fluid. Carbohydrates can attach to the extracellular loops,

Intracellular Loops

phosphate groups can attach to the intracellular loops.

Lipid Anchored Proteins

. lipid-anchored proteins are covalently bound to lipid tails that insert themselves into the bilayer • many are found in association with membrane sphingolipids, leading to the formation of specialized patches of the membrane called lipid rafts

Peripheral Proteins

. peripheral proteins do not span the entire width of the cell membrane • they attach themselves loosely to transmembrane proteins or to polar heads of the phospholipids • peripheral proteins include enzymes and some structural binding proteins that anchor the cytoskeleton to the membrane

Functional Classification

Membrane-Spanning Proteins

Function in protein-mediated transport

Membrane Transporters

move molecules across the membranes and the transporter proteins can be subdivided into two categories:

Carrier Proteins

bind to the substrates that they carry but never form a direct connection between the ICF and ECFChange conformation

Uniport

ii.

Symport

iii.

Antiport

II.

Channel Proteins

water-filled passageways that directly link the intracellular and extracellular compartments An ion’s charge makes it difficult for the ion to move across the lipid bilayer. However, the rapid movement of ions across a membrane is an important aspect of many cellular functions. This movement occurs through selective ion channels. Ion channels are integral proteins spanning the width of the plasma membrane and are normally composed of several polypeptide subunits. Certain specific stimuli cause the protein subunits to open a “gate”, creating an aqueous channel through which the ions can move rapidly from one side of the membrane to the other. Most ion channels usually open in response to a specific stimulus. Ion channels can be classified according to their gating mechanisms or by the signals that make them open or close. There are voltage-gated channels, ligand-gated channels, and some channels are always open and are referred to as nongated “leak” channels. Ion channels are often selective for various anions and cations but the relationship between the amino acid composition of the channel protein and ion selectivity of the channel is still under intense investigation.

Gated

Voltage

. voltage-gated ion channels are sensitive to the voltage difference across the cell membrane (figure C) • these channels are typically closed and they open when the membrane potential changes beyond a certain threshold value

Ligand/Chemical

. ligand-gated ion channels are directly activated by the binding of a specific agonist, a chemical substance, to a membrane receptor (figure B) • when the agonist (ligand) binds to its receptor, the associated ion channels can either open or close to permit or block the movement of specific ions across the cell membrane - the ligand can be a neurotransmitter arriving from the extracellular medium - it may be an intracellular second messenger, produced in response to some cell activity or hormone action, that reaches the ion channel from inside of the cell

Mechanically (not for ions?)

ii.

Open/"Leak"

nongated ion channels are always open and are responsible for the influx of Na+ and the efflux of K+ when the excitable cell is in its resting state (figure A) • ion movement is determined by an electro-chemical gradient • these are referred to as “leak” channels

Membrane Receptors

Functions

are part of the body’s chemical signaling system
• the binding of a receptor with its ligand usually triggers another event at the membrane
- such as activation of an enzyme
- can play an important role in some forms of vesicle transport

Structural Proteins

Functions

• connect the membrane to the cytoskeleton to maintain the shape of the cell

create cell junctions that hold tissue together, such as tight junctions and gap junctions

attach cells to the extracellular matrix by linking cytoskeleton fibers to extracellular collagen
and other protein fibers

Membrane Enzymes

Functions

catalyze chemical reactions that take place either on the cell’s external surface or just inside the cell

• enzymes attached to the intracellular surface play an important role in transferring signals from the extracellular compartment to the cytoplasm

- for example, cells lining the lumen of the small intestine are responsible for secreting enzymes involved with the digestion of peptides and carbohydrates

Organelle Membranes

Functions

Physical Isolation

Regulation of Exchange with Environment

Simple Diffusion

properties

passive process

molecules move from high to low concentration.

mvmt continues until molecules are equal everywhere.

Rapid over short distances, much slower under longer ones.

related to temperature

inversely related to molecular size

can take place in an open system or across a partition separating 2 systems

rates

Fick's Law

membrane permeability

osmosis

osmotic pressure

example

Mediated Transport

Types

Facilitated Diffusion

For many solutes of physiological importance, such as sugars and amino acids, the relationship between transport rate and concentration difference follows a curve that reaches a plateau (figure on the right). Furthermore, the rate of transport of these hydrophilic substances across the cell membrane is much faster than expected for simple diffusion through a lipid bilayer, this was found to be due to facilitated diffusion. Facilitated diffusion refers to the process of using protein carrier-mediated transport because it uses an integral membrane protein, the carrier (usually very specific), that binds to the transported solute on one side of the membrane and releases it at the other side. No outside source of energy is needed to move molecules across the cell membrane. Facilitated diffusion only mediates the transport of a substance down its chemical or electrochemical gradient, they can not move substances against concentration gradients. Facilitated diffusion acts to equalize concentrations of transported substances on the two sides of the membrane, and net movement stops at equilibrium. Facilitated diffusion differs from simple diffusion through an open channel in the following important way: although the rate of diffusion through an open channel increases proportionately with the concentration of the diffusing substance, in facilitated diffusion, the rate of diffusion approaches a maximum, called the Vmax, as the concentration of the substance increases (figure on the right). The main reason that facilitated diffusion reaches a maximal transport capacity, the Vmax, is due to the time it takes for the transporting protein to go through conformational changes to open to the opposite side of the membrane and return back to its original conformation (figure on the left).

example: Glucose

Active Transport

Primary

Na+/k+ - ATPase

ca2+ - ATPase

H+ - ATPase or proton pump

H+k+ - ATPase

Secondary

The sodium ion concentration gradient, with Na+ concentration high in the extracellular fluid and low in the intracellular fluid, is the source of potential energy that the cell can harness for other functions. Membrane transporters that use potential energy stored in concentration gradients to move molecules are called secondary active transport systems. Secondary active transport uses the kinetic energy of one molecule moving down its concentration gradient to push other molecules against their concentration gradient. As sodium ions move into the cell, it either brings one or more molecules with it or trades places with molecules existing in the cell. The most common secondary active transport systems dependent on Na+ are listed on the left in the above figure. Note that the cotransport substances may be either other ions or uncharged molecules, such as glucose.

Symport

Sodium Dependent Carriers

Antiport

Sodium Dependent Carriers

non sodium dependent transporters

Examples

Secondary Active Transport in the GI Tract

Intestinal glucose and galactose absorption uses transporters identical to those found in the renal proximal tubule: an apical Na+-glucose SGLT symporter (SGLT1) and a basolateral GLUT2 transporter, these transporters move galactose as well as glucose. Fructose absorption, however, is not Na+-dependent. Fructose moves across the apical membrane by facilitated diffusion on the GLUT5 transporter and across the basolateral membrane by GLUT2.

Absorption of AAs

The primary products of protein digestion are free amino acids, dipeptides and tripeptides, all of which can be absorbed. Amino acid structure is so variable that multiple amino acid transport systems are found in the intestine; most free amino acids are carried by Na+-dependent cotransport proteins. A few amino acids transporters are H+ dependent. Dipeptides and tripeptides are carried into the mucosal cell using H+-dependent cotransport. Once inside the epithelial cell, these peptides have two possible fates: 1. most are digested by cytoplasmic peptidases into amino acids, which are then transported across the basolateral membrane and into the circulation 2. those that are not broken down to amino acids are transported intact across the basolateral membrane ♥ the transport system that moves these peptides also is responsible for intestinal uptake of certain drugs - beta-lactam antibiotics - angiotensin-converting enzyme (ACE) inhibitors - thrombin inhibitors

for larger molecules

endocytosis

phagocytosis

pinocytosis

classifications

There are two ways to categorize the energy requirements required to move molecules across cell membranes:

physical requirements

for movement through the phospholipid bilayer

transported with the aid of a membrane protein

transported by using vesicles

energy requirements

insert MAP OF ENERGY REQUIREMENTSFOR MEMBRANE TRANSPORT

Classification

passive transport

does not require the direct input of energy

Two types

simple diffusion

An example of simple diffusion

Any solute will tend to uniformly occupy the entire space available to it.

This movement, known as diffusion, is a result of the spontaneous Brownian (random) movement that all molecules experience.

The net result of diffusion is the movement of substances according to their difference in concentrations, from regions of high concentration to regions of low concentration

Diffusion has the following seven properties:

diffusion is a passive process which means the energy used for molecular movement is only the kinetic energy possessed by all molecules

molecules move from an area of high concentration to an area of lower concentration

net movement of molecules continues until the concentration is equal everywhere

diffusion is rapid over short distances but much slower over long distances

diffusion is directly related to temperature

diffusion is inversely related to molecular size;

the bigger → the slower

diffusion can take place in an open system or across a partition that separates two systems

OSMOSIS AND OSMOTIC PRESSURE

OSMOSIS ACROSS A SEMIPERMEABLE MEMBRANE

insert OSMOSIS ACROSS A SEMIPERMEABLE MEMBRANE

Osmosis

The spontaneous movement of water across a membrane driven by a gradient of water concentration is the process known as osmosis.

Concentration

the number of particles per unit volume:

a solution with a high concentration of solutes has a low concentration of water and visa versa.

Osmosis can be viewed as the movement of water from a solution of high water concentration (low concentration of solute) toward a solution with a lower concentration of water (high solute concentration).

Osmosis is a passive transport mechanism that tends to equalize the total solute concentrations of the solutions on both sides of every membrane.

Water is able to move freely between cells and the extracellular fluid, and will distribute itself until water concentrations are equal throughout the body

the body is in a state of osmotic equilibrium.

THE MEASUREMENT OF OSMOTIC PRESSURE

insert THE MEASUREMENT OF OSMOTIC PRESSURE

The driving force for the movement of water across the plasma membrane is the difference in water concentration between the two sides of the membrane.

Osmotic Pressure

the pressure necessary to stop net movement of water across a selectively permeable membrane that separates the solution from pure water.

a concentration gradient across the membrane exist for glucose, but the membrane is not permeable to glucose

water can move across the membrane freely by osmosis, thus water moves from compartment A to dilute the more concentrated solution in compartment B

the pressure that must be exerted to exactly oppose the osmotic movement off ater into compartment B is the osmotic pressure of solution B

units of the osmotic pressure are mm Hg

DISTRIBUTION OF SOLUTES IN THE BODY FLUID COMPARTMENTS

Insert DISTRIBUTION OF SOLUTES IN THE BODY FLUID COMPARTMENTS

The distribution of solutes between the extracellular and intracellular fluid is summarized in the above set of graphs.

The composition of the of the intracellular fluid (C ) is maintained by the action of various specific membrane transport proteins.

Principle among these transporters is the Na+/K+-ATPase, which converts the energy in ATP into ion and electrical gradients, which in turn can be used to drive the transport of other ions and molecules.

The composition of the plasma (P) and interstitial fluid compartments (I) of the ECF is similar because they are separated only by the capillary endothelium

, a barrier that is freely permeable to ions and small molecules.

The major difference between interstitial fluid and plasma is that the plasma contains significantly more protein (primarily albumen).

