Cellular regulation of RGS proteins: Modulators and integrators of G protein signaling

Regulators of G protein signaling (RGS) and RGS-like proteins are a family (>30 members) of highly diverse, multifunctional signaling proteins that bind directly to activated Galpha subunits. Family members are defined by a shared RGS domain, which is responsible for Galpha binding and markedly stimulates the GTPase activity of Galpha subunits leading to their deactivation and termination of downstream signals. Although much has been learned in recent years about the biochemistry of RGS/Galpha interactions, considerably less is known about the broader cellular roles and regulation of RGS proteins. Recent findings indicate that cellular mechanisms such as covalent modification, alternative gene splicing, and protein processing can dictate the activity and subcellular localization of RGS proteins. Many family members also directly link G proteins to a growing list of signaling proteins with diverse cellular roles. New findings indicate that RGS proteins act not as dedicated inhibitors but, rather, as tightly regulated modulators and integrators of G protein signaling. In some cases, RGS proteins modulate the lifetime and kinetics of both slow-acting (e.g., Ca2+ oscillations) and fast-acting (e.g., ion conductances, phototransduction) signaling responses. In other cases, RGS proteins integrate G proteins with signaling pathways linked to such diverse cellular responses as cell growth and differentiation, cell motility, and intracellular trafficking. These and other recent studies with animal model systems indicate that RGS proteins play important roles in both physiology and disease. Recognition of the central functions these proteins play in vital cellular processes has focused our attention on RGS proteins as exciting new candidates for therapeutic intervention and drug development.