GPCR downstream signalling

GPCRs are involved in many diverse signaling events, using a variety of pathways that include modulation of adenylyl cyclase, phospholipase C, the mitogen activated protein kinases (MAPKs), extracellular signal regulated kinase (ERK) c-Jun-NH2-terminal kinase (JNK) and p38 MAPK. Regulator of G-protein Signalling (RGS) proteins can directly inhibit the activity of the G-alpha subunit.

The general function of the G alpha-s subunit (Gs) is to activate adenylate cyclase, which in turn produces cyclic-AMP (cAMP), leading to the activation of cAMP-dependent protein kinases (often referred to collectively as Protein Kinase A). The signal from the ligand-stimulated GPCR is amplified because the receptor can activate several Gs heterotrimers before it is inactivated.

The classical signalling mechanism for G alpha-i (Gi) is inhibition of the cAMP dependent pathway through inhibition of adenylate cyclase. Decreased production of cAMP results in decreased activity of cAMP-dependent protein kinases.

G alpha-z (Gz) is a member of the Gi family. Unlike other Gi family members it is pertussis toxin-insensitive. Gz interacts with Rap1 GTPase activating protein (RAP1GAP) to attenuate Rap1 signaling.

The classic signalling route for G alpha-q (Gq) is activation of phospholipase C beta, leading to phosphoinositide hydrolysis, calcium mobilization and protein kinase C activation. This provides a path to calcium-regulated kinases and phosphatases, GEFs, MAP kinases and many other proteins.

The G-alpha-12/13 (G12/13) family is probably the least well characterized, at least in part because G12/13 coupling is more difficult to determine than for other subtypes, G12/13 is best known for involvement in the processes of cell proliferation and morphology, such as stress fiber and focal adhesion formation. Interactions with Rho guanine nucleotide exchange factors (RhoGEFs) are thought to mediate many of these processes. (Buhl et al.1995, Sugimoto et al. 2003). Activation of Rho or the regulation of events through Rho is often taken as evidence of G12/13 signaling. Receptors that are coupled with G12/13 invariably couple with one or more other G protein subtypes, usually Gq.