The terms osmolarity and osmolality are frequently confused and incorrectly interchanged:

osmolarity

refers to the osmotic pressure generated by the dissolved solute molecules in 1 L of solvent

measurements of osmolarity are dependent on temperature because the volume of solvent varies with temperature

osmolarity = concentration x number of dissociable particles

mOsm/L = mmol/L x number of particles/mol

example 1

one mole of glucose dissolved in enough water to create 1 liter of solution yields a 1 molar solution (1 M),

glucose does not dissociate therefore

1 M glucose x 1 particle per glucose molecule = 1 OsM glucose

Example 2

add NaCl which dissociates into two ions

thus 1 mole NaCl results in 2 moles of particles

one of Na and one of Cl = a 2 Osm NaCl

1 M NaCl x 2 ions per NaCl = 2 Osm NaCl

osmolality

number of molecules dissolved in 1 kg of solvent (water)

independent of temperature

expressed as osmoles of solute/Kg H2O

usually used in clinical situations because it is easy to estimate people’s body water content by weighing them

TONICITY DEPENDS ON THE RELATIVE CONCENTRATION OF NONPENTRATING SOLUTES

Insert TONICITY DEPENDS ON THE RELATIVE CONCENTRATION OF NONPENTRATING SOLUTES

Tonicity

the physiological term used to describe a solution and how that solution affects cell volume

; it describes the cell volume once the cell has come to equilibrium with the solution

key in predicting tonicity is knowing the relative concentrations of nonpenetrating solutes in the cell and in the solution:

if the cell has a higher concentration of nonpenetrating solutes than the solution, there will be net movement of water into the cell

the cell swells and the solution is hypotonic (figure a)

ii.

if the cell has a lower concentration of nonpenetrating solutes than the solution, there will be net movement of water out of the cell

the cell shrinks and the solution is hypertonic

iii.

if the concentrations of nonpenetrating solutes are the same in the cell and the solution, there is no net movement of water at equilibrium

the solution is isotonic to the cell, no change in intracellular volume (figure b)

The differences between tonicity and osmolarity are

osmolarity describes the number of particles dissolved in a volume of solution and it has units (ex. osmoles/liter);

tonicity has no units and is only a comparative term

ii.

osmolarity can be used to compare two solutions, and the relationship is reciprocal (solution A is hyperosmotic to solution B; therefore , solution B is hyposmotic to solution A);

tonicity always compares an extracellular solution to the intracellular fluid

iii.

osmolarity alone does not predict what happens to a cell when placed in a solution

tonicity by definition predicts what happens to cell volume when the cell is placed in the solution

ECF AND ICF CHANGES WHEN PURE WATER IS ADDED

Despite the different compositions of ICF and ECF, the total solute concentration (osmolality) of these two fluid compartments is normally the same

ICF and ECF are in osmotic equilibrium because of the high water permeability of cell membranes, which does not permit an osmolality difference to be sustained

If the osmolality changes in one compartment, water moves so as to restore a new osmotic equilibrium

The distribution of water between intracellular and extracellular compartments changes in a variety of circumstances.

In the above figures

the y-axis represents total solute concentration or osmolality (mOsm/Kg H2O)

the x-axis the volume (L)

the area of a box gives the amount of solute present in a compartment

note that the height of the boxes is always equal, because osmotic equilibrium (or equal osmolalities) has been achieved

the dashed lines indicate the normal condition, and the solid lines the situation after a new osmotic equilibrium has been attained

In the normal situation (figure A)

⅔ of total body water (28 L) is in the ICF

⅓ in the ECF (14 L)

the osmolality of both fluids is 285 mOsm/Kg H2O.

When 2 L of pure water is added to the ECF (figure B)

plasma osmolality is lowered and water moves into the cell compartment along the osmotic gradient

the entry of water into the cells causes them to swell (water is therefore hypotonic)

the intracellular osmolality falls until a new equilibrium (solid lines) is achieved

the new total body water volume is 44 L

no solute was added, so the new osmolality at equilibrium is 272 mOsm/Kg H2O

⅔ of the added water ends up in the intracellular compartment and ⅓ stays in the ECF

ECF AND ICF CHANGES WHEN AN ISOTONIC AND HYPERTONIC SOLUTION ARE ADDED

Since isotonic saline is isosmotic to plasma or ECF by definition, when 2.0 L of isotonic saline (0.9% NaCl solution) is added to the ECF (figure C), there is no change in cell volume

Therefore all of the isotonic saline is retained in the ECF and there is no change in osmolality.

The effects of infusing intravenously 1.0 L of a 5% NaCl solution (osmolality about 1580 mOsm/Kg H2O) are shown in figure “D”:

all the salt stays in the ECF which creates a hypertonic environment for the cells

water leaves the cells leaving behind the solutes making the ICF more concentrated

a new equilibrium will be established, with a final osmolality higher than normal (about 315 mOsm/Kg H2O) but equal inside and outside of the cells

the addition of a hypertonic saline solution to the ECF increased the volume in the extracellular compartment in part because of water loss from the intracellular compartment

the final ECF volume is increased by 3.7 L

1 L from the intravenous infusion

2.7 L from the intracellular comparment

People normally stay in a stable water balance

that is, water input and output are equa

Body fluid volumes and plasma osmolality are kept constant by three major aspects to control water balance:

arginine vasopressin (antidiuretic hormone, ADH

excretion of water by the kidneys

drinking habits and the perception of thirst

ii.

facilitated diffusion

THE PASSIVE MOVEMENT OF SOLUTES ACROSS A CELL MEMBRANE

DIFFUSION THROUGH A LIPID BILAYER

insert DIFFUSION THROUGH A LIPID BILAYER

The diffusion of a solute across a cell membrane is driven by the difference in the concentration on the two sides of the membrane;

the solute molecules move randomly by Brownian movement.

Initially, random movement from left to right across the membrane is more frequent than movement in the opposite direction because there are more molecules on the left.

This results in a net movement of solute from left to right across the membrane until the concentration of solute is the same on both sides (figure on the left).

Diffusion across a membrane has no preferential direction; it can occur from the outside of the cell toward the inside or visa versa.

THE RATE OF SOLUTE TRANSPORT BY SIMPLE DIFFUSION

The graph on the right shows solute transport across a plasma membrane by simple diffusion according to concentration gradients; inside vs. outside, high to low.

The rate of solute entry increases linearly with extracellular concentration, increasing the extracellular concentration increases the gradient that drives solute entry.

The rules for simple diffusion can be combined mathematically into an equation known as Fick’s law of diffusion, a relationship that is expressed as:

Insert Fick's Law of DIffusion

Rate of diffusion = surface area x concentration gradient x membrane permeability
 membrane thickness

Membrane permeability is the most complex (variable) of the four terms in Fick’s law because several factors influence it:

the size of the diffusing molecules

the lipid-solubility of the molecule

the composition of the lipid bilayer across which it is diffusing

In most physiological systems, membrane thickness is a constant (stable); therefore Fick’s law equation can be rearranged to:

Diffusion rate = concentration gradient x membrane permeability
 Surface area

active transport

requires the input of energy from some outside source, such 
 as the high-energy phosphate bond of ATP

Communication between the Cell and Its Environment

Structural Support

Membrane Potentials

Resting Membrane Potential

Cells have an electrical potential difference (voltage difference), called the resting membrane potential, across their plasma membranes. The cytoplasm is usually electrically negative relative to the extracellular fluid. The resting membrane potential is necessary for the electrical excitability of neurons, skeletal muscle, smooth muscle, and the heart.The difference in potential energy of an ion across a membrane depends on its concentration difference and the electrical potential difference across the membrane.

Electrochemical Potential Difference

A membrane separates aqueous solutions in two chambers, A and B, in this figure: 1. ion X+ is at a higher concentration on side A than on side B 2. if no electrical potential differences exists between A and B, a concentration force for X+ tends to cause X+ to flow from A to B (yellow arrow) • just as if it were an uncharged particle 3. if side A is electrically negative with respect to B, an electrical force tends to cause X+ to flow from B to A (red arrow) 4. the direction of net X+ movement depends on whether the effect of the concentration difference or the effect of the electrical potential difference is larger • by comparing the two tendencies, the direction of net X+ movement can be predicted The quality that allows a comparison of the relative contributions of ionic concentration differences and electrical potential differences across a membrane is called the electrochemical potential difference (Δµ) of an ion. The electrochemical potential difference of X+ across the membrane is defined as:Δµ(X) = µA (X) - µB (X) = RT ln[X]A/[X]B + zF(EA - EB)The different passive and active transport systems are coordinated in a living cell to maintain intracellular ions and other solutes at a concentration compatible with life. Consequently, the cell does not equilibrate with the extracellular fluid but exists in a steady state with the extracellular solution. Maintenance of this steady state with ion concentrations inside the cell different from those outside the cell is the basis for the difference in electrical potential across the plasma membrane. the gradient of electrochemical potential across the membrane for a specific solute is based on the sum of 2 forces: the electric potential force and the chemical potential force.. Net movement of an ion into or out of a cell continues as long as the driving force exists. Net movement stops and equilibrium is reached only when the driving force of electrochemical potential across the membrane becomes zero.

Electrical Potential Difference

the difference in electrical potential between the two sides of the membrane and applies only to ions and other charged solutes • positive ions tend to move toward the negative side, whereas negative ions tend to move toward the positive side

Separation of CHarges

In the body, separation of charge takes place across the cell membrane.

In theory, a cell can be filled with neutral molecules that dissociate into positive and negative ions

The diagram in figure (a) illustrates an artificial cell filled with molecules that dissociate into positive and negative ions, represented by the plus and minus signs. Because the molecules were electrically neutral to begin with, there are equal numbers of positive and negative ions inside the cell.

The cell can be placed in a solution that is also electrically neutral and contains the same types of positive and negative ions

. The cell is placed in an aqueous solution, also electrically neutral, that contains the same types of cations and anions.

The phospholipid bilayer of the artificial cell, like the bilayer of a real cell, acts as an insulator to prevent free movement of ions between the intracellular and extracellular compartments.

Water can freely cross this cell membrane, making the extracellular and intracellular osmotic pressures equal.

This makes the system shown in figure (a) to be in osmotic, chemical, and electrical equilibrium.

An active transport carrier is now inserted into the membrane and uses energy to move positive ions out of the cell against their concentration gradient shown in figure (b).

. as soon as the first positive ion leaves the cell, the electrical equilibrium between the ECF and ICF is disrupted

• the cell’s interior has a net charge of -1 while the cell’s exterior has a net charge of +1 (absolute charge)

the input of energy to transport ions across the membrane has created an electrical gradient, a difference in the net charge between two regions

In living systems, electrical gradients are measured on a relative scale rather than an absolute scale because we cannot measure electrical charge as numbers of electrons gained or lost.

. On an absolute charge scale, the extracellular fluid (ECF) would be at +1 and the intracellular fluid (ICF) would be at -1.

Physiological measurements are always on a relative scale, on which the ECF is assigned a value of zero. This shifts the scale to the left and gives the inside of the cell a relative charge of -2 (figure c).

When positive ions are pumped out of the cell this creates a separation of charge known as a dipole layer.

When positive ions are pumped out of the cell, they line up along the outside of the membrane, and on the inside, the negative ions that have been left behind line up. This creates a separation of electrical charge across the cell membrane consisting of a thin cloud of positive and negative ions spread over the inner and outer surfaces of the membrane, this is known as a dipole layer.

at rest, the cell has an excess of positive charges on the outside of the membrane and an excess of negative charges on the inside

the excess of both charges on either side of the membrane at rest represents a small fraction of the total number of ions inside and outside the cell membrane

this separation of charge is maintained because the lipid bilayer acts as a barrier to the diffusion of ions

. the charge separation gives rise to an electrical potential difference across the membrane - The resting membrane potential

- it is directly proportional to the charge separation across the membrane

Principle of LEctric Neutrality

everywhere except adjacent to the surfaces of the cell membrane itself, the negative and positive charges in the cytoplasm are equal - this is called the principle of electrical neutrality

Creation of the Electric Capacitator

This arrangement of ions on either side of the lipid bilayer results in the membrane acting as an “electrical capacitor”; only minimal amount of positive ions must be transported outward to create an electrical dipole layer

an incredibly small number of ions need to be transferred through the membrane to establish a membrane potential of -90 mV

• only 1/5,000,000 to 1/100,000,000 of total positive charges inside the cell

this allows for very rapid changes in the membrane potential

less energy is required to reestablish normal ion concentrations when disrupted

Chemical Potential Difference

the force resulting from the difference in the concentration of a substance between the inside and outside of the cell • all substances tend to move from areas of high concentration to areas of low concentration

Nernst Potential

The potential level across the membrane that prevents net diffusion of an ion in either direction through the membrane is called the Nernst potential for that ion.

Nernest Equation
EMF = +/- 61 xlog (conc inside)/(Conc outside)

The magnitude of this potential is determined by the ratio of the ion concentration on the two sides of the membrane - the greater this ratio, the greater the tendency for the ions to diffuse in one direction. The above equation can be used to calculate the Nernst potential for any univalent ion, usually assuming that -the potential outside the membrane always remains at exactly zero potential,- and the Nernst potential that is calculated is the potential inside the cell

Ion Potentials

A membrane’s selectivity for permeant ions is determined by the relative proportions of various types of ion channels.

Potassium

Excitable cells have nongated channels that for the most part are selectively permeable to K+ ions when the cell is at restThe flux of K+ across the membrane is determined by both the K+ concentration gradient and the electrical potential across the membrane:

. in a cell permeable only to K+ the resting membrane potential is generated by the efflux of K+ down its concentration gradient (figure A)

the continued efflux of K+ builds up an excess of positive charge on the outside of the cell and leaves behind on the inside an excess of negative charge (figure B)

this buildup of charge acts to impede the further efflux of K+, so that eventually an equilibrium is reached

when the electrical and chemical driving forces are equal and opposite, this is known as the equilibrium potential

Effects of Inserting Potassium Leak Channels into a theoretical cell

The artificial cell in figure (a) has a membrane that is impermeable to ions and large negatively charged proteins, represented by Pr-.

