RGS Proteins and Signaling by Heterotrimeric G Proteins

Abstract

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 G␣ subunit in its GTP-bound state from the G␤␥ 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 G␣ (6), 5 G␤, and 6 G␥ isoforms (1), allowing many combinatorial possibilities. Three-dimensional structures of several G␣ subunits and two different G␣␤␥ 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 G␤␥) (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 G␣ subunits. The Cycle of G Protein Activation and InactivationActivation of a G protein is initiated by agonist binding to a receptor, eliciting conformational change that is transmitted to the G protein, causing the G␣ subunit to release GDP and to bind GTP ( Fig. 1). GTP binding alters the conformation of three "switch" regions in G␣ that are its primary contact sites with G␤␥, promoting subunit dissociation (7,8). Guanine nucleotide exchange can occur spontaneously, but is accelerated by agonist-activated receptor and retarded by G␤␥ binding. Thus, the receptor acts as a GDS, 1 whereas G␤␥ acts as a GDI (15).Inactivation requires hydrolysis of the GTP bound to G␣, shifting the equilibrium in favor of subunit reassociation, preventing further signaling. Purified G␣ subunits display a measurable intrinsic rate of GTP hydrolysis, but the turnover number in vitro cannot account, in some systems, for the rate at which signaling is terminated in vivo (16,17). Other regulatory processes (such as those mediated by arrestin or phosducin) could be rate-limiting. Nonetheless, the importance of GTP hydrolysis provoked a search for factors that accelerate the GTPase activity of G␣ subunits, termed GAPs (for "GTPase-activating proteins") (Fig. 1). Effector enzymes can serve this role: phospholipase C␤ stimula...

Isolation, tissue expression, and chromosomal assignment of human RGS5, a novel G-protein signaling regulator gene

“…Recently, novel regulatory molecules for these G-protein signaling pathways, termed RGS, have been identified (Koelle and Horvits 1996;Koelle 1997;Dohlman and Thorner 1997).…”

Plasma membrane localization is required for RGS4 function in Saccharomyces cerevisiae

“…A recently appreciated form of regulation has come from the discovery that members of a protein family called regulators of G protein signaling, or RGS proteins, stimulate the rate of GTP hydrolysis by G protein ␣ subunits (3)(4)(5). RGS proteins are found in species ranging from yeast to mammals and constitute a family of at least 20 mammalian proteins (6)(7)(8).…”

Differential effects of RGS proteins on Gαq and Gα11 activity

“…This is not surprising as many RGS proteins function against more than one Gα subunit and, in a reciprocal arrangement, several mammalian RGS proteins have been shown to act as GAPs for GPA1 in the Sc. cerevisiae pheromone-response pathway [6]. However, this is the first demonstration that the Sz.…”

“…Most studies use the pheromoneresponse pathway within the budding yeast Saccharomyces cerevisiae and have made a number of significant contributions to our understanding of GPCR signalling [5][6][7]. Although many components can be functionally replaced by their mammalian counterparts [8], few studies have reported the expression of non-yeast Gα proteins in Sc.…”