RGS Proteins and Signaling by Heterotrimeric G Proteins*

A ubiquitously employed mechanism for signal transduction involves ligand binding to a cell surface receptor coupled to a heterotrimeric guanine nucleotide-binding protein (G protein). Receptor activation stimulates nucleotide exchange and dissociation of the G protein, releasing the Ga subunit in its GTP-bound state from the Gbg complex. The released subunits can stimulate a variety of target (effector) enzymes (1), thereby eliciting biochemical responses and changes in cellular physiology. Hundreds of G proteincoupled receptors have been identified (2, 3). These receptors share a common architecture containing seven membrane-spanning segments (4, 5). G proteins also comprise a superfamily that includes at least 17 distinct Ga (6), 5 Gb, and 6 Gg isoforms (1), allowing many combinatorial possibilities. Three-dimensional structures of several Ga subunits and two different Gabg heterotrimers (7, 8) have been determined, providing insights about how these molecular “switches” operate. How are the strength and duration of signaling adjusted to achieve an appropriate response? Attention in this regard has been devoted primarily to receptors, where phosphorylation by protein kinases (9) and receptor-binding proteins, like arrestins (10, 11), contribute to signal desensitization. However, additional proteins participate in signal attenuation at other levels, including phosducins (which act on Gbg) (12) and recoverins (13, 14). Here we focus on discovery of another superfamily of evolutionarily conserved proteins, dubbed RGS proteins, for “regulators of G protein signaling.” RGS proteins act as negative regulators of G proteindependent signaling, at least in part, because they stimulate hydrolysis of the GTP bound to activated Ga subunits.