The cell is placed in a solution of Na+ and Cl-. Both the cell and the solution are electrically neutral, and the system is in electrical equilibrium.

However, it is not in chemical equilibrium:

there are concentration gradients for all four types of ions in the system

all the ions would all diffuse down their respective concentration gradients if they could cross the cell membrane

A potassium ion leak channel is inserted into the cell membrane and potassium leaks out of the cell because of the concentration gradient (figure b):

as K+ leaves the cell, the negatively charged proteins (Pr-) are unable to follow which results in a gradual build up of a negative charge on the inside of the cell

if only the force acting on K+ were the concentration gradient, K+ would leak out until he K+ concentration inside the cell equaled the K+ concentration outside

the loss of positive ions from the cell creates an electrical gradient

Because opposite charges attract each other, the negative proteins inside the cell try to pull K+ back into the cell (figure c).

When the electrical force attracting K+ into the cell becomes equal in magnitude to the chemical concentration gradient driving K+ out of the cell, there is an equilibrium potential generated.

Calculating the Electrochemical Equilibrium for Potassium Ions

EA - EB = -60 mV x log [K+]A [K+]B

The Nernst equation reveals that at an electrical potential difference (EA - EB) of -60 mV, K+ is in electrochemical equilibrium; K+ tends to move from side B to side A due to the electrical potential difference, which counteracts the tendency for K+ to move from side A to side B due to the concentration difference.

Note that an electrical potential difference of about 60 mV is required to balance a 10-fold concentration difference of a univalent ion (this is a useful rule of thumb to remember).

Sodium

The same artificial cell model used in the previous page (K+, Pr-, and Na+ inside; Na+ and Cl- outside) is now used to explain the effects of making the membrane only permeable to Na+.

Because Na+ is more concentrated outside the cell, some Na+ moves into the cell and accumulates there.

meanwhile, Cl- left behind in the extracellular fluid gives that compartment a negative charge

this imbalance creates an electrical gradient that tends to “pull” Na+ back out of the cell

when the Na+ concentration is 150 mM outside and 15 mM inside, the equilibriumpotential for Na+ is about +60 mV

the concentration gradient moving Na+ into the cell is exactly opposed by a positive membrane potential of +60 mV

Normal Ion Concentraions

Potassium

Extracellular = 5nM (bw 3-5nM)

Intracellular = 150 nM

Eion at 37degrees = -90mV

Sodium

Extracellular = 145nM (135-145)

Intracellular = 15nM

Eion at 37degrees = +60mV

Chloride

Extracellular = 108nM (bw 100-108nM)

Intracellular = 10 nM (5-15)

Eion at 37degrees = -63mV

Calcium

Extracellular = 1 mM

Intracellular = 0.0001 nM

Diffusion Potentials (no active transport)

Electrical potentials exist across the membranes of essentially all cells of the body. The above figure illustrates the generation of the equilibrium potential for both potassium and sodium ions, there is no active transport.

. the establishment of an equilibrium potential across a cell membrane, caused by potassium ions diffusing from inside the cell to the outside through a membrane selectively permeable only to potassium (shown in figure A)

the equilibrium potential for potassium is -94 mV, this is the voltage required at the inside surface of the membrane for the net diffusion of potassium tobe zero. - the electrical gradient force is equal but opposite to the chemical gradient force

the establishment of an equilibrium potential when the membrane is permeable to only to sodium ions is shown in figure B

• the equilibrium potential for sodium is +61 mV, this is the voltage required at the inside surface of the membrane for the net diffusion of sodium to be zero; the electrical gradient force is equal but opposite to the chemical gradient force

note that the internal membrane potential is negative when potassium ions diffuse out and positive when sodium ions diffuse in because of the opposite concentration gradients of these two ions

Three factors affecting diffusion potentials

the polarity of the electrical charge of each ion

the permeability of the membrane (P) to each ion

the concentrations (C) of the respective ions on the inside (i) and outside (o)

Golfman-Hodgkins-Katz Equation

Thus the following formula, called the Goldman-Hodgkin-Katz equation, gives the calculated membrane potential on the inside of the membrane when the membrane is permeable to more than one univalent ion:

EMF (mV) = log CNa+i PNa+ + CK+i PK+ + CCl-o PCl-
CNa+o PNa+ + CK+o PK+ + CCl-i PCl-

The importance and meaning of the Goldman-Hodgkin-Katz equation are

sodium, potassium, and chloride ions are the ions most importantly involved in the
development of the membrane potential

the degree of importance of each of the ions in determining the voltage is proportional to the membrane permeability for that particular ion

the resting membrane potential will be primarily determined by the most permeable ion and the voltage will be closest to the electrical potential of that ion

the permeability of the membrane to potassium is about 100 times greater as to sodium

- using this value in the Goldman equation gives an internal membrane potential of -86 mV, which is near to the potassium potential shown above

a positive ion concentration gradient from inside the membrane to the outside causes electronegativity inside the membrane

the permeabilities of the sodium and potassium channels undergo rapid changes during conduction of an action potential

Na+/K+ - ATPase Pump

The most abundant ion pump in higher organisms is the sodium-potassium ion pump, also known as Na+/K+-ATPase. It is found in the plasma membrane of practically every eukaryotic cell and is responsible for maintaining the low sodium and high potassium concentration in the cytoplasm. The sodium-potassium pump is an integral membrane protein consisting of two subunits, one large and one small. Sodium ions are transported out of the cell and potassium ions are brought into the cell.

Functions

The pump counterbalances the tendency of sodium ions to enter the cell passively and the tendency of potassium ions to leave passively.

It maintains a high intracellular potassium concentration, which is necessary for protein synthesis.

It also plays a role in the resting membrane potential by maintaining ion gradients which are required for the ion “leak” channels to function.

For a cell to have a steady resting membrane potential, the charge separation across the membrane must be constant; the influx of positive charge must be balanced by the efflux of positive charge. If these fluxes were not equal, the charge separation across the membrane, and thus the membrane potential, would vary continually. Therefore, for the cell to achieve a resting state, the movement of K+ out of the cell must balance the movement of Na+ into the cell. Although these steady ion leaks cancel each other, they can not be allowed to continue unopposed for any appreciable length of time. Otherwise, the [K+]i would be depleted and the [Na+]i would increase, and the ionic gradients would gradually run down, reducing the resting membrane potential. Dissipation of ionic gradients is prevented by the Na+/K+ -ATPase pump, which extrudes 3Na+ from the cell while taking in 2K+. Because the pump moves these two ions against their net electrochemical gradients, energy must be provided to drive these actively transported fluxes. The energy comes from the hydrolysis of ATP.

Mechanisms

Binding of intracellular Na+ and phosphorylation by adenosine triphosphate (ATP) inside the cell may induce a conformational change that transfers Na+ to the outside of the cell (steps 1 - 3).

Subsequent binding of extracellular K+ and dephosphorylation return the protein to its original form and transfer K+ into the cell.

During one cycle, three Na+ are exchanged for two K+, and one ATP molecule is hydrolyzed to ADP and phosphate (Pi), illustrated in steps 4 - 5 above.

The fact that the number of ions exchanged is not equal, a net movement of positive ions out of the cell occurs creating positivity outside the cell and leaves a deficit of positive ions inside the cell; that is, it causes negativity on the inside.

The sodium-potassium pump is said to be an “electrogenic pump” because it creates an electrical potential across the cell membrane as it cycles, adding to its influence on the resting membrane potential.

Comparison of Resting Membrane Potential with Pump Added to Membrane

the resting membrane potential generated when the membrane is onlypermeable to potassium ions = -94 mV

this occurs when the [K+]i = 140 mEq/L and [K+]o = 4 mEq/L

the resting membrane potential generated when the membrane is permeable to both sodium ions (+61 mV) and potassium ions (-94 mV) = -86 mV

this occurs when the [Na+]i = 14 mEq/L and [Na+]o = 142 mEq/L
- the ratio is: [Na+]i / [Na+]o = 0.1

this occurs when the [K+]i = 140 mEq/L and [K+]o = 4 mEq/L
- the ratio is: [K+]i / [K+]o = 35.0

the resting membrane potential generated when the membrane is permeable to both sodium ions (+61 mV) and potassium ions (-94 mV) plus pumping of both of these ions by the Na+/ K+ -ATPase pump = -90 mV

Balance of Ion Exchange

Conditions Required for Resting Membrane Potential

Conditions Required for Actional Potential in the Refractory Period

Measuring Membrane Potential Difference

Equipment

Electrodes/Micropipettes

Electrodes are created from hollow glass tubes drawn to very fine points. These micropipettes are filled with a fluid that conducts electricity

Voltemeter

Micropipettes are then connected to a voltmeter, which measures the electrical difference between two points in units of either volts (V) or millivolts (mV). When the recording electrode is placed inside a living cell, the voltmeter measures the membrane potential;the electrical difference between the ICF and the ECF.

REcording Electrode

. A recording electrode is inserted through the cell membrane into the cytoplasm of the cell. When the recording electrode is placed inside a living cell, the voltmeter measures the membrane potential;the electrical difference between the ICF and the ECF.

Reference Electrode

A reference electrode is placed in the external bath, which represents the extracellular fluid. In living systems, by convention, the ECF is designated as the ground and assigned a charge of 0 mV.

CHart Recorder

A chart recorder connected to the voltmeter can make a recording of the membrane potential versus time.

Reading the Measurement

Variability in Resting Membrane Potentials across different Tissues

The resting membrane potential is not stable in all cells of the body and the variability is associated with the tissue’s function. Changes in membrane potential are associated with mechanical, electrical, and chemical stimulation plus spontaneous depolarization.

Smooth Muscle Cells

The smooth muscle of the gastrointestinal tract is subject to almost continual but slow electrical activity (figure on the left). This activity tends to have two basic types of electrical waves:

Slow Wave Potentials

occur rhythmically and are slow undulating changes in the resting membrane potential, thought to be due to a slow undulation of the Na+/K+ pump activity

Spike/Pacemaker Potentials

. spike potentials are true action potentials which occur automatically when theresting membrane potential (RMP) becomes more positive than about -40 to -45 mV (note: the normal resting membrane potential is between -50 and -60 mV)

SA Nodal Cells

The membrane potential for the SA node is small and unstable (figure on the right).

The initial potential is only -50 to -70 mV because the nodal cells possess fewer K+ leak channels, which are responsible for the big, stable resting membrane potential of atrial and ventricular myocytes.

fewer active ion channels → fewer positive ions leaving the cell → more positive ions are left within the cell → resting membrane potential becomes more positive (or remains positive).

Effects of Extracellular Potassium

In the clinical scenario, the concentration of K+ in the blood and interstitial space is the major determinant of the resting membrane potential. If K+ concentration in the blood moves out of the normal range of 3.5 - 5.0 mmol/L, the result is a change in the resting membrane potential of cells. Clinically it is extremely important to understand how the extracellular K+ level influences the resting membrane potential; it can effect both neural and muscle (skeletal, smooth, and cardiac) activity.

at normal K+ levels, subthreshold graded potentials (figure a) do not trigger action potentials, and suprathreshold graded potentials do (figure b)

if the blood K+ level is abnormally elevated, hyperkalemia (figure c), the membrane potential becomes more positive and shifts the resting membrane potential closer to threshold

this causes the cells to fire action potentials in response to smaller graded potentials

if the blood level falls too low, hyperkalemia, the resting membrane potential becomes more negative (hyperpolarized) moving farther from threshold

a stimulus of normal strength will not reach the threshold value (figure d)

Primary Hyperkalemic Paralysis and Effects on Na+ Channels

In an inherited disorder called primary hyperkalemic paralysis, patients have episodes of painful spontaneous muscle contractions (“muscle spasms”) followed by periods of paralysis of the affected skeletal muscle. These symptoms are accompanied by and caused by increased blood plasma and interstitial fluid potassium ion concentrations.

Some patients with this disorder have mutations of voltage-gated Na+ channels that result in a decreased rate of voltage inactivation, which results in longer-lasting action potentials in skeletal muscle cells and increased efflux of K+ during each action potential.

This will result in an increase in the extracellular [K+].

A pathological condition which is due to an abnormal “leakage” of intracellular potassium ions will result in an elevation in extracellular [K+] causing the resting membrane potential of the skeletal muscle cells to become more positive.

