Biochemistry Questions Biochemistry Questions / Explain the role of GPCRs in signal transduction and how ligand binding leads to the activation of G proteins.

G-protein coupled receptors (GPCRs) play an important role in signal transduction, allowing extracellular ligand binding to activate intracellular G proteins, activating signalling pathways.

On ligand binding to the GPCR, a conformational change is induced in the connecting loop from transmembrane helix 5 to 6 - the binding site for the G protein. This conformational change causes the G protein to become active, dissociating from the GPCR by inducing the exchange of GDP for GTP. This causes the $$G_\alpha$$ subunit to dissociate, moving along the membrane and activating adenylyl cyclase. Adenylyl cyclase catalyses the conversion of ATP to cAMP, a second messenger signalling molecule. cAMP activates protein kinase A, which goes on to activate CREB through phosphorylation. Activated CREB recruits CREB-binding protein, allowing the complex to bind to cAMP response elements on the chromosome, upregulating transcription.

This allows the activation of signalling cascades from a low concentration of ligand binding to a GPCR. By activating this cascade, the amplification of the signal occurs, and this enables a larger response to be mounted. This allows ligands to be released at low concentrations but still allowing a large effect.