GPCRcascades

GPCR cascades refer to the signaling networks triggered when a G protein-coupled receptor binds its ligand and transduces the signal to intracellular effectors via heterotrimeric G proteins. These cascades connect extracellular cues to diverse cellular responses, ranging from metabolism to gene expression.

Core components include GPCRs, G proteins (Gs, Gi/o, Gq/11, G12/13), effector enzymes such as adenylyl cyclase and phospholipase Cβ, second messengers (cAMP, IP3, DAG, Ca2+), and downstream kinases (PKA, PKC, CaMK) as well as MAP kinase cascades. Signaling is often amplified and compartmentalized by scaffold proteins and localized pools of second messengers.

Major pathways: Gs stimulates adenylyl cyclase increasing cAMP; Gi inhibits adenylyl cyclase; Gq stimulates PLCβ producing IP3 and DAG, which release Ca2+ and activate PKC. Beta-arrestins mediate receptor desensitization and can initiate alternative signaling such as MAPK activation independent of G proteins.

Regulation and dynamics: Desensitization via GPCR kinases (GRKs) and beta-arrestins; receptor internalization; termination of signaling; spatial aspects include localization to membrane microdomains. Temporal dynamics include rapid signaling peaks and slower, longer-lasting gene regulatory effects.

Physiological and pharmacological relevance: GPCR cascades govern senses such as vision and olfaction, autonomic and endocrine signaling, mood, pain, and cardiovascular control. Many drugs target these cascades; concepts like biased agonism recognize that different ligands stabilize distinct receptor conformations, favoring G protein or arrestin pathways, with important therapeutic implications.