As the depolarization of cells increases, the cells become refractory because of inactivation of the voltage-gated Na+ channels (the inactivation gates are closed due to the less negative membrane potential).

Consequently, the cells become unable to fire action potentials and are not able to contract in response to action potentials generated within their motor axons (paralysis).

Conditions Leading to Arrhythmias

There are three different conditions that have the capability of causing an impulse to continue to travel around the circle, one or more of these conditions must exists alongwith a unidirectional block to allow myocytes to be stimulated during the relative refractory phase and initiate re-entry → arrhythmias

an increase in action potential impulse pathway length, therefore it takes a longer time to travel the circuit (shown in figure above)

examples: hypertrophy and cardiomyopathy

a decrease in action potential impulse conduction velocity

examples: ischemia and hyperkalemia - both conditions will result in a more positive resting membrane potential, therefore increasing the number of non-excitable Na ion channels → decreases slope and magnitude of phase 0 = decrease action potential conduction velocity → increased potential for developing an arrhythmia

a shortening of the absolute refractory period

can be caused by repeated electrical stimulation and epinephrine administration during cardiac resuscitation (!!!)

ACTION POTENTIALS AND THEIR CONDUCTION

TERMINOLOGY ASSOCIATED WITH CHANGESIN THE MEMBRANE POTENTIAL

Insert TERMINOLOGY ASSOCIATED WITH CHANGESIN THE MEMBRANE POTENTIAL

If the cell’s permeability to an ion changes, the change in the cell’s membrane potential can be monitored by recording electrodes (illustrated in the above figure).

The membrane potential (Vm) begins at a steady resting value of -70 mV

When the trace moves upward (becomes less negative), the potential difference between the inside of the cell and the outside (set at 0 mV) decreases, and the cell is said to have depolarized

If the membrane potential difference is decreasing, the value of Vm is moving closer to the ground value of 0 mV and is becoming less negative.

A return to the resting membrane potential is termed repolarization.

If the membrane potential difference is increasing, the value of Vm must be moving away from the ground value of 0 mV and becoming more negative.

When the resting membrane potential moves away from the 0 mV becoming more negative, it is called hyperpolarization.

THE EFFECTS OF STIMULATION ON THE MEMBRANE POTENTIAL OF AN EXCITABLE CELL

Insert THE EFFECTS OF STIMULATION ON THE MEMBRANE POTENTIAL OF AN EXCITABLE CELL

Basically, any factor that causes sodium ions to begin to diffuse inward through the membrane in sufficient numbers will set off the automatic regenerative opening of the sodium ion channels.

This can result from

simple mechanical disturbance of the membrane

chemical effects on the membrane

passage of electricity through the membrane

The effects of successively applied stimuli of progressive strength are shown above

a very weak stimulus may not be able to produce any change in the resting membrane potential

at point “A” a weak stimulus causes the membrane potential to change from -90 mV to -85 mV, but this change is not sufficient for the automatic regenerative processes of the action potential to develop


at point “B”, the stimulus is greater but the intensity is still not enough to excite the cell membrane

the stimulus is strong enough to disturb the membrane potentially locally

these local potential changes are called acute local potentials and when they fail to elicit and action potential, they are called acute subthreshold potentials

at point “C”, the stimulus is even stronger and the local potential change barely reaches the level to elicit an action potential, called the threshold

at point “D”, the stimulus is now strong enough to increase the acute local potential change to rise to a threshold level and generate an action potential

an action potential is defined as an electrical signal that propagates over a long distance without a change in magnitude

action potentials depend on a regenerative wave of ion channels opening and closing

PHASES OF AN ACTION POTENTIAL

Insert PHASES OF AN ACTION POTENTIAL

The action potential is a transient change in the membrane potential from its resting level (the resting membrane potential) characterized by

a gradual depolarization from the resting level to threshold

the membrane potential becomes more positive due to an influx of positive ions

a rapid rising phase - a significant influx of positive ions becomes great enough for the membrane potential to become less negative (depolarize)

this increase in the membrane potential will initiate the mechanisms responsible for the propagation of the action potential

an overshoot

the influx of positive ions may continue long enough for the 
membrane potential to become a positive value

repolarization

the efflux of positive ions out of the cell will result in the membrane potential returning back towards its resting level

afterhyperpolarization

the efflux of positive ions may continue long enough for the membrane potential to become a more negative value than its resting membranepotential

regulated membrane ion exchange (Na+/K+ pump) will return the membrane potential to its normal resting level

THE GENERATION OF AN ACTION POTENTIAL

Insert the Generation of An action potential

Action potentials occur when voltage-gated ion channels open, altering membrane permeability to Na+ and K+.

The figure above illustrates the voltage and ion permeability changes that take place in one section of the membrane during the generation of an action potential.

The lower graph shows the action potential can be divided into three phases:

the rising phase (depolarization)

due to a sudden temporary increase in the cell’s permeability to Na+, causing the inside of the cell to progressively become less negative and possibly positive (> 0 mV)

an action potential begins when a graded potential reaching the trigger zone (“2” in upper figure) depolarizes the membrane to threshold (-55 mV, “3” in upper figure)

the falling phase (repolarization)

corresponds to an increase in K+ permeability

at a positive membrane potential, the concentration and electrical gradients for K+ favors movement of K+ out of the cell

as K+ moves out of the cell, the membrane potential rapidly becomes more negative, creating a falling phase of the action potential (“6” in upper figure) and moving the cell towards its resting potential

the after-hyperpolarization phase

occurs because when the falling membrane potential reaches -70 mV

the voltage-gated K+ channels have not yet closed

potassium continues to leave the cell through both voltage-gated and K+ leak channels, and the cell hyperpolarizes (“7” in upper figure)

Before and after the action potential (“1” and “9” in upper figure), the cell membrane is at its resting membrane potential of -70 mV.

THE STATES OF Na+ AND K+ CHANNELS CORRELATEDWITH THE COURSE OF AN ACTION POTENTIAL

Insert THE STATES OF Na AND K CHANNELS CORRELATED WITH THE COURSE OF AN ACTION POTENTIAL

As discussed earlier, the depolarizing and repolarizing phases of the action potential can be explained by the relative changes in membrane conductance (permeability) to sodium and potassium ions

During the rising phase, the cell membrane becomes more permeable to sodium;

as a consequence, the membrane potential begins to shift more towards the equilibrium potential for sodium

However, before the membrane potential reaches ENa, sodium permeability begins to decrease and potassium permeability increases

This change in membrane conductance again drives the membrane potential towards EK, accounting for repolarization of the membrane.

The action potential can be viewed in terms of the flow of charged ions through selective ion channels as illustrated above:

. figure “A” shows the resting membrane potential with both Na+ and K+ voltage-gated ion channels closed (inactive but excitable)

the cell membrane is in a “resting state” with no ion exchange through the voltage--gated channels

figure “B” shows that during the depolarization phase of the action potential, the voltage-gated Na+ channels are activated (open)

opening of the activation gate allows sodium ions to flow into the cell which results in depolarization

the potassium channels open more slowly and, therefore, have not yet responded to the depolarization

figure “D” shows that during the after-hyperpolarization , the sodium channels are closed and the potassium channels remain in their active state

the K+ channels will close and the Na+ channels will become excitable with the membrane potential returning to its resting level

note the K+ channels have no inactivated state

ACTION POTENTIAL REFRACTORY PERIODS

Insert ACTION POTENTIAL REFRACTORY PERIODS

The explosive depolarizing phase of the action potential may be compared to a chemical explosion.

A chemical explosion requires a critical mass of material

the spike of the action potential can be generated only if a critical number of Na+ channels are recruited (activated),

this is the threshold value.

When a cell is partly depolarized, the pool of excitable voltage-gated Na+ channels is reduced

consequently, a stimulus may not be able to recruit a sufficient number of Na+ channels to generate an action potential

Voltage inactivation of Na+ channels partially accounts for important properties of excitable cells, such as the refractory periods.

During much of the action potential, the membrane is completely refractory (unexcitable) to further stimulation.

This means that no matter how strongly the cell is stimulated, it is unable to fire a second action potential

this unresponsive state is called the absolute refractory period.

The cell is refractory because most of its Na+ voltage-gated channels are inactivated and cannot be reopened until the membrane is repolarized.

During the latter part of the action potential, the cell is able to fire a second action potential, but a stronger-than-normal stimulus is required

this is called the relative refractory period

Early in the relative refractory period, before the membrane potential has returned to the resting potential level, some Na+ voltage-gated channels are becoming excitable while others remain inactivated thus requiring a stronger stimulus to open the critical number of Na+ channels needed to trigger an action potential (threshold)

The resetting of the inactivation gate determines when the absolute refractory period ends and the relative refractory period begins.

Throughout the relative refractory period, the conductance of K+ is elevated, which opposes depolarization of the membrane adding to the refractoriness.

A single channel during a phase in the above figure means that the majority of channels are in this state.

Where more than one channel of a particular type is shown, the population is split between the states.

ION EXCHANGE IN A CARDIAC MUSCLE CELL

Insert ION EXCHANGE IN A CARDIAC MUSCLE CELL

Note the complexity of ion exchange that is occurring during a ventricular electrical action potential. There is an incredible degree of balancing the chemical and electrical gradients for each ion to achieve the desired results.

TYPICAL TRANSMEMBRANE ACTION POTENTIALSOF VARIOUS CARDIAC MUSCLE CELLS

Insert TYPICAL TRANSMEMBRANE ACTION POTENTIALSOF VARIOUS MUSCLE CELL TYPES FOUND WITHIN THE HEART

The parts of the heart normally beat in an orderly sequence: contraction of the atria is followed by contraction of the ventricles, and during diastole all four chambers are relaxed.

The heart beat originates in a specialized cardiac conduction system and spreads via this system to all parts of the myocardium.

The structures that make up the conduction system are the

sinoatrial node (SA node),

the internodal atrial pathways

the atrioventricular node (AV node)

the bundle of His and its branches

and the Purkinje system

The transmembrane action potentials along with the correlation to the extracellular electrical activity (ECG) are shown in the figure above.

VARIOUS CHEMICALS CAN INACTIVATE THE VOLTAGE-GATED Na+ AND K+ CHANNELS

Insert VARIOUS CHEMICALS CAN INACTIVATE THE VOLTAGE-GATED Na+ AND K+ CHANNELS

tetrodotoxin (TTX)

The ovaries of certain species of puffer fish, also known as blowfish, contain tetrodotoxin (TTX) which is one of the most potent poisons known.

It binds to the extracellular side of the voltage-gated Na+ channels causing inactivation of the channel (blocks the activation gate), therefore no action potentials can be generated in nerve and/or muscle fibers.

Raw puffer fish is a highly prized Japanese food dish. Connoisseurs of puffer fish enjoy the tingling numbness of the lips that is caused by very small amounts of TTX present in the flesh.

What are the possible causes for this sensation?

Sushi chefs are trained to remove the ovaries safely and are licensed by the government. Nevertheless, several people die each year from eating improperly prepared puffer fish.

What are the possible causes of death from ingesting TTX?

Saxitoxin

is another voltage-gated Na+ channel blocker

Saxitoxin is produced by red dinoflagellates that are responsible for the so-called “red tide”.

Shellfish eat the dino-flagellates, and saxitoxin becomes concentrated in their tissue.

What could be the possible causes of death?

Tetra ethylammonium (TEA+)

blocks the voltage-gated K+ channels by entering the channel from the cytoplasmic side and completely blocks the membrane channel.

What effect will this have on the repolarization process?

What will this do to further development of generating additional action potentials (propagation of an impulse)?

What could be the possible causes of death?

GRADED POTENTIALS DECREASE IN STRENGTH AS THEY SPREAD OUT FROM POINT OF ORIGIN

Graded potentials in neurons are depolarizations that occur in the dendrites and cell body or, less frequently near the axon terminals.

These changes in membrane potential are called “graded” because their size, or amplitude is directly proportional to the strength of the triggering event.

A large stimulus causes a strong graded potential, and a weak stimulus results in a weak graded potential.

A graded potential that begins when a stimulus opens monovalent cation channels on the cell body of a neuron. Sodium ions move into the neuron, bringing in electrical energy.

The positive charge carried by the Na+ spreads as a wave of depolarization through the cytoplasm, just as a stone thrown into water creates ripples or waves that spread outward from the point of entry.

The wave of depolarization that moves through the cell is known as local current flow.

