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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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Research Output
A role for Regulator of G protein Signaling-12 (RGS12) in the balance between myoblast proliferation and differentiation
Schroer, A. B., Mohamed, J. S., Willard, M. D., Setola, V., Oestreich, E. & Siderovski, D. P., 1 Jan 2019, In : PLoS ONE. 14, 8, e0216167.Research output: Contribution to journal › Article
Open Access
Chemerin-activated functions of CMKLR1 are regulated by G protein-coupled receptor kinase 6 (GRK6) and β-arrestin 2 in inflammatory macrophages
Serafin, D. S., Allyn, B., Sassano, M. F., Timoshchenko, R. G., Mattox, D., Brozowski, J. M., Siderovski, D. P., Truong, Y. K., Esserman, D., Tarrant, T. K. & Billard, M. J., Feb 2019, In : Molecular Immunology. 106, p. 12-21 10 p.Research output: Contribution to journal › Article
Four single nucleotide polymorphisms in genes involved in neuronal signaling are associated with opioid use disorder in West Virginia
Kaski, S. W., Brooks, S., Wen, S., Haut, M. W., Siderovski, D. P., Berry, J. H., Lander, L. R. & Setola, V., 1 Jan 2019, In : Journal of Opioid Management. 15, 2, p. 103-109 7 p.Research output: Contribution to journal › Article
Preclinical Testing of Nalfurafine as an Opioid-sparing Adjuvant that Potentiates Analgesia by the Mu Opioid Receptor-targeting Agonist Morphine
Kaski, S. W., White, A. N., Gross, J. D., Trexler, K. R., Wix, K., Harland, A. A., Prisinzano, T. E., Aubé, J., Kinsey, S. G., Kenakin, T., Siderovski, D. P. & Setola, V., 1 Jan 2019, In : Journal of Pharmacology and Experimental Therapeutics. 371, 2, p. 487-499 13 p.Research output: Contribution to journal › Article
Role of RGS12 in the differential regulation of kappa opioid receptor-dependent signaling and behavior
Gross, J. D., Kaski, S. W., Schmidt, K. T., Cogan, E. S., Boyt, K. M., Wix, K., Schroer, A. B., McElligott, Z. A., Siderovski, D. P. & Setola, V., 1 Sep 2019, In : Neuropsychopharmacology. 44, 10, p. 1728-1741 14 p.Research output: Contribution to journal › Article