G protein GTPase-activating proteins: Regulation of speed, amplitude, and signaling selectivity

Numerous hormones of every chemical class use G protein-mediated signaling pathways to convey information from their receptors on the cell surface to the effector proteins that propagate these signals within the target cell. G proteins convey information from receptor to effector by traversing a controlled cycle of activation deactivation. When a receptor binds hormone, it promotes the binding of GTP to a select subset of the G proteins on the inner face of the plasma membrane. GTP binding activates these G proteins and allows them in turn to activate one or more effector proteins. G protein activation is terminated when a G protein hydrolyzes bound GTP to GDP; GDP remains bound but does not activate (for review see Kaziro et al., 1991). Cells use this basic pathway - receptor → G protein → effector - to form a complex information-processing network in the plasma membrane (Fig. 1). A cell responds to selected hormones by expressing appropriate receptors, which may be highly selective for a single G protein or may activate multiple G proteins. Expression of receptor isoforms that are selective for different G proteins can generate diverse cellular signals in response to a single hormone. At the next level in the network, a G protein (some cells express six or more) may respond to several different receptors, one G protein may activate or inhibit one or more of at least a dozen effector proteins. Effectors include enzymes that generate or degrade second messengers (adenylyl cyclase, cyclic GMP phosphodiesterase, phosphoinositide-specific phospholipase C-βs), ion channels (for Na⁺, Ca²⁺, or K⁺), and, probably, transport proteins. As at the previous two levels, effector isoforms respond selectively to distinct G proteins. G protein networks are thus analog computers that propagate an array of cellular signals in response to stimulatory and inhibitory hormones in the milieu of the target cell.