GPCR–G protein activation cycle. (I) Membrane-bound GDP bound Gα:βγ adjacent to GPCR, prior to R–G complex formation. (II) Interaction between agonist bound GPCR and G protein, with C-terminus of Gα inserted into the GPCR hydrophobic core. GPCR and Gβγ catalyze the release of GDP. (III) Binding of GTP to Gα induces a conformational change resulting in dissociation of Gα and Gβγ from each other and from GPCR. (IV) Gα and Gβγ regulate membrane-bound and cytosolic effectors. Intrinsic GTPase activity of Gα, aided by RGS proteins, causes GDP bound Gα to reassociate with Gβγ and relocate to the membrane as in I to repeat the cycle. The grey area indicates the points in the cycle which are addressed by the model.