By convention, current in biological systems is the net movement of positive electrical charge.

If more Na+ channels open, more Na+ enters, and the graded potential has a higher initial amplitude.

The stronger the initial amplitude, the farther the graded potential can spread through the neuron before dying out.

The reasons that graded potentials lose strength as they move through the cytoplasm is because of two reasons:

current leak

due to some of the positive ions leaking back across the membrane due to some of the positive ions leaking back across the membrane

the membrane in the neuron cell body is not a good insulator and has open leak the membrane in the neuron cell body is not a good insulator and has open leak channels that allow positive charge to flow out of the cell

cytoplasmic resistance

to the electrical flow is provided by the cytoplasm itself, just like water creates resistance that diminishes the wave from the stone

GRADED STRENGTH OF A STIMULUS

Two neurons with three recording electrodes placed at intervals along the cell body and trigger zone are shown in this figure.

A single stimulus triggers a subthreshold graded potential, one that is below threshold by the time it reaches the trigger zone.

Although the cell is depolarized to -40 mV at the site where the graded potential begins, the current decreases as it travels through the cell body.

As a result the graded potential is below threshold by the time it reaches the trigger zone (figure a).

A stronger initial that initiates a stronger depolarization and ultimately causes an action potential stimulus (figure b).

Although this graded potential also diminishes with distance through the neuron, its higher initial strength ensures that it is above threshold at the trigger zone.

In muscle cells, the graded potential occurs at the neuromuscular junction and is referred to as the End Plate Potential (EPP), this will be discussed in more detail in the neuromuscular junction lecture.

A COMPARISON OF GRADED POTENTIALSTO ACTION POTENTIALS

THE FREQUENCY OF ACTION POTENTIAL FIRING INDICATES THE STRENGTH OF A STIMULUS

One distinguishing characteristic of action potentials is that every action potential in a given neuron or muscle fiber is identical to every other action potential in that neuron or muscle.

The transmission of information is not dependent on the strength and/or duration of the stimulus,

therefore it is not the amplitude of the action potential, but the frequency of the action potentials that results in transmitting the desired information.

A graded potential reaching the trigger zone does not usually trigger a single action potential, instead it triggers a burst of action potentials (figure b)


CONDUCTION OF AN ACTION POTENTIAL

The high speed movement of an action potential along the axon or muscle fiber is called conduction of the action potential.

In action potentials, the flow of electrical energy is a process that constantly replenishes lost energy, which is why an action potential does not lose strength over distance as a graded potential does.

The action potential that reaches the end of the axon or muscle fiber is identical to the action potential that started at the trigger zone on an axon or the site of stimulation on a muscle fiber.

At the cellular level, the depolarization of a section of an axon or muscle fiber causes positive current to spread through the cytoplasm in all directions by local current flow, as illustrated in the figure above.

Simultaneously, on the outside of the cell membranes, current flows back toward the depolarized section.

The current flow in the cytoplasm diminishes over distance as energy dissipates, and would eventually die out if not for voltage-gated channels.

The axon or muscle cell membrane is well supplied with voltage-gated Na+ channels.

Whenever depolarization reaches those channels, they open, allowing more Na+ to enter the cell reinforcing the depolarization.

This process initiates the positive feedback loop or the propagation of the action potential

Mechanism

The initiation and the sequential propagation of an action potential down an axon or across a muscle fiber is illustrated above

” a stimulus that is a graded potential above threshold that enters the trigger zone an axon or is generated at the motor endplate of the neuromuscular junction

shows that depolarization opens voltage-gated Na+ channels and Na+ enters the cell and the local area depolarizes (trigger zone or motor endplate)

shows that a positive charge from the depolarized region spreads to adjacent sections of the membrane

repelled by the Na+ that entered the cytoplasm and attracted by the negative charge of the resting membrane potential

charge of the resting membrane potential

the voltage-gated Na+ channels on the cell membrane distal to the depolarized region begin to open, allowing Na+ to enter into the cell

this starts the positive feedback loop:

depolarization opens Na+ channels

Na+ enters

causing more depolarization and opening more Na+ channels in the adjacent membrane

continuous entry of Na+ down the axon toward the axon terminal (or muscle fiber) means that the strength of the signal does not diminish as the action potential propagates itself (compare this to a graded potential)

at the peak of each action potential, the Na+ channels become inactivated and K+ channels open allowing K+ to exit the cell initiating repolarization

the section of cell membrane proximal to the active area is in an absolute refractory period

therefore the direction of propagation is in one direction

THE GENERATION OF ACTION POTENTIALS ALONG AN AXON

When talking about action potentials, it is important to realize that there is no single action potential that moves through the cell.

The action potential that occurs at the trigger zone (or motor endplate) is like the movement in the first domino of a series of dominos standing on end (top figure).

As the first domino falls, it strikes the next, passing on its kinetic energy to the second domino which then falls, and so on.

AXON DIAMETER CORRELATES TO THE SPEED OFACTION POTENTIAL CONDUCTION

After an action potential is generated, it propagates along the axon toward the axon terminal:

: it is conducted along the axon with no decrement in amplitude.

The speed with which action potentials propagate depends on two key physical parameters:

Diameter

the diameter of the axon will influence the speed of propagation because of a decrease in the resistance to electrical current flow

will influence the speed of propagation because of a decrease in the resistance to electrical current flow
diameter pipe because of their decreased resistance, large-diameter axons have less cytoplasmic resistance, thereby permitting a greater flow of ions

this increase in ion flow in the cytoplasm causes greater lengths of the axon to be depolarized, decreasing the time needed for the action potential to travel the length of the axon

the space constant (λ) determines the length along the axon that a voltage change is observed after a local stimulus is applied in this case, the local stimulus is the inward sodium current that accompanies the action potential

the larger the space constant, the farther along the membrane a voltage change is observed after a local stimulus is applied

the speed at which an action potentials are conducted, or conduction velocity, increases as a function of increasing axon diameter and concomitant increase in the space constant

Myelination

SCHWANN CELLS FORM MYELIN AROUND PERIPHERAL NERVES

The second key parameter that is involved with determining the conduction velocity of an action potential traveling down a membrane is myelin

Two different cell types in the CNS produce myelin

Schwann cells in the peripheral nervous system (PNS)

Each Schwann cell wraps around a 1.0 - 1.5 mm segment of the axon leaving tiny gaps

nodes of Ranvier

At each node a tiny section of axon remains in direct contact with the extracellular fluid and has ion channels through which current can leak

therefore the node plays an important role in the transmission of electrical signals along the axon.

SALTATORY CONDUCTION

In myelinated axons, voltage-gated Na+ channels are highly concentrated in the nodes of Ranvier where the myelin sheath is absent and are in low density beneath the segments of myelin.

When an action potential is initiated, the influx of Na+ causes the adjacent node of Ranvier to depolarize, resulting in an action potential at the node.

Action potentials are successively generated at neighboring nodes of Ranvier, therefore the action potential in a myelinated axon appears to jump from one node to the next

a process called saltatory conduction

This process results in a faster conduction velocity for myelinated than for unmyelinated axons

The conduction velocity in mammals ranges from 3 to 120 m/sec for myelinated axons and 0.5 to 2.0 m/sec for unmyelinated axons.

The reason that conduction velocity is more rapid in myelinated axons is because the mechanical process of ion channel opening slows conduction slightly.

In unmyelinated axons, channels must open all the way down the axon membrane to maintain the amplitude of the action potential.

In myelinated axons, only the nodes need Na+ channels because of the insulating properties of the myelin sheath.

As the action potential passes along myelinated segments, conduction is not slowed by channel opening.

ii.

oligodendrocytes in the central nervous system (CNS)

They wrap themselves around axons to form myelin, a substance composed of multiple concentric layers of phospholipid.

Myelin forms when these glial cells wrap around an axon, squeezing out the glial cytoplasm so that each wrap becomes two membrane layers

This myelin sheath insulates the axon and prevents the passage of ions through the axonal membrane

creates a high-resistance wall

MODES OF ACTION POTENTIAL CONDUCTION

The above figure summarizes the modes of action potential conduction in unmyelinated and myelinated axons:

Figure “A” shows the propagation of an action potential in an unmyelinated axon

by sequentially depolarizing adjacent segments of the axon, the action potential propagates or moves along the length of the axon from point to point, like a traveling wave

figure “B” shows a sheath of myelin surrounding an axon

figure “C” shows the propagation of an action potential in a myelinated

the initiation of an action potential in one node of Ranvier depolarizes the next node

jumping from one node to the next is referred to as Saltatory Conduction

DEMYELINATING DISEASES AFFECT CONDUCTION VELOCITY

The normal saltatory conduction of an action potential down a myelinated axon is illustrated in this figure.

In demyelinating diseases, the loss of myelin from vertebrate neurons can have devastating effects on neural signaling.

In the central and peripheral nervous systems, the loss of myelin slows the conduction velocity of action potentials

In addition, when ions leak out of the now-uninsulated regions of membrane, between the channel-rich nodes of Ranvier, the depolarization that reaches a node may not be above threshold and conduction may fail.


Most demyelinating diseases are either inherited or autoimmune disorders and result in the deterioration of the myelin sheath

These diseases are characterized by a variety of neurological complaints such as:

Basic Biological Concepts Involved with Maintaining Human Life

Homeostasis

homeostasis is defined as the maintenance of a relatively stable internal environment which is maintained by monitoring and adjustments by physiological control systems

Types of Control Loops

Negative Feedback System

the reflex responses to the disturbance will be opposite to the disturbance (by far the most common physiological mechanism used)• examples - if arterial blood pressure decreases, the reflex response will be to increase the pressure; if plasma sodium decreases, the reflex response is to increase plasma sodiumIf the response loop is successful, it shuts itself off. In a negative-feedback control system, information flows along a closed loop. The regulated variable is sensed and information about its level is fed back to a feedback controller, which compares it with the desired value (set point). If there is a difference, an error signal is generated, which drives the effector to bring the regulated variable closer to the normal value. The reflex response is opposite to the disturbance = negative feedback.

Long Distance Control via Reflex Responses: Systemic Changes

(more complicated reflex loops) respond tochanges that are more widespread throughout the body or systemic in nature • an integrating center located away from the affected tissue receives information, evaluates it, and decides whether to send a chemical or electrical signal to initiate a response • the long-distance reflex pathway normally involves two control systems: - the nervous system, normally is a rapid response system - the endocrine system, normally is a more prolonged effect because of increased time in signaling and extended target tissue effect

Physiological Control Systems/Reflexive Pathways

Homeostasis is the ability of the body to maintain a relatively stable internal environment. This is accomplished by a continuous process that uses a physiological control system (i.e. physiological response loop) to monitor key functions, which are often referred to as regulated variables. In its simplest form, any control system has three basic parts: Input Signal, Controller, Outpurt SIgnal Each reflex control mechanism has a different ability to return a disturbance to a physiological system to normal. As shown above, each control system regulating mean arterial blood pressure has its own time course of action and its own efficiency in returning a disturbance towards normal. Each system uses different physiological mechanisms to accomplish their goal.Gain is how efficiently a control system can return a disturbance back to normal

(Regulated Variable)

As with any control system, the three components of a response loop can be broken down into seven steps to form a pattern that is associated with all reflex pathways (with slight variations):stimulus → sensor or receptor → afferent pathway →integrating center →efferent pathway → target or effector → response 1. a stimulus is the disturbance or change that sets the pathway in motion • the stimulus may be a change in temperature, arterial blood oxygen content, plasma glucose levels, or arterial blood pressure 2. a sensor or sensory receptor continuously monitors its environment 3. an afferent signal links the receptor to the integration center (incoming sensory signals) 4. the integration center evaluates the incoming signal and compares it to the set point (or desired value) and decides the appropriate response 5. the integrating center then initiates the efferent pathway • outgoing efferent signals may be either stimulatory or inhibitory in nature 6. an electrical or chemical signal then travels to the effector 7. the effector carries out the appropriate response to bring the situation back to within normal limits

Outside of Desired Range

Away from set point

1. Stimulus

. a stimulus is the disturbance or change that sets the pathway in motionExample: the stimulus may be a change in temperature, arterial blood oxygen content,plasma glucose levels, or arterial blood pressure

2. Sensor

. a sensor or sensory receptor continuously monitors its environment

3. (Input Signal) Afferent Signal

1. an input signal consists of the regulated variable and a specialized sensor • if the variable moves out of its programmed range, the sensor is activated and sends signals to the controlleran afferent signal links the receptor to the integration center (incoming sensory signals)

