(A) Functional cycle of a heterotrimeric G protein. In the resting state (left), heterotrimeric G proteins consist of α, β and γ subunits bound together. The α subunit is bound to a molecule of GDP, and the complex is anchored to the intracellular surface of the cell membrane. When a G protein-coupled receptor (GPCR) is activated by an agonist molecule binding to its extracellular surface, the heterotrimeric complex can interact with the cytosolic surface of the GPCR. Pertussis toxin (PTX) can inhibit this interaction. The molecule of GDP bound to the α subunit is released and a molecule of GTP binds in its place, causing the heterotrimer to dissociate into Gα-GTP and Gβγ subunits. Upon the breakdown of GTP to form GDP and phosphate (Pi), the heterotrimer reforms. (B) Signal transduction through the Gα subunit. Some classes of Gα activate (αs) or inhibit (αi) adenylyl cyclase (AC), the enzyme that produces the second messenger cyclic AMP (cAMP) by removing the terminal pyrophosphate (PPi) from ATP. Others (αq) activate the enzyme phospholipase C-β (PLC-β), which cleaves an important component of the plasma membrane's inner leaflet called phosphatidylinositol bisphosphate (PIP2), converting it into diacylglycerol (DAG) and inositol trisphosphate (IP3). (C) Signal transduction through the Gβγ subunit. Gβγ activates G-protein-gated inward rectifier K+ (GIRK) channels (left) but inhibits voltage-gated calcium ion channels (CaV; right). (D) TRPM3 channels are inhibited by direct binding of Gβγ.