- G protein-coupled receptor (GPCR) signaling represents one of the largest and most versatile signaling systems in eukaryotic cells. These receptors feature a characteristic seven-transmembrane domain structure and couple to heterotrimeric G proteins composed of α, β, and γ subunits.
- When a ligand binds to a GPCR, it triggers a conformational change that activates the associated G protein. This activation causes the Gα subunit to exchange GDP for GTP and dissociate from the Gβγ complex. Both the activated Gα and the free Gβγ complex can then interact with various effector proteins to initiate distinct signaling cascades.
- The major classes of Gα proteins (Gs, Gi, Gq, and G12/13) regulate different cellular responses. Gs proteins stimulate adenylyl cyclase to produce cAMP, while Gi proteins inhibit this enzyme. Gq proteins activate phospholipase C, leading to calcium release and protein kinase C activation. G12/13 proteins regulate Rho GTPases and affect cytoskeletal organization.
- Signal termination occurs through multiple mechanisms. The Gα subunit’s intrinsic GTPase activity hydrolyzes GTP to GDP, leading to reassociation with Gβγ. Additional regulation comes from RGS (Regulators of G protein Signaling) proteins, which accelerate GTP hydrolysis, and from receptor desensitization through phosphorylation by G protein-coupled receptor kinases (GRKs).
- GPCRs respond to an extraordinarily diverse range of signals including hormones, neurotransmitters, odors, light, and tastants. This versatility makes them major therapeutic targets – approximately one-third of all approved drugs act through GPCRs.
