Pharmacodynamics Module 1

Ligand-gated ion channels (ionotropic receptors)

Structure

four transmembrane domains

ligand binding domain coupled to pentameric complex of different subunits

ion channel complex

membrane localized

Mechanisms

rapid response

neurotransmitters: Ach or glutamate

controls synaptic events

direct; no-mediator activation

conductance (speed of ion transfer/ion flow rate through pore) doesn't vary between endogenous or agonist drugs

duration of channel opening varies between agonist or drug

desensitization occurs when channel closes and ligand remains bound

G-protein coupled receptors (metabotropic receptors)

Structure

seven transmembrane domains alpha-helices

extracellular domain at N-terminal

cytoplasmic domain at C-terminal

alpha, beta, gamma subunits anchored to membrane

membrane localized but diffuse freely around membrane associating with different receptors

20 alpha subunit isoforms that are very selective

some inhibit and some activate effector protein

Mechanisms

mediates olfaction

rapid response

act as messengers for receptors coupled to them

Subtopic

Alpha subunit (in)activates itself

GDP converted to GTP activates receptor

GTP hydrolyzed to GDP inactivates receptor

GTP hydrolyzed to GDP inactivates receptor

desensitization through down regulation of receptor through phosphorylation of cytoplasmic tail (interferes with binding) and marks for endocytic internalization destruction

Protein kinase A and C phosphorylate

Subfamilies

Rhodopsin family

amine neurotransmitters, neuropeptides, purines, protanoids, cannnabinoids

short extracellular tail (N-terminal)

ligands bind to helices or extracellular hoops

Secretin/Glucagon family

receptors for peptide hormones

EC tail with ligand binding domain

Metabotropic glutamate receptors/Ca sensor

GABA receptors

Downstream Effects

one agonist bound GPCR can activate several G-protein complexes = amplification

Kinase-linked receptors

Structure

membrane localized

single transmembrane domain (helix) links extracellular domain to intracellular kinase domain

form dimer pairs when activated

Subfamilies

Receptor Tyrosine Kinases

Serine/Threonine Kinase

Cytokine Receptors

Mechanisms

intrinsic protein kinase activity or linked to free protein kinases

role in inflammation, tissue repair, cell cycle progression, apoptosis, and immune response

ligands include GF, cytokines, hormones, bacterial LPS

ligand binds --> dimerization of receptor --> autophorylation of tyrosine residues on cytoplasmic portion --> activate intracellular signaling proteins (phospholipases/protein kinases)

signaling protein activated by receptor tyrosine kinase = activation or inhibition of nuclear transcription factors by phosphorylation and suppression or activation of genes

intermediate response (minutes to hours)

Downstream effects

kinase cascades

Nuclear receptors

Structure

no transmembrane domain

intracellular

translocates to nucleus

separate receptor and DNA binding domains

C-terminal domain w/ region that governs nuclear localization of receptor

N-terminal region controls interaction of receptor w/ co-activator or co-repressor proteins that control transcription

Subfamilies

Class I

in cytoplasm

form homodimers

receptors for steroid hormones and targets for endocrine mediators

high affinity

Hybrid Class

mainly endocrine

RXR heterodimers

Class II

in nucleus

heterodimers (except RCR)

low affinity

mainly lipid ligands

Mechanisms

direct interaction with DNA --> gene transcription --> protein synthesis --> cellular effects

Nuclear receptor effectors = post-transcriptional products of gene activation

slower response (hours to days)

Classical receptors **

Ion Channels

Enzymes

Transporters