4. (Controller) Integration Centre

a controller acts as an integrating center that evaluates information coming from the sensor and initiates a response that is designed to bring the regulated variable back into the normal range 4. the integration center evaluates the incoming signal and compares it to the set point (or desired value) and decides the appropriate response

5. (Output Signal)/Efferent Pathway

. the integrating center then initiates the efferent pathway originating from the integrating center is often from a neuron or an endocrine cellsoutgoing efferent signals may be either stimulatory or inhibitory in nature

6. Effectors

Effectors are muscles or other tissues that influence that regulated variable an electrical or chemical signal then travels to the effector

7. Response

the effector carries out the appropriate response to bring the situation back to within normal limits

Successful

Example

Water Temperature is below the set point

Thermometer senses the decrease

Signal passes from centre to control box through wire

Control box is programmed to response to a temperature below 29 degrees

Signal Passes from wire to heater

Heater turns on

Water temperature increases

Not Successful

If the body fails to maintain homeostasis, the normal function is disrupted and a pathological condition will exist. Diseases can be divided into two general groups according to their origin:In both internally and externally caused diseases, when homeostasis is disrupted, the body attempts to compensate. If the compensation is successful, homeostasis is restored. If compensation fails, illness and disease may result. The study of body functions in a disease state is known as pathophysiology

Internal Failure

. those in which the problem arises from internal failure of some normal physiological process • examples would include cancer, autoimmune diseases, and inherited disorders

External Failure

2. external causes of disease include toxic chemicals, physical trauma, and foreign invaders such as viruses and bacteria

Within the desired range (homeostasis)

No Action Required

Signalling System involved

Nervous System

Rapid response, less prolonged.- involves the rapid transmission of action potentials, often over long distances, and the release of a neurotransmitter at a synapse

Endocrine

normally is a more prolonged effect because of increased time in signaling andextended target tissue effectinvolves the release of a hormone into the bloodstream and the binding of the hormone to a specific target cell membrane

Neuroendocrine

involves the release of a hormone from a nerve cell and the transport of the hormone by the blood to a distant target cell

Local Control: Isolated Changes

a relatively isolated change occurs in the vicinity of a cell or tissue and evokes a paracrine or autocrine response (discussed on next page) • the response is restricted to the region where the change took place an example: cells lining small blood vessels (arterioles) can sense a decrease in oxygen concentration and respond by secreting a paracrine signal which causes:smooth muscle in the blood vessel to relax (dilate) → decreases vascular resistance → increases blood flow → increases oxygen delivery

Signalling Systems Involved

Autocrine

a chemical messenger diffuses a short distance through the extracellular fluid and binds to a receptor on the same cell

Paracrine

- a chemical messenger diffuses a short distance through the extracellular fluid and binds to a nearby cell

Cell to Cell

cells may communicate with each other directly via gap junctions or chemical messengers

Feedforward Control

Negative feedback loops can stabilize a function and maintain it within a normal range but are unable to prevent the change that triggered the reflex. A few reflexes have evolved that enable the body to predict that a change is about to occur and start the response loop in anticipation of the change. These anticipatory responses are called feedforward control. An example of feedforward control is how the sight, smell, or even the thought of food can stimulate the secretion of saliva in the oral cavity and hydrochloric acid in the stomach.

Gain

GAIN = CORRECTION RESIDUAL ERROR -the less variation you can tolerate, the greater the gain (eg. body temp has gain of 27, blood pressure is 2) (i.e. can tolerate great change in blood pressure without dying, but can’t tolerate great change in body temperature)The degree of effectiveness with which a control system maintains a constant condition is determined by the gain of the negative feedback control system. The efficiency of a control system is related to the range within which the controlled variable must be maintained. The smaller the normal range of a given physiological variable, the higher the gain must be and therefore a more efficient control system to maintain the variable within the normal limits (or the established set point). Some examples are: 1. body temperature control system gain averages about 27 2. baroreceptor arterial blood pressure control system <2 3. renal arterial blood pressure control system is infinite Set point is defined as the normal value a control system attempts to maintain.As illustrated in the previous page, there may be many control systems with unequal gains involved with maintaining a given physiological variable. All the control systems shown, plus others, are required for maintaining arterial blood pressure and preserve homeostasis so life can continue.

Examples

Mean Arterial Blood Pressure

Subtopic

The neural reflex system that regulates mean arterial blood pressure (MAP) operates as a series of negative feedback loops. A dual system of sensors and neural reflexes controls mean arterial blood pressure: 1. the primary sensors are baroreceptors which are actually stretch receptors or mechano-receptors that detect distension of the vascular wall • arterial blood pressure detectors are located in the vascular walls of the carotid sinus and in the muscular walls of the aortic arch 2. the secondary sensors are chemoreceptors that detect changes in blood PO2, PCO2, and pH The control centers are located within the CNS, mostly in the medulla, but sites within the cerebral cortex and hypothalamus also exert control. The effectors include the pacemaker and contractile muscle cells in the heart, the vascular smooth muscle cells in arteries and veins, and the adrenal medulla. The entire control process can be referred to as the baroreceptor reflex control of arterial blood pressure and consists of the: 1. arterial baroreceptors = the detectors (sensors) 2. afferent neural pathways = the input pathways 3. control centers in the medulla = the integrating centers 4. efferent neural pathways = the output pathways 5. heart and blood vessels = the target tissues

Cardiovascular Response to Hemorrhage

Hemorrhage will stimulate both the arterial baroreceptors and the stretch receptors of the renal afferent artery. Arterial blood pressure receptors are responsible for acute reflex (nervous reflexes) responses to a decrease in blood pressure while the renal system is responsible for chronic reflex (hormonal) control to reestablish arterial blood pressure. Increasing TPR will result in net absorption in the capillaries to increase intravascular volume.

Arterial Baroreceptor Reflex

Non-Homeostatic - Positive Feedback System

. in a positive feedback system, the reflex response to the disturbance will be the same as the disturbance • this type of control is mostly used for intensifying a change, not to correct it An outside factor will be required to shut of the positive feedback loop • examples - the propagation of an action potential down a cell membrane; oxytocin increases uterine smooth muscle contractions which stimulate more oxytocin secretion; blood clotting cascadeA few reflex pathways are not homeostatic. In a positive feedback control system, a variable is sensed and action is taken to reinforce the change of the variable. Since the response is in the same direction as the disturbance, there is a cumulative or amplified effect associated with the reflex. Positive feedback does not lead to stability or regulation, but to the opposite - a progressive change in one direction. This type of control is mostly used for intensifying a change, not to correct it.The small figure in the upper right shows that A stimulating B results in Bstimulating A.

Parturition

An example of a positive feedback loop involves the hormonal control of uterine contractions during childbirth (figure on the right). When a baby is ready to be delivered, it drops lower in the uterus and begins to put pressure on the cervix. Sensory signals from the cervix to the brain cause release of the hormone oxytocin, which causes the uterus to contract and push the baby’s head even harder against the cervix, further stretching it. The increased stretch causes more oxytocin release, which causes more contractions that push the baby harder against the cervix. This cycle continues until the baby is delivered, ending the stretch on the cervix and stopping the positive feedback loop.

Other Examples

Initiation of Urination when Bladder is full

during the follicular phase of the menstrual cycle, estrogen stimulates the release of luteinizing hormone which in turn stimulates further estrogen synthesis by the ovaries

the calcium-induced calcium ion release in cardiac cells during each heart beat

the propagation of an action potential

the blood clotting cascade

Pathological Effects

The above diagram shows how a positive feedback mechanism leads to the loss of homeostasis. It shows that as the abdominal cavity fills with fluid leaked from injured organs, the increased pressure impairs blood flow and leads to cell death. This initiates a cascade of positive feedback events that can eventually lead to death of the patient. Sudden loss of 2 L of blood from the body leads to a condition where heart muscle will not get enough blood for normal functioning. Thus, a weakened heart will pump less blood to heart muscle which further reduces the efficiency of the heart. These cyclical processes continue and death will eventually occur.

Biological Energy Use

biological energy use involves the synthesis and breakdown of molecules to provide energy used to transport substances across cell membranes and to create movement

Structural-Functional Relationships

. structural-functional relationships demonstrates the molecular interactions, the division of the body into discrete compartments, and the mechanical properties of cells, tissues, and organs

Compartmentalization

Mechanical Properties of Cells, Tissues and Organs

Molecular Interactions

Communication

Communication between both structure and function (integration) is required for cells in the body to communicate rapidly and efficiently

Information Flow

information flow in the body takes the form of either chemical signals or electrical signalsinformation may pass from cell to its neighbors (local communication) or from one part of the body to another (long-distance communication)information stored in the genetic code of DNA is passed from one cell to its daughter and from an organism to its offspring

Information Type

Chemical

Electrical

Distance Travelled

Long Distance

i.e. from one body part to another

Short Distance

i.e. from a cell to its neighbours

Mass Flow

mass flow refers to the movement of substances within and between compartments of the body- the movement of materials in mass flow is made possible by a driving force such as a pressure or concentration gradient

Subtopic

The Physiological Components of the Body

Physiology is a special focus on the integration of function among systems across many levels of human body organization. The figure below is a “map” of how all the physiological components of the body are linked together to maintain life. Maps in physiology usually focus either on the relationships between anatomical structures and physiological processes or on normal homeostatic control pathways and responses to abnormal events. Mapping is a way of organizing material to help study the importance of and relationships between various pieces of information.

respiratory System

Lungs

Cardiovascular System

Blood Vessels

Heart

Digestive System

Mouth

Stomach

Intestines

Immune System

Lymph Nodes

Nervius System

Brain

Endocrine System

Thyroid Gland

Reproductive System

Testes

Ovaries

Uterus

Urinary System

Bladder

Kidneys

Intgumentary System

Musculoskeletal System

Muscle Physiology

Types of Muscles

Striated

Skeletal

Structure of Skeletal Muscle

Muscle ensheathed by Epimysium

Composed of Fascicles ensheathed by Perimysium

Composed of Myofibres ensheathed by Epimysium

Also known as muscle cell or myocyte

Length: Can be very long (length of a muscle)

Diameter: 10-80 micrometers

Plasma Membrane: Sarcolemma

Nucleus: Multi-nucleated

Mitochondria: Many

ER: Extensive sarcoplasmic reticulum

Composed of 100s - 1000s of Myofibrils

Composed of very organized system of Myofilaments

Contractile Filaments

Composed of fibres/proteins

Primary Contractile Fibres

Actin

3000 per myofibril

About twice as many actin filaments as myosin filaments

Each actin is one micrometer long, anchored in Z line

Components

Double helix of F-actin protein (backbone)

made of G-actin molecules .

Each bead is a G-actin.

Each G-actin molecule has one ACTIVE SITE where ADP is attached.

Tropomyosin

fiber like” molecule 50nm long

wrap around F-actin helix.

Cover active sites on G-actin molecules preventing attachment of myosin cross bridges.

Function is to keep active sites covered.

Troponin

attached to tropomyosin has strong affinity for

Tropomyosin

Actin

Ca++

When Ca++ influx occurs and Ca++ binds with troponin, it pulls on tropomyosin causing a conformational change that exposes actin binding sites.

Myosin

1500 per myofibril

Components

200 Myosin Molecules

Each molecule is composed of

heavy chain tail,

head

Subcomponents

Heavy Chain Molecules

Light Chain Molecules

ii.

Important characteristics

it has ATP-binding sites into which fit molecules of ATP

arranged with tails bunched together so that arms & heads are free to swivel

Heads face out in all directions.

Hinges at two places

Head

Arm

Ancillary Proteins

Nebulin

Titin

filaments (MW of 3,000,000).

Very flexible and springy.

Holds microfilaments in place and provides elastic recoil.

Troponin Complex

Tropomyosing

Organized functionally into sarcomeres

Might be considered the functional units of the muscle.

Regular organization with six actin filaments surrounding each myosin filament.

Shared by adjacent myosin filaments

Overall light/dark areas depend on density of fibers.

I Band

(light) contains only actin at rest.

A band

dark) contains both actin and myosin.

H zone

in center contains only myosin

Z line

(disc) separates sarcomeres.

Actin filaments pierce Z line and have an end in each of two sarcomeres.

They are anchored here

M Line

Bare Zone

A small area close to the M-line contains no crossbridge heads.

As actin fibers move close together and enter this zone, they cannot produce additional force.

