G Protein Coupled Receptor (GPCR); Structure and function || GPCR-cAMP Signaling Pathway Steps

GPCRs represent largest family of cell surface receptors targeted by 30-50% clinically used drugs. 

Ligands of GPCR

GPCR is capable of binding to diverse ligands, ranging from a single photon to large proteins and including ions, odorants, amines, peptides, lipids, hormones, nucleotides, and metabolic intermediates. GPCR control important functions like heart rate and blood pressure.

Structure of GPCR

G Protein Coupled Receptor (GPCR); Structure

  • GPCR is a single peptide with a cytosolic region, a ligand-binding extracellular region and 7 hydrophobic transmembrane helices 
  • (7TM receptors)  
  • The transmembrane domains are connected via three intracellular and three extracellular loops.

Why called as G protein coupled receptor?

This transmembrane receptor is associated with a GTP/GDP binding protein called G protein.

Structure of G protein

  • Trimeric (α, β, γ subunits)
  • α and β subunits have small lipid molecules that anchor them to inner layer of plasma membrane
  • GDP bound is the “off” state
  • On ligand binding, GDP is exchanged for GTP; thus GTP bound state is the “on” state
  • These subunits have many subclasses.
  • It is the Gα subunit that confers the name of the G protein. 
  • For instance, G proteins that stimulate an effector (e.g., adenylate cyclase) are classified as Gs (for stimulatory), whereas those that inhibit an effector are called Gi (for inhibitory).
Understand more: Diagram Quiz on Cell Signaling 

Steps in GPCRcAMP Pathway

GPCR-cAMP Signaling Pathway Steps

Step 1: GPCRs undergo conformational change upon ligand binding and binds to the G protein complex.

Step 2: G-α subunit exchanges GDP (guanosine diphosphate) for GTP (guanosine triphosphate). This causes the activation of G-α subunit.

Step 3: The active Gα subunit then separates from the β and γ subunits, and moves laterally in the membrane. Then activates adenylyl cyclase (AC), that converts ATP to cAMP. cAMP is a second messenger.

This video summarizes the structure; function and pathways of GPCR

Step 4: Elevated cAMP levels, then activate protein kinase A (PKA).

Step 5: PKA phosphorylates several enzymes and transcription factors downstream [e.g., cAMP-response element-binding protein (CREB)], causing gene expression that mediate cell growth and differentiation or changes important physiological functions.

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