Friday, 17 May 2013

Pharmacology: Receptor types

Receptor types:

1.       Ligand gated ion channels:
These are membrane proteins similar to other ion channels and incorporate a ligand binding site. Usually these are receptors on which fast neurotransmitters act. Generally cause an increase in Na+ and K+ permeability. Direct coupling between receptor and ion channel and no intermediate steps are needed in the transduction process.

E.g. Nicotinic acetylcholine receptor: 4 subunits: α, β, γ, δ (each 40 – 58 kDa). Two acetylcholine binding sites, each at the interface between one of the two α subunits and its neighbour. Each subunit spans the membrane 4 times.

Other examples:
GABAA receptor, 5-HT3 receptor

Ion channels:
·         4-5 subunits
·         Ligand gated
·         Conduct Na+, K+, Cl-, Ca2+
·         Alter cell membrane potential or intracellular ionic composition
·         Fast communication (µs-ms)
o   Examples:
o   Nicotinic Acetylcholine receptor (nAChR)
o   GABAA receptor
o   Glycine receptor
o   Glutamate receptor
o   5-HT3 receptor
o   P2x purine receptor

2.      G-protein coupled receptors:
GCPRs are the most targeted receptor type for therapeutic drugs. Many neurotransmitters can interact with both GCPRs and ligand-gated channels leading to a wide variety of effects.

GCPRs consist of a single polypeptide chain of up to 1100 residues. They have a characteristic seven transmembrane α helix structure, with an extracellular N-terminal and an intracellular C terminal domain.

The G-protein consists of three subunits, α, β, γ, the α subunit having GTPase activity. When this binds the agonist-occupied receptor, the α subunit dissociates and activates the effector (usually adenylyl cyclase, phospholipase C or ion channel). Activation is terminated when the bound GTP molecule is hydrolysed, which allows the α subunit to recombine.

mAChRs, adrenoceptors, dopamine receptors, 5-Ht receptors, opiate receptors, purine receptors.

G-protein-coupled receptors
·         Receptors linked to effectors (adenylate cyclase/ phospholipase C/ ion channels) that change intracellular levels of second messenger via GTP-binding proteins
·         Spans membrane 7 times
·         Third intracellular loop couples to G-protein and determines G-protein selectivity
·         Nitrogen side extracellular, Carbon side intracellular
o   Examples:
o   Muscarinic acetylcholine receptor (mAChR)
o   Adrenoceptors
o   5-HT (serotonin) receptors (except 5-HT3)
o   Histamine H2 receptor
o   Eicosanoid receptor,
o   Many peptide receptors
o   Purine receptor
o   Chemorectors
o   Thrombin and other protease receptors
o   GABAB receptor
o   Dopamine receptors
o   Opioid receptors
§  Thrombin receptor activated by protease cleavage of N-terminus domain,à tethered agonist
·         Subtypes:
o   Activate (Gs, Gq)
o   Inhibit (Gi, G0)
·         Seconds to minutes
·         Signal amplification
·         Second messengers activate protein kinases:
o   PKA
o   PKG
o   PKC
o   DAG-dependent PKC

3.      Kinase linked receptors:
Most are large proteins with a single membrane spanning helical region with a large extracellular binding domain and a variable intracellular domain. They play a major role in controlling cell division, growth, differentiation, inflammation, tissue repair, apoptosis and immune response.

Main types:
·         Receptor tyrosine kinases:
·         Serine/ threonine kinases:
·         Cytokine receptors
·         Guanylyl cyclase – linked receptors

Signal transduction generally involves dimerization of receptors, followed by autophosphorylation of tyrosine residues. These act as acceptors for SH2 domains of intracellular proteins.

The two important pathways are:
-         The Ras/ Raf/ mitogen activated protein (MAP) kinase pathway, which is important in cell division, growth and differentiation
-         The Jak/ Stat pathway activated by many cytokines, which controls the synthesis and release of many inflammatory mediators

Receptors with direct kinase activity (Kinase-linked receptors):
·         For hormones regulating proliferation and differentiation (growth factors)
·         Monomers (single polypeptide chain)
o   Ligand binding site
o   Single α-helix crossing membrane
o   Intracellular domain with catalytic activity:
§  Tyrosine kinase
·         Regulate growth, differentiation, development
·         E.g. insulin, EGF, PDGF
§  Serine/threonine kinase
·         E.g. TGF β receptor
§  Guanylate cyclase

4.      Nuclear receptors
Located in the cytoplasm. The liganded receptor complexes initiate changes in gene transcription by binding to hormone response elements in gene promoters and recruiting coactivator or corepressor factors

Intracellular receptors
·         Minutes to hours
·         *Lag in response à slow onset anti-inflammatory effect of glucocorticoids can persist long after agonist concentration is reduced to zero
·         Mediate response to:
o   Steroids
o   Vitamin D
o   Thyroid hormone
o   Inducers of drug metabolism (via Ah receptor)
§  Barbituates,
·         Eg.
o   Glucocorticoid receptor
(The glucocorticoid receptor is expressed in almost every cell in the body and regulates genes controlling the development, metabolism and immune response. When the glucocorticoid receptor binds the glucocorticoids, its primary mechanism of action is the regulation of gene transcription. The unbound receptor resides in the cytosol. The receptor-glucocorticoid complex up-regulates the expression of anti-inflammatory proteins in the nucleus or represses the expression of pro-inflammatory proteins in the cytosol)