Note that the sheaths travel length of muscle to form tendons at each end

Cardiac

Smooth

Skeletal and SMooth muscle

Myosin

Sarcoplasm = Cytoplasm

Contains normal organelles and cytoskeleton

Sarcoplasmic Reticulum = Endoplasmic Reticulum

Add in picture

Smooth

Extensive network for storage of Ca++ ions in terminal cisternae.

Can release or clear sarcoplasm of Ca++ ions (clears Ca++ via active transport).

Smooth SR surrounds each myofibril

T-Tubules

Transverse (t) tubules carry electrical signal from sarcolemma into fiber.

They branch when inside the cell forming extensive "plates" for efficient delivery of the electrical signal.

Where t-tubules contact terminal cisternae. Forms a "triad" including t-tubule with cisternae on both sides.

Mammalian skeletal muscle has two T tubules per sarcomere.

Rough

Covered with ribosomes.

Protein synthesis.

Constant replacement / synthesis of contractile proteins.

Sliding Filament Theory

Excitation

Signal at neuromuscular junction (motor end plate)

Depolarization of sarcolemma from center toward ends of cell

Signal moves down t-tubules to SR

Change in voltage of SR induces release of Ca++ from cisternae (voltage-gated Ca++ channels in SR)

Ca++ receptors along the SR open even more Ca++ channels

Ca++ floods the muscle cell

A muscle fiber is excited via a motor nerve that generates an action potential that spreads along the surface membrane (sarcolemma) and the transverse tubular system into the deeper parts of the muscle fiber.

A receptor protein dihydropyridine receptor (DHP) senses the membrane depolarization, alters its conformation, and

activates the ryanodine receptor (RyR) that releases Ca2+ from the SR.

10.

Ca2+ then bind to troponin and activates the contraction process (Jurkat-Rott and Lehmann-Horn 2005)

Contraction

Ca++ binds with troponin (on the actin filament) causing conformational change that removes inhibition from binding site.

ATP in myosin cross bridge head already cleaved to ADP + Pi by ATPase in head but all are still bound to head. It puts arm and head into “cocked” position.

Myosin cross bridge binds to site on actin filament, creating ACTOMYOSIN.

Insert ACtin-Myosin Interaction picture

Continued Contraction

ADP and Pi leave the myosin head triggering Power Stroke.

New ATP then binds head, causing release from actin.

New ATP splits and the released energy “cocks” head again for next stroke.

“Walk-Along or “Ratchet” theory

As long as Ca++ remains in sarcoplasm, actin sites remain exposed, and ATP is available, the heads will recycle rapidly repeatedly pulling actin past their position.

Changes in Resting vs. Active Sarcomere

Length-Tension Relationship Sarcomeres

At point 1 in Graph, the sarcomere is overly contracted. There is a high degree of overlap between the thin and thick filaments. Muscle contraction causes actin filaments to slide over one another and the ends of myosin filaments. Further muscular contraction is halted by the butting of myosin filaments against the Z-discs. Tension decreases due to this pause in cross-bridge cycling and formation.

Maximum tension is produced when sarcomeres are about 2.1 to 2.2 μm long, as seen at point 2. This is the optimal resting length for producing the maximal tension.At point 3, there is little interaction between the filaments. Very few cross-bridges can form. Less tension is produced.

When the filaments are pulled too far from one another, as seen at point 4, they no longer interact and cross-bridges fail to form. Zero tension results

The Motor End Plate

Insert Picture - Motor End PLate

Innervated by myelinated somatic neurons (alpha)

Branch to stimulate 3 – 100s of muscle fibers at motor end plates (neuromuscular junction). Each branch is myelinated by schwann cells.

Typically near center of muscle fiber. Extremely long fibers may have two neuromuscular junctions.

Lots of mitochondria in neuron terminal to provide ATP energy for synthesis of ACh.

Picture Captions

Invagination of post-synaptic membrane called a “trough” or “gutter”. 20-30nm wide.

Acetylcholinesterase in synaptic cleft to lyse and clear ACh from cleft when signal ends.

Folds in the bottom of the trough, “subneural clefts”, to increase surface area for stimulation by Ach.

Release of Ach at the neuromuscular Junction

Depolarization reaches axon terminal.

Voltage gated Ca++ channels open.

Terminal vesicles containing ACh move to the membrane

Bound to membrane with docking proteins.

Exocytosis releases ACh into cleft.

Diffuses across to post-synaptic side.

Post-synaptic membrane receives signal

lots of ACh receptors located near mouths of subneural clefts.

Excitation Contraction Coupling

Add picture - excitation contraction coupling

Simply means the process that excites the cell membrane at the neuromuscular junction is coupled to the processes that cause muscle contraction.

Removal of Ca++ from the sarcoplasm (relaxation)

Calcium pump actively transports Ca++ out of the sarcoplasm to end the contraction. Very efficient in clearing the intracellular fluid almost entirely of Ca++.

SR is very effective storage unit for calcium and calcium ions. Pump actively moves ions into cisternae.

Large additional stores of un-ionized calcium is bound in SR by a protein called calsequestrin. Will be released as ionized Ca++ to maintain stores in cisternae if they get low.

Mechanisms of Skeletal Muscle Contraction

Muscle contraction is based on a twitch of the muscle fiber which is like an action potential is an all or nothing event.

A twitch is the mechanical response of an individual muscle fiber, an individual motor unit, or a whole muscle to a single action potential.

Phases of the the Twitch

When a stimulus is applied and a fiber contracts the twitch can be divided into three phases

add picture of phases

Latent

Ca build up?

is the delay of a few milliseconds between an action potential and the start of a contraction and reflects the time for excitation-contraction coupling.

Contraction

starts at the end of the latent period and ends when the muscle tension peaks (tension = force expressed in grams). During this time cytosolic calcium levels are increasing as released calcium exceeds uptake.

Relaxation

is the time between peak tension and the end of the contraction when the tension returns to zero. During this time cytosolic calcium is decreasing as reuptake exceeds release.

Types of Twitch

Isometric Twitch

When the load (force opposing contraction) is greater than the force of contraction of the muscle, the muscle creates tension when it contracts but does not shorten.

An isometric twitch is measured by keeping the muscle immobile while stimulating it and measuring the tension that develops during contraction.

The rise and fall of tension traces a bell-shaped curve.

add isometric twitch

Isotonic Twitch

When the force of contraction of the muscle is at least equal to the load so that the muscle shortens, the muscle is said to contract isotonically.

An isotonic twitch is measured by attaching the muscle to a moveable load.

add isotonic twitch

The tension curve for an isotonic twitch shows a plateau during which the force or tension is constant (iso-same; tonic- tension).

Relationship between Isotonic and Isometric Contraction in Real Life

add isometric vs. isotonic

When the load exceeds the amount of force the muscle can generate, an isometric twitch results which is always of the same size and shape.

The greater the load the higher the plateau and the greater the time lag between stimuli and the start of muscle shortening.

The motor unit consists of a motor neuron and all the muscle fibers it innervates.

insert motor unit

Factors Affecting the Force Generation of Individual Muscle Fibers

Frequency of Stimulation

add frequency of stimulation

When a muscle is stimulated at a frequency so that twitches follow one another closely, the peak in tension rises in a step-wise fashion.

add frequency of stimulation 2

This phenomenon is called treppe.

add freq of stim 1(switch 3 somewhere else)

Treppe may occur because Ca++ released from previous twitches exceeds Ca++ reuptake and this results in an increase in Ca++ concentration.

This in turn increases the number of crossbridges that form in the following contractions.

Another possibility is that frequent stimulation "warms up" the muscle and thereby increases the enzymatic rate.

As muscle twitch is fairly slow compared to an action potential many action potentials can arrive before a single twitch is completed. This causes the twitches to bunch up and results in the generation of a force that is greater than a single twitch. This process is called summation.

Increasing action potential frequency increases force by SUMMATION.

When the frequency of stimulation is so high that Ca++ levels rise to peak levels, summation results in the level of tension reaching a plateau called tetanus.

When the frequency of stimuli is high enough to cause tetanus but tension oscillates around an average level, the tetanus is called incomplete or unfused.

At greater frequencies of stimulus, levels of Ca++ peak and cause a maximum number of crossbridges to cycle.

At this point the tension plateau smoothes out and tetanus is called complete or fused.

Fiber Diameter

The greater the number of sarcomeres arranged in parallel, the greater the force generating capacity.

The number of sarcomeres arranged in parallel correlates with a fiber's diameter.

The greater the cross-sectional area of a fiber, the more force it can generate.

Changes in Fiber Length

Add changes in fibre length

When the muscle is at the optimum length the number of active cross bridges is the greatest.

When the muscle is stretched beyond this length the number of active cross bridges decreases because the overlap between the actin and myosin fibers decrease.

As the muscle becomes shorter than the optimum length the thin filaments at opposite ends of the sarcomere first begin to overlap one another and interfere with each other's movements.

This results in a slow decrease in tension as the sarcomeres get shorter.

Then as the sarcomeres get shorter the thick filaments come into contact with the Z lines and the decrease in tension with decreasing length becomes even steeper.

Preload and Afterload

Example - outstretched arm picking up bucket of water - hold it straight - preload - stretching sarcomeres to optimal length

when you actually bend and lift - afterload

Preload is blood coming to hear to stretch it; afterload is blood in aorta and pushing it out into the vascular system

Preload

is the load on a muscle in a relaxed state, prior to contraction.

Stretching a muscle to optimize actin and myosin filament interaction is known as Preloading.

Too little - you will fall on the left side of the curve.

Too much - you will fall on the right side of the curve

Afterload

the load the muscle is working against or trying to move during stimulation.

Afterload also determines how fast a muscle contracts during a lift.

Minimal loads allow the muscle to contract at maximal velocity.

Isometric Contractions occur when afterload is too heavy to lift

Velocity of Shortening

When a muscle contracts isotonically under increasing loads the contractions display the following effects:

The latent period (time lag between stimulation and shortening) increases.

The duration of shortening decreases.

The velocity of shortening decreases

Graph of velocity against load

add distance shortening - time

preload - isotonic - isotonic - isometric (rt. side = afterload)

Zero load -

latent phase is shortest;

highest velocity of shortening

Longest duration of contraction

Heavy load

latent phase is increased the most.

Lowest velocity of shortening

Shortest duration of contraction

When the velocity of shortening is plotted as a function of load, as the load increases the velocity of shortening gradually decreases

add velocity of shortening

Different types of fibers differ in their velocity of shortening

ADD tension-time graph for different muscles

This is because there are fast-twitch and slow-twitch fibers.

Slow Twitch Oxidative (aerobic)

Certain muscles (e.g. soleus) contain mostly slow twitch fibers and will contract slowly.

Red in color.

Highly vascularized.

Lots of mitochondria.

Low strength,

high endurance.

Fast Twitch

Glycolytic

White in color, lacking much vascularization.

Lots of contractile protein (large fiber size).

Extensive SR.

Lots of constituents and enzymes for glycolysis.

Few mitochondria.

Contains "fast myosin" which is able to hydrolyze ATP at a faster rate.

High strength

Low endurance

Oxidative Glycolytic

crossover fiber.

Can mimic actions of FTG or STO fibers in response to specific muscle training.

Some contain predominantly fast-twitch fibers (e.g. extraocular) and contract quickly.

E.g. extraocular muscles

Fast-twitch fibers also have higher maximum shortening velocities compared to slow-twitch.

Energetics of Muscle Contraction

insert energetics of muscle contraction

Phosphagen System

addd phosphagen system

ATP is the immediate source of energy for muscle contraction.

However, the ATP stores in the muscle can sustain muscle contraction for up to 3 seconds.

In about 3 sec, all the ATP is depleted from the muscle cell.

Thereafter, ATP is regenerated using the energy released by the dephosphorylation of creatine phosphate reserves of the muscle fiber.

Creatine phosphate + ADP-------------------- > creatine + ATP

The creatine phosphate reserves of the muscle fiber can sustain contraction for about 5 to 8 seconds.

Creatine phosphate (CP) releases stored energy to convert ADP to ATP:

Returns energy to ATP via enzyme creatine phosphokinase (CPK)

excess in blood with muscle damage.

