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Review ArticleReview Article

Regulators of G-Protein Signaling and Their Gα Substrates: Promises and Challenges in Their Use as Drug Discovery Targets

Adam J. Kimple, Dustin E. Bosch, Patrick M. Giguère and David P. Siderovski
Arthur Christopoulos, ASSOCIATE EDITOR
Pharmacological Reviews September 2011, 63 (3) 728-749; DOI: https://doi.org/10.1124/pr.110.003038
Adam J. Kimple
Department of Pharmacology, UNC Neuroscience Center, and Lineberger Comprehensive Cancer Center, the University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina
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Dustin E. Bosch
Department of Pharmacology, UNC Neuroscience Center, and Lineberger Comprehensive Cancer Center, the University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina
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Patrick M. Giguère
Department of Pharmacology, UNC Neuroscience Center, and Lineberger Comprehensive Cancer Center, the University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina
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David P. Siderovski
Department of Pharmacology, UNC Neuroscience Center, and Lineberger Comprehensive Cancer Center, the University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina
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Arthur Christopoulos
Department of Pharmacology, UNC Neuroscience Center, and Lineberger Comprehensive Cancer Center, the University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina
Roles: ASSOCIATE EDITOR
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Abstract

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: members of the “regulators of G-protein signaling” (RGS protein) superfamily, as well as their substrates, the heterotrimeric G-protein α subunits. Highlighted are recent advances, stemming from mouse knockout studies and the use of “RGS-insensitivity” and fast-hydrolysis mutations to Gα, in our understanding of how RGS proteins selectively act in (patho)physiologic conditions controlled by GPCR signaling and how they act on the nucleotide cycling of heterotrimeric G-proteins in shaping the kinetics and sensitivity of GPCR signaling. Progress is documented regarding recent activities along the path to devising screening assays and chemical probes for the RGS protein target, not only in pursuits of inhibitors of RGS domain-mediated acceleration of Gα GTP hydrolysis but also to embrace the potential of finding allosteric activators of this RGS protein action. The review concludes in considering the Gα subunit itself as a drug target, as brought to focus by recent reports of activating mutations to GNAQ and GNA11 in ocular (uveal) melanoma. We consider the likelihood of several strategies for antagonizing the function of these oncogene alleles and their gene products, including the use of RGS proteins with Gαq selectivity.

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  • This article is available online at http://pharmrev.aspetjournals.org.

    doi:10.1124/pr.110.003038.

  • © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Pharmacological Reviews: 63 (3)
Pharmacological Reviews
Vol. 63, Issue 3
1 Sep 2011
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Review ArticleReview Article

Regulators of G-Protein Signaling and Their Gα Substrates: Promises and Challenges in Their Use as Drug Discovery Targets

Adam J. Kimple, Dustin E. Bosch, Patrick M. Giguère and David P. Siderovski
Pharmacological Reviews September 1, 2011, 63 (3) 728-749; DOI: https://doi.org/10.1124/pr.110.003038

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Review ArticleReview Article

Regulators of G-Protein Signaling and Their Gα Substrates: Promises and Challenges in Their Use as Drug Discovery Targets

Adam J. Kimple, Dustin E. Bosch, Patrick M. Giguère and David P. Siderovski
Pharmacological Reviews September 1, 2011, 63 (3) 728-749; DOI: https://doi.org/10.1124/pr.110.003038
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  • Article
    • Abstract
    • I. Introduction
    • II. Selected Functional Vignettes among the Complement of Regulators of G-Protein Signaling
    • III. Pursuing Chemical Probes for Regulators of G-Protein Signaling GTPase-Accelerating Protein Activity
    • IV. Activated Gαq/11 Point Mutants as Targets for Ocular Melanoma Therapeutic Strategies
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