RGS2: a multifunctional regulator of G-protein signaling

doi:10.1016/S1357-2725(01)00141-8

The International Journal of Biochemistry & Cell Biology

Volume 34, Issue 5, May 2002, Pages 432-438

https://doi.org/10.1016/S1357-2725(01)00141-8 Get rights and content

Abstract

Regulators of G-protein signaling (RGS) proteins enhance the intrinsic rate at which certain heterotrimeric G-protein α-subunits hydrolyze GTP to GDP, thereby limiting the duration that α-subunits activate downstream effectors. This activity defines them as GTPase activating proteins (GAPs). As do other RGS proteins RGS2 possesses a 120 amino acid RGS domain, which mediates its GAP activity. In addition, RGS2 shares an N-terminal membrane targeting domain with RGS4 and RGS16. Found in many cell types, RGS2 expression is highly regulated. Functionally, RGS2 blocks Gqα-mediated signaling, a finding consistent with its potent Gqα GAP activity. Surprisingly, RGS2 inhibits Gs signaling to certain adenylyl cyclases. Like other RGS proteins, RGS2 lacks Gsα GAP activity, however it directly inhibits the activity of several adenylyl cyclase isoforms. Targeted mutation of RGS2 in mice impairs anti-viral immunity, increases anxiety levels, and alters synaptic development in hippocampal CA1 neurons. RGS2 has emerged as a multifunctional RGS protein that regulates multiple G-protein linked signaling pathways.

Introduction

Many extracellular stimuli elicit physiological responses in target tissues by activating receptors that couple to heterotrimeric G-proteins. Activated receptors trigger Gα subunits to exchange GTP for GDP resulting in the dissociation of the Gα subunit from the βγ heterodimers and the subsequent activation of downstream effectors. The duration that Gα subunits remain GTP bound is limited because Gα subunits possess an intrinsic GTPase activity. Once the Gα-subunits hydrolyze GTP to GDP, the heterotrimer reforms thereby terminating signaling. Thus, heterotrimeric G-proteins behave as molecular switches, which coordinate the transfer of information from environmental signals to the cell interior [1].

Cells possess another important mechanism that limits the duration that Gα subunits remain GTP bound. Members of the regulator of G-protein signaling (RGS) protein family dramatically increase the intrinsic rate at which Gα subunits hydrolyze GTP to GDP, a property that defines them as GTPase activating proteins or GAPs. Genetic studies in yeast, Caenorhabditis elegans, and Aspergillus nidulans first identified such proteins, which quantitatively limited heterotrimeric G-protein signaling in those organisms. Independently, a mammalian protein termed GAIP was discovered to interact with a Gα subunit and four mammalian RGS protein were shown to substitute for Sst2p, a yeast RGS protein. Approximately, 25 human RGS proteins have now been identified by polymerase chain reaction with degenerative primers and by genome and EST database searches [2], [3].

When tested in standard in vitro GAP assays, most RGS proteins possess GAP activity for members of the Gi (Giα1-3, Goα, Gzα, Gtα, and Ggustα) and Gq (Gqα, G11α, G14α, and G16α) subfamilies. While some RGS proteins selectively accelerate the GTPase actitvity of specific Gα subfamily members, others are surprisingly promiscuous. In contrast, the Rho guanine nucleotide exchange factors, which have a divergent RGS domain, selectively act as GAPs for G12α and G13α. A RGS protein that regulates Gsα or Golfα mediated GTP hydrolysis has not been reported [2], [3].

RGS2-like other members of the RGS protein family possesses a 120 amino acid domain that mediates its GAP activity and the interaction with Gα subunits. It is a 211 amino acid protein whose cDNA was first identified in a screen for activation genes in human lymphocytes [4]. Originally named G0S8 following the establishment of the RGS nomenclature, it was renamed RGS2.

Section snippets

RGS2 structure

The RGS protein family can be broadly divided into two groups, those composed predominantly of an RGS domain with small N-terminal and C-terminal extensions, and those that possess multiple other domains besides their RGS domain. RGS2-like RGS1, RGS4, RGS5, RGS10, RGS13, RGS16, RGS18, and RGS-GAIP, falls into the small subfamily. These RGS proteins have little or no affinity for Gα-GDP complexes. Rather they bind with high affinity to Gα subunit complexed with GDP and AlF4, which induces a

Regulation of RGS2 expression

Northern blot analysis of the distribution of RGS2 mRNA transcripts indicates wide spread expression. In situ hybridization studies localizes RGS2 mRNA in the cerebral cortex layers, several thalamic and hypothalamic nuclei and hindbrain regions [9]. Injection of cocaine or amphetamine increases RGS2 mRNA expression in rat striatum suggesting a role for dopamine receptors in the regulation of RGS2 expression in the brain. Ovarian stimulation by LH increases RGS2 mRNA transcripts and in situ

RGS2 biological functions

A whole series of studies indicate that RGS2 potently interferes with signaling through receptors that couple to Gqα. Most of these studies have relied on the over-expression of RGS2 and utilized either an endogenous receptor or a co-expressed receptor. Following receptor activation, the activation of phospholipase C, intracellular Ca²⁺ mobilization, or ion channel activity was monitored in the presence or absence of RGS2. The results of many of these studies are summarized in Table 1

Conclusions

RGS proteins can set thresholds for the activation of heterotrimeric G-proteins, function as feedback inhibitors, sharpen signal termination following stimulus removal, and interact with other components in G-protein signaling pathways. Recent studies have elucidated some of the biochemical pathways and physiological processes regulated by RGS proteins. One of these proteins, RGS2, potently inhibits signaling through receptors that couple to Gq and substantially inhibits the activation of

Acknowledgements

The author would like to thank Ms. Mary Rust for her editorial assistance and Dr. Anthony Fauci for his continued support.

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Published by Elsevier Ltd.

Molecules in focusRGS2: a multifunctional regulator of G-protein signaling

Abstract

Introduction

Section snippets

RGS2 structure

Regulation of RGS2 expression

RGS2 biological functions

Conclusions

Acknowledgements

Immunity

Cell.

J. Biol. Chem.

J. Biol. Chem.

Brain Res. Mol. Brain. Res.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Immunity

Neuropharmacology

J. Biol. Chem.

J Biol Chem.

G-proteins: transducers of receptor-generated signals

Annu. Rev. Biochem.

GTPase-activating proteins for heterotrimeric G-proteins: regulators of G-protein signaling (RGS) and RGS-like proteins

Annu. Rev. Biochem.

Molecules in focus
RGS2: a multifunctional regulator of G-protein signaling