GTPase-Activating Proteins for Heterotrimeric G Proteins: Regulators of G Protein Signaling (RGS) and RGS-Like Proteins

Abstract

GTPase-activating proteins (GAPs) regulate heterotrimeric G proteins by increasing the rates at which their subunits hydrolyze bound GTP and thus return to the inactive state. G protein GAPs act allosterically on G subunits, in contrast to GAPs for the Ras-like monomeric GTP-binding proteins. Although they do not contribute directly to the chemistry of GTP hydrolysis, G protein GAPs can accelerate hydrolysis >2000-fold. G protein GAPs include both effector proteins (phospholipase C-¿, p115RhoGEF) and a growing family of regulators of G protein signaling (RGS proteins) that are found throughout the animal and fungal kingdoms. GAP activity can sharpen the termination of a signal upon removal of stimulus, attenuate a signal either as a feedback inhibitor or in response to a second input, promote regulatory association of other proteins, or redirect signaling within a G protein signaling network. GAPs are regulated by various controls of their cellular concentrations, by complex interactions with G¿ or with G¿5 through an endogenous G-like domain, and by interaction with multiple other proteins.

Association of RGS2 Gene Polymorphisms with Suicide and Increased RGS2 Immunoreactivity in the Postmortem Brain of Suicide Victims

“…More than 30 mammalian RGS family members have been identified (Ross and Wilkie, 2000). Their primary functions are to act as GTPase-activating proteins that negatively regulate signaling by G proteincoupled receptors, such as serotonin, by accelerating GTP hydrolysis of the Ga subunit.…”

RGSZ1 and GAIP Regulate μ- but Not δ-Opioid Receptors in Mouse CNS: Role in Tachyphylaxis and Acute Tolerance

“…Also, its long N terminus comprises a phosphotyrosine-binding (PTB) domain plus a PDZ (PSD-95 (mammalian postsynaptic density protein), Dlg (drosophila disc-large protein), ZO-1 (a mammalian tight junction protein)) domain. The Rz subfamily includes RGS17 (Z2), Ga interacting protein (GAIP), RGSZ1, and retinal RET-RGS1 (Ross and Wilkie, 2000). The Gai/o subunits are moderately acidic (pI 5.2-5.7) with a net negative charge at physiological pH.…”

“…Flanking the RGS box domain they have an N terminus with a heavily palmitoylated cysteine string motif involved in membrane targeting (De Vries et al, 1996), and a short C terminus of 11 or 12 amino-acid residues. GAIP also has an amphipathic helix at the N terminus and a PDZ binding motif at the C terminus (De Vries et al, 1998a;Ross and Wilkie, 2000). The PDZ-binding motif of the GAIP C terminus interacts specifically with the PDZ domain of GIPC (GAIP interacting protein C-terminus) (De Vries et al, 1998b).…”

The R7 Subfamily of RGS Proteins Assists Tachyphylaxis and Acute Tolerance at μ-Opioid Receptors

“…Based on this domain, the mammalian RGS proteins have been grouped into five subfamilies, RZ, R4, R7, R12, and RA (Ross and Wilkie, 2000). The members of the R7 subfamily, RGS6, RGS7, RGS9, and RGS11 are similarly organized.…”

“…However, the selectivity of RGS proteins towards certain receptors has been substantiated, although it is unknown whether this occurs by direct interaction of the RGS to the receptor, by subcellular localization, or by the influence of distinct activating properties of the receptors on the G-proteins (see eg Ross and Wilkie, 2000). The sequence identity and presence of R7 proteins in CNS suggest a homologous modulatory role on intracellular signals originating at opioid receptors.…”