Aerobic metabolism (requires O2) provides most ATP needed for contraction:

Glycolysis in cytoplasm;

oxidative phosphorylation in mitochondria

At peak activity, anaerobic glycolysis needed to generate ATP:

Fermentation- lactate from pyruvate

temporarily maintains glycolysis without O2

far less ATP produced

Muscle blood flow during exercise

add muscle blood flow in exercise

resting = 3-6 ml/100g/min

max work = 90 ml/100g/min

the increase is due to vasodilation and increase BP

Muscle blood flow may increase more than 20 fold during exercise

States of Muscle Tone

Hypertrophy (fibers)

Increase in number of contractile proteins causing an increase in size of myofibrils up to 50%.

Increase in enzymes for glycolysis and in the number and size of mitochondria.

More sarcomeres added to increase length if muscle is repeatedly over-stretched.

Muscle atrophy

Occurs at approximately the same rate as hypertrophy during periods of non-exercise.

Happens more quickly when muscle is prevented from moving as in a cast following injury.

Happens very quickly in cases of loss of nerve supply.

Needs the signals that maintain muscle tone to keep the muscle at a normal size.

Muscle dystrophy :

Recessive X –linked mutation in dystrophin gene in Duchenne muscular dystrophy.

Eventually causes death because of paralysis of respiratory muscles

Rigor mortis:

Muscle stiffen after death.

ATP reserves are quickly exhausted from the muscle contraction and other cellular processes.

This means that the actin and myosin fibers will remain linked until the muscles themselves start to decompose.

Regulation of Muscular Contraction

Muscle Spindle

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Diagrammatic cross-section of a muscle spindle showing

Intrafusal Fibres

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Afferent

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There are two types of sensory receptors associated with the intrafusal fibers that detect the degree of stretch of these fibers which in turn monitors the degree of stretch of the entire muscle:

Annulospiral endings

This is the end of a type Ia afferent fiber that wraps around the central bag region.

Flower-spray endings

The branching end of the type II afferent fibers of these neurons are located on either side of the central bag region

Efferent

Alpha

to extrafusal (normal) muscle fibres

Gamma

to intrafusal muscle fibres

Keep muscles stretched to keep signal going again and again to know how much load there is

important in preventing muscle injury

don't stop sending signals

Normal musccle fibers that surround the spindle are called extrafusal fibers.

Reflexes

Stretch Reflexes

The stretch reflex is generated as a protective mechanism when the spindle and its skeletal muscles are being stretched.

During stretch, an action potential is transmitted to the central nervous system (CNS) at the spinal cord; the frequency of the action potential is proportional to the degree of stretching.

As the skeletal muscles contract, the intrafusal muscles shorten;

this relaxes the tension on the muscle spindles, and reduces the discharge rate of the gamma efferents on the annulospiral endings.

Patellar Reflex (GTOs)

Add patellar reflex

Striking the patellar tendonwith a tendon hammer just below the patella stretches the muscle spindle in the quadriceps femoris muscle. This produces a signal which travels back to the spinal cord and synapses (without interneurons) at the level of L4 in the spinal cord, completely independent of higher centres.

From there, an alpha-motor neuron conducts an efferent impulse back to the quadriceps femoris muscle, triggering contraction.

This contraction, coordinated with the relaxation of the antagonistic flexor hamstring muscle causes the leg to kick.

otherwise its a monosynaptic reflex

This reflex is a reflex of proprioception which helps maintain posture and balance, allowing to keep one's balance with little effort or conscious thought.

It tests L2, L3, and L4

Write out steps from picture.

Cardiac Muscle

Smooth Muscle

Spindle shaped cells

Relatively small compared to skeletal and cardiac muscle

2-5 mm wide; 50-200 mm long.

Actin/myosin ratio:

greater in smooth muscle (10:1) than in skeletal muscle.

Overall architecture

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The arrangement of dense bodies with connective-tissue fibers running throughout the cell and into adjacent gives structural integrity to the entire smooth muscle tissue, and anchor points for actin filaments

Contractile Apparatus

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myosin (thick, white filament).

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Light Chains - Play a key regulatory role

The organization of myosin molecules on the myosin filament is somewhat different than in skeletal muscle.

A main difference is the lack of a bare region in the middle lacking cross-bridges.

So there are cross-bridge heads along the entire length of the myosin filament.

Location and action of the myosin light chains allows it to control activation of myosin cross-bridge heads.

actin (thin-filament)

F-Actin strands of G-Actin pearls

Tropomyosin present in smooth muscle actin but:

Exact functional role, if any, unclear.

No troponin present at all

Therefore, Troponin-I does not inhibit cross-bridge cycling in smooth muscle as it does in skeletal muscle.

Lack neat hexagonal arrangement of actin and myosin

Intermediate Filaments

Cytoskeletal elements which form a structural backbone against which contraction occurs.

Dense Bodies.

Serve as anchors for the thin-filament protein actin.

Analogous to z-lines in striated muscle

GAP JUNCTIONS

Allow direct electrical communications between adjacent smooth muscle cells

Lots of gap junctions in smooth muscle, but density varies from tissue to tissue.

No T-tubules or terminal cistern system.

Small size of smooth muscle cells.

Smooth muscle has no t-tubules, and a much less developed SR. Result is a slower, often less precise response

Smooth muscle does not always require action potential to contract.

May involve graded potentials, that sometimes build into action potentials.

Poorly developed sarcoplasmic reticulum.

Smooth muscle does have a SR containing Ca++, so Ca++ can be released from intracellular stores.

Often needs additional extracellular Ca++ for activation and/or contraction.

Compare: Dependence on extracellular Ca++

cardiac muscle (partial-dependence)

skeletal muscle (negligible-dependence).

Smooth Muscle Innervation

Innervated by the autonomic nervous system.

Autonomic neurons do not form synapses with specific cells but with groups of cells.

Neurotransmitter is released at varicosities (swellings) found along the length of the axon

add smooth muscle varicosities

no specialized nerve cell junction

This causes a neighboring group of cells to contract together. Smooth muscle cells contract in groups also because of gap junctions between cells that allow electrical signals to spread from one cell to another.

Mechanism of Smooth Muscle COntraction

Add mechanism of smooth muscle contraction

Calcium ions combine with calmodulin to cause activation of myosin light chain kinase (MLCK )and phosphorylation of myosin light chain (head)

Myosin light chain phosphatase (MLCP) is important for cessation of contraction i.e relaxation of muscle.

High Ca++ therefore causes contraction by increasing MLCK activity (increased in comparison with MLCP activity)

High MLCK/MLCP Activity Ratio initiates smooth muscle contraction

Mechanism of Smooth Muscle Relaxation

Low intracellular [Ca++] will cause the cell to relax.

Calcium extrusion from the cell eg. 3Na+/Ca++ exchanger

Sarcolemma Ca++ATPase

Reuptake by the sarcoplasmic reticulum by SR.

Phospholamban (PLB) is an intracellular protein, when phosphorylated, it increases Ca++ re-uptake into SR by sarcoplasmic reticulum calcium pump (SERCA), clearing Ca++ from the cytosol.

High cAMP causes relaxation by effectively lowering myosin light chain kinase [MLCK]

c AMP activates PKA which phosphorylates MLCK into a state where Ca+/calmodulin cannot bind.

Nitric oxide causes smooth muscle relaxation in the same manner.

c GMP mediated response.

Note: Both cAMP/PKA, and cGMP/PKG can phosphorylate phospholamban (PLB).

Ischemia (decrease in blood flow) opens ATP-sensitive K+ channels, hyperpolarization, closes Ca++ channels

Ca++ channel blockers (L-type channels)

Muscarinic Receptors

M2 receptors

Use Gi proteins to inhibit adenylyl cyclase, lowering cAMP and thus causing smooth muscle contraction.

M3 receptors (and a smaller number of M1 receptors)

Use Gq protein to increase intracellular Ca++ and cause smooth muscle contraction.

For relaxation of a sphincter (such as for urination) M3 receptors use their Gq protein to increase Ca++ in endothelial cells that produce NO.

The NO then diffuses into the sphincter muscle and causes it to relax.

Comparison of SMooth and Skeletal Muscle Contraction

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Slow cycling of actin and myosin cross bridges. About 1/10 to 1/300 that in skeletal muscles.

Low energy requirement to sustain the same tension. About 1/10 to 1/300 that in skeletal muscles.

Contraction time is 1 to 3 sec, about 30 times longer than in skeletal muscle.

Maximum force of contraction is more. 4-6kg/cm sq. Skeletal muscle about 3-4 kg.

Stress-relaxation: Hollow organs maintain same pressure despite changes in pressure.

Latch mechanism:

After reaching full contraction even if force of stimulus decreases the contraction is maintained for a long time

Latch State

Contraction of SM is much slower than that of skeletal muscle. Force production can be equal to skeletal muscle.

With latch state, ENERGY EXPENDITURE economy is high:

Sustained smooth muscle contractions are executed with minimal expenditure of ATP.

Slow cycling and long attachment of cross-bridges take place due to decrease in ATPase activity, and possibly a reduction in both MLCK and MLCP activity.

Types of smooth muscle-

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Multi-Unit Extreme end of Spectrum

Each smooth muscle cell acts mostly independently (more like skeletal muscle).

Less gap junctions between cells

Higher innervation ratios than visceral smooth muscle.

These are found in places where fine control of contraction is needed

Ciliary muscles of the eye

Tracheal Muscle

GI Sphincters

Larger Blood Vessels

Bronchial muscles

Iris Muscle

Vas deferens

All sphincters of the body

Electrical Characteristics

Multiunit smooth muscle is neurogenic- that is, its contraction must be initiated by a motor neuron.

Membrane potential of multiunit smooth muscle is stable, and lacks many voltage-gated channels

Typically, do not display action potentials when stimulated to contract but displays graded potentials.

Multiunit Smooth Muscle uses graded potentials (PSPs)

add multiunity smooth muscles graded potentials

Multi-unit smooth muscle cell membrane lacks the voltage-gated channels that can cause action potentials.

More stimulation causes graded-depolarization and graded response.

Tone:

Constant and stable low level of contraction

Example:

GI sphincters.

Tone is intrinsic property of the muscle itself -- does not depend on nerves (unlike skeletal muscle)

Tone may be modified by:

nerves

hormones

drugs

Contraction Mechanism

add multiunit smooth muscle contraction mechanism

actin and myosin interact according to the sliding filament mechanism

Ca2+ is released from the SR and from the extracellular space

Ca2+ interacts with calmodulin and myosin light chain kinase to activate myosin

Ca2+ binds to calmodulin and activates it

activated calmodulin activates the kinase enzyme

phosphorylated cross bridges interact with actin to produce shortening

Single-Unit Extreme end of Spectrum

add single unit smoothh muscle

Also called unitary or visceral smooth muscle.

Behaves in a syncytial manner.

In this organization the smooth muscle cells are connected by gap junctions and there are fewer neurons..

Relatively sparse innervation

This organization is present in

the wall of the gastrointestinal tract

Ureters and urinary bladder

Smaller arteries / arterioles / smaller veins

Lymphatic vessels

Uterus

Electrical Characteristics:

Single-unit visceral smooth muscle is myogenic; it can contract regularly without input from a motor neuron .

Slow Wave Potentials:

Slow wave potential are unstable resting membrane potentials that continuously cycle through depolarization- and repolarization phases. However, not every cycle reaches depolarization threshold and thus an action potential (AP) will not always fir

Graph 1

GRaph 2

Resting Membrane Potential

Relatively positive (perhaps -55 mV) due to high Na+ leak.

Threshold potential is about -30mV

Single-unit muscle cell membrane has voltage-gated channels, so can create an action potential when stimulated

Action potentials (all or none) spikes.

add single smooth unit action potentials

Almost always cause an associated contraction. Cell membrane depolarization will periodically reach depolarization threshold and an action potential will fire, triggering contraction of the myocyte.

Subtopic

Organ Systems of the Body and their Function

Function and processes are two related concept in physiology:Function of a physiological event or system refers to why it exists or happens. This is know. as the teleological approach to physiology.An example of the teleological answer to the question why the RBCs transport oxygen is "because cells need oxygen and the RBCs bring it to the,"Physiological processes or mechanisms are the "how" of achieving a function. This is known as the mechanistic answerers to "why red blood cells transport oxygen" is because oxygen binds to Hb molecules in RBCs.

Representative Functions

Transport of Materials between all cells of the body

Conversion of Food into particles that can be transported into wastes

Coordination of body function through synthesis and release of reguatory molecules.

Defense against foreign invaders

Protection from the external environment

Support and Movement

Coordination of body function through electrical signals and the release of regulatory molecules

Perpetuation of the species

Exchange of oxygen and carbon dioxide between the internal and external environments