Pharmacodynamics Module 1

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Classical receptors

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Pharmacodynamics Module 1

Major drug targets

Transporters

Enzymes

Ion Channels

Classical receptors **

Major Classes of Classical Receptors

Nuclear receptors

slower response (hours to days)

Nuclear receptor effectors = post-transcriptional products of gene activation

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

Class II

mainly lipid ligands

low affinity

heterodimers (except RCR)

in nucleus

Hybrid Class

RXR heterodimers

mainly endocrine

Class I

high affinity

receptors for steroid hormones and targets for endocrine mediators

form homodimers

in cytoplasm

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

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

separate receptor and DNA binding domains

translocates to nucleus

intracellular

no transmembrane domain

Kinase-linked receptors

Downstream effects

kinase cascades

intermediate response (minutes to hours)

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

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

ligands include GF, cytokines, hormones, bacterial LPS

intrinsic protein kinase activity or linked to free protein kinases

Cytokine Receptors

Serine/Threonine Kinase

Receptor Tyrosine Kinases

form dimer pairs when activated

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

G-protein coupled receptors (metabotropic receptors)

Downstream Effects

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

Subfamilies

Metabotropic glutamate receptors/Ca sensor

GABA receptors

Secretin/Glucagon family

EC tail with ligand binding domain

receptors for peptide hormones

Rhodopsin family

ligands bind to helices or extracellular hoops

short extracellular tail (N-terminal)

amine neurotransmitters, neuropeptides, purines, protanoids, cannnabinoids

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

Alpha subunit (in)activates itself

GTP hydrolyzed to GDP inactivates receptor

GDP converted to GTP activates receptor

act as messengers for receptors coupled to them

Subtopic

mediates olfaction

alpha, beta, gamma subunits anchored to membrane

20 alpha subunit isoforms that are very selective

some inhibit and some activate effector protein

membrane localized but diffuse freely around membrane associating with different receptors

cytoplasmic domain at C-terminal

extracellular domain at N-terminal

seven transmembrane domains alpha-helices

Ligand-gated ion channels (ionotropic receptors)

Mechanisms

desensitization occurs when channel closes and ligand remains bound

duration of channel opening varies between agonist or drug

rapid response

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

direct; no-mediator activation

controls synaptic events

neurotransmitters: Ach or glutamate

Structure

membrane localized

ion channel complex

ligand binding domain coupled to pentameric complex of different subunits

four transmembrane domains