g protein coupled receptor

G-PROTEIN COUPLED RECEPTOR

Moderator Dr. Dilshad Ali Rizvi Fardan Qadeer JR II

OVERVIEW:

• WHAT ARE RECEPTORS

• TYPES OF RECEPTORS

• G PROTEIN COUPLED RECEPTORS

• STRUCTURE OF GPCR

• SINGNAL TRANSDUCER MECHANISM

• SECOND MESSENGERS

• RECENT ADVANCES

RECEPTOR:

• Any target molecule with which a drug molecule has to combine in order to elicit its specific effect

• A major group of drug receptors consists of proteins that normally serve as receptors for endogenous regulatory ligands.

Type 1: ligand-gated ion channels

Type 2: G-protein-coupled receptors

Type 3: receptor kinases

Type 4: nuclear receptors

Location Membrane Membrane Membrane Intracellular

Effector Ion channel Channel or enzyme Protein kinases Gene transcription

Time frame Milliseconds Seconds Hours Hours

Examples Nicotinic acetylcholine receptor, GABAA receptor

Muscarinic acetylcholine receptor, adrenoceptors

Insulin, growth factors, cytokine receptors

Steroid receptors

Structure Oligomeric assembly of subunits surrounding central pore

Monomeric or oligomeric assembly of subunits comprising seven transmembrane helices with intracellular G-protein-coupling domain

Single transmembrane helix linking extracellular receptor domain to intracellular kinase domain

Monomeric structure with separate receptor- and DNA-binding domains

• Humans express over 800 GPCRs that make up the third largest

family of genes in humans.

• Majority of these are involved in sensory perception and the

remaining receptors regulate various physiological functions

including nerve activity, tension of smooth muscle, metabolism,

rate and force of cardiac contraction, and the glandular secretion.

• GPCRs are the targets for many drugs; perhaps half of all non-

antibiotic prescription drugs act at these receptors.

Netter’s illustrated pharmacology

Selected G Protein Coupled Receptor/Ligands

Hormones

Thyroid hormoneParathyroid hormoneFSH

VasopressinLHACTHGlucagon

Autocoids:

Histamine5-HT

LeukotrienesBradykinin

Autonomic Nervous Control:

Muscarinic Cholinergic Receptors EpinephrineOthers:

Angiotensin Melatonin

Adenosine Dopamine

Glutamate Neuropeptide Y

GABA Somatostatins

Opioids

Structure:

GPCRs share a common

structural signature of

seven hydrophobic

transmembrane

segments, with an

extracellular amino

terminus and an

intracellular carboxyl

terminusNetter’s illustrated pharmacology

Netter’s illustrated Pharmacology

A:Rhodopsin family:

Short extracellular (N terminal) tail. Ligand binds to transmembrane helices (amines) or to extracellular loops (peptides)

The largest group.

Receptors for most• amine neurotransmitters, • many neuropeptides,• purines• prostanoids• cannabinoids

B:Secretin/glucagon receptor family:

Receptors for peptide hormones• secretin• glucagon• calcitonin

Intermediate extracellular tail incorporating ligand-binding domain

C:Metabotropic glutamate receptor/ calcium sensor family

Smallest group • Metabotropic glutamate receptors• GABAB receptors• Ca2+-sensing receptors

Long extracellular tail incorporating ligand-binding domain

The transducer mechanism

Ligand receptor interaction

Second Messenger pathway

Protein activation

Rang et al: Rang & Dale’s Pharmacology 7e

G-protein subunits with second messenger

β γ α

Gs Gi Gq

cAMP stimulationβ receptorHistamineSerotoninDopamine

cAMP inhibitionα2 receptorM2 receptorOpioid receptorD2 receptor5HT1 receptor

PLC(IP3 & DAG)α1

M1

AT1

5HT2

Vasopressin

•Activate potassium channels• Inhibit voltage-gated calcium channels• Activate mitogen-activated protein kinase cascade.

The adenylyl cyclase system • cAMP is a nucleotide

• Synthesized within the cell from ATP by membrane-bound, adenylyl cyclase

• Produced continuously

• Inactivated by hydrolysis to 5´-AMP, by the Phosphodiesterase

• Common mechanism, namely the activation of protein kinases

Effect of Glycogen on the muscle cell


Netter’s illustrated pharmacology

Phosphodiesterase

Theophylline

Caffine

Rolipram

Sildenafil

Phospholipase-c signaling system

PIP2

IP3 DAG

Release of Ca+2

from ER

intracellular Ca+2

Along with Ca+2 Activate Protein Kinase-C

Cellular functions- Proliferation, differentiation, apoptosis, cytoskeletal Remodeling, vesicular trafficking, ion channels conductance,neurotransmission

PLC

Targets that act through PLC and IP3

Acetylcholine M1 Glutamate Platelet derived growth factor

Angiotensin II Vasopressin Serotonin 5 HT 2C

Oxytocin Histamine H1 GnRH

α1 Adrenergic agonist


Effect of Toxins

Gαs Activated by cholera toxin which blocks GTPase activity

Gαi Blocked by pertussis toxin and prevents dissociation of αβϒ complex

Gαo? Blocked by pertussis toxin


G protein gated Ion Channels

• G-protein-coupled receptors can control ion channel function directly.

(A) Typically, the activated effector protein begins a signaling cascade which leads to the eventual opening of the ion channel.

(B) The GTP-bound α-subunit in some cases can directly activate the ion channel.

(C) In other cases, the activated βγ-complex of the G protein may interact with the ion channel.

Increase Ca++ Decrease Ca++ Increase K+

Adrenergic β1 (Heart) Dopamine D2 Adrenergic α2

Adenosine A1 Muscarinic M2

GABA-B Dopamine D2

Somatostatin 5-HT 1A

Opioid K GABA B

Receptor desensitization

Often, the effect of a drug gradually diminishes when it is given continuously or repeatedly• change in receptors • translocation of receptors • exhaustion of mediators • increased metabolic degradation of the drug • physiological adaptation • active extrusion of drug from cells

Recent advances

Orphan GPCRs

• 200 or so known GPCRs whose endogenous ligands and functions are not known

• Attempts have been made to deorphanise these receptors

• Evidence that some recently deorphanised GPCRs, such as orexin receptor, may dimerise or associate with more classical GPCRs

British Journal of Pharmacology (2008) 153 S339–S346

GPCR mutations, disease and novel drug discovery

• Loss of function mutations in GPCRs involved in the control of endocrine systems

• Gain of function mutations in GPCRs also cause disease

• Mutations in GPCRs could be responsible for variations in drug sensitivities among different populations

g protein coupled receptor

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