Because G-protein coupled receptors (GPCRs) continue to represent excellent targets for the discovery and development of small-molecule therapeutics, it is posited that additional protein components of the signal transduction pathways emanating from activated GPCRs themselves are attractive as drug discovery targets. This review considers the drug discovery potential of two such components: mem...

RGS14 is a 60 kDa protein that contains a regulator of G protein signaling (RGS) domain near its N-terminus, a central region containing a pair of tandem Ras-binding domains (RBD), and a GPSM (G protein signaling modulator) domain (a.k.a. Gi/o-Loco binding [GoLoco] motif) near its C-terminus. The RGS domain of RGS14 exhibits GTPase accelerating protein (GAP) activity toward Gαi/o proteins, whil...

The bifunctional protein RGS14 is both a GTPase activating protein (GAP) for GiR and GoR and a guanine nucleotide dissociation inhibitor (GDI) for GiR. This GDI activity is isolated to a region of the protein distinct from the RGS domain that contains an additional G protein-binding domain (RBD/ GL). Here, we report that RGS14 missing its RGS domain (R14-RBD/GL) binds directly to Go and Gi to m...

Regulators of G protein signaling (RGS) accelerate intrinsic GTP hydrolysis on alpha subunits of trimeric G proteins and play crucial roles in the physiological regulation of G protein-mediated cell signaling. The control mechanisms of the action of RGS proteins per se are poorly clarified, however. We recently showed a physiological mode of action of a RGS protein in cardiac myocytes. The volt...

Regulators of G protein signaling (RGS) proteins of the R7 subfamily limit signaling by neurotransmitters in the brain and by light in the retina. They form obligate complexes with the Gβ5 protein that are subject to proteolysis to control their abundance and alter signaling. The mechanisms that regulate this proteolysis, however, remain unclear. We used genetic screens to find mutations in Gβ5...

Regulators of G protein signaling (RGS) proteins are potent negative modulators of G protein signaling and have been proposed as potential targets for small-molecule inhibitor development. We report a high-throughput time-resolved fluorescence resonance energy transfer screen to identify inhibitors of RGS4 and describe the first reversible small-molecule inhibitors of an RGS protein. Two closel...

Regulators of G protein signaling (RGS) proteins limit the lifetime of activated (GTP-bound) heterotrimeric G protein a subunits by acting as GTPase-activating proteins (GAPs). Mutation of two residues in RGS4, which, based on the crystal structure of RGS4 complexed with G(i alpha1)-GDP-AIF4-, directly contact G(i alpha1) (N88 and L159), essentially abolished RGS4 binding and GAP activity. Muta...

Regulator of G protein signaling (RGS) proteins act to temporally modulate the activity of G protein subunits after G protein-coupled receptor activation. RGS proteins exert their effect by directly binding to the activated Galpha subunit of the G protein, catalyzing the accelerated hydrolysis of GTP and returning the G protein to its inactive, heterotrimeric form. In previous studies, we have ...

Heterotrimeric G proteins of the G12 family regulate the Rho GTPase through RhoGEFs that contain an amino-terminal regulator of G protein signaling (RGS) domain (RGS-RhoGEFs). Direct regulation of the activity of RGS-RhoGEFs p115 or leukemia-associated RhoGEF (LARG) by Galpha13 has previously been demonstrated. However, the precise biochemical mechanism by which Galpha13 stimulates the RhoGEF a...

The regulator of G protein signaling (RGS) proteins are a family of guanosine triphosphatase (GTPase)-accelerating proteins. We have discovered a novel function for RGS2 in the control of protein synthesis. RGS2 was found to bind to eIF2Bepsilon (eukaryotic initiation factor 2B epsilon subunit) and inhibit the translation of messenger RNA (mRNA) into new protein. This effect was not observed fo...