Figure 1. The G-protein GTPase cycle. Potential sites for disease-causing abnormalities are numbered. Under physiological conditions, effector regulation by G-protein subunits is transient and is terminated by the GTPase activity of the subunit. The latter converts bound GTP to GDP, thus returning the subunit to its inactivated state with high affinity for the dimer, which reassociates again to form the heterotrimer. In the figure, the G protein shown is Gs with its effector, adenylyl cyclase. Activation of adenylyl cyclase generates the intracellular second messenger, cAMP, which activates protein kinase A (PKA). The latter enzyme phosphorylates a variety of proteins that mediate the physiological effects of agonists for Gs-coupled receptors. Cholera toxin covalently modifies the Gs- subunit (_s) blocking its GTPase activity. Somatic mutations of the Gs- subunit likewise block GTPase activity. In both cases, constitutive activation and agonist-independent cAMP formation result. In each case the top of the plasma membrane represents the outside of the cell and the bottom the inside.