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G protein-coupled receptors remain the single largest group of “druggable” proteins that continue to find tremendous utility in academic lab and pharmaceutical company drug-discovery programs. In 1994, Siderovski was the first to report the sequencing of a “Regulator of G protein Signaling” (RGS protein): 'G0/G1-switch gene-8' or G0S8 (subsequently renamed RGS2). Before the discovery of RGS proteins, the duration of heterotrimeric G-protein signaling was thought to be controlled solely by the intrinsic GTP hydrolysis rate of the G-alpha subunit. What Siderovski originally identified as the G0S8-homology ("GH") domain in proteins from several eukaryotic genomes (human, Drosophila melanogaster, Caenorhabditis elegans, Saccharomyces cerevisiae) is now known as the "RGS domain", a 130 amino-acid domain that contacts G-alpha switch regions to stabilize the transition state, thus accelerating GTP hydrolysis (i.e., RGS proteins act as GTPase-accelerating proteins or "GAPs" for G-alpha-GTP). Discovery of a superfamily of RGS domain-containing proteins that negatively regulate G-alpha-dependent signaling resolved a prior paradox that GPCR-stimulated signals are seen to terminate much faster in vivo than predicted from the slow GTP hydrolysis rates exhibited by purified G-alpha subunits in vitro. RGS proteins are now considered key desensitizers of heterotrimeric G protein signaling and, as such, as new drug discovery targets.
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Enzymatic Screen for RGS Protein Modulators
Siderovski, D. & SIDEROVSKI, D. P.
National Institute on Drug Abuse
1/05/10 → 30/04/12
Project: Research
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Structural Determinants of Heterotrimeric G-protein Nucleotide Cycling
Siderovski, D. & SIDEROVSKI, D. P.
National Institute of General Medical Sciences
1/08/08 → 31/07/13
Project: Research
Research output
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Contribution of HCN1 variant to sinus bradycardia: A case report
Yu, H., Gall, B., Newman, M., Hathaway, Q., Brundage, K., Ammer, A., Mathers, P., Siderovski, D. & Hull, R. W., Oct 2021, In: Journal of Arrhythmia. 37, 5, p. 1337-1347 11 p.Research output: Contribution to journal › Article › peer-review
Open Access -
Potential for Kappa-Opioid Receptor Agonists to Engineer Nonaddictive Analgesics: A Narrative Review
Kaski, S. W., White, A. N., Gross, J. D. & Siderovski, D. P., 1 Feb 2021, In: Anesthesia and analgesia. p. 406-419 14 p.Research output: Contribution to journal › Review article › peer-review
2 Scopus citations -
The stability of tastant detection by mouse lingual chemosensory tissue requires Regulator of G protein Signaling-21 (RGS21)
Schroer, A. B., Branyan, K. W., Gross, J. D., Chantler, P. D., Kimple, A. J., Vandenbeuch, A. & Siderovski, D. P., 2021, In: Chemical Senses. 46, bjab048.Research output: Contribution to journal › Article › peer-review
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Erratum: Regulation of T cell activation, anxiety, and male aggression by RGS2 (Proc. Natl. Acad. Sci. U.S.A. (2000) 97 (12272–12277) DOI: 10.1073/pnas.220414397)
Oliveira-Dos-Santos, A. J., Matsumoto, G., Snow, B. E., Bai, D., Houston, F. P., Whishaw, I. Q., Mariathasan, S., Sasaki, T., Wakeham, A., Ohashi, P. S., Roder, J. C., Barnes, C. A., Siderovski, D. P. & Penninger, J. M., 6 Oct 2020, In: Proceedings of the National Academy of Sciences of the United States of America. 117, 40, p. 25182 1 p.Research output: Contribution to journal › Comment/debate
Open Access -
Genetic deletion of Rgs12 in mice affects serotonin transporter expression and function in vivo and ex vivo
White, A. N., Gross, J. D., Kaski, S. W., Trexler, K. R., Wix, K. A., Wetsel, W. C., Kinsey, S. G., Siderovski, D. P. & Setola, V., Dec 2020, In: Journal of Psychopharmacology. 34, 12, p. 1393-1407 15 p.Research output: Contribution to journal › Article › peer-review
1 Scopus citations