|Summary of probe development for inhibitors of the regulator of G-protein signaling 4 (RGS4) - BioAssay Summary
HTS execution: Joseph Babcock, Zhihong Lin Ph.D., Shunyou Long M.S., Xiaofang Huang M.S., Owen McManus Ph.D., and Meng Wu Ph.D. ..more
Depositor Specified Assays
Data Source: Johns Hopkins Ion Channel Center (JHICC_RGS4_inh_summary)
BioAssay Type: Summary
Source (MLPCN Center Name): Johns Hopkins Ion Channel Center (JHICC)
Center Affiliation: Johns Hopkins University, School of Medicine
Screening Center PI: Min Li, Ph.D.
Assay Provider: Richard Neubig, M.D., Ph.D. University of Michigan
Network: Molecular Libraries Probe Production Centers Network (MLPCN)
Grant Proposal Number: 1 R03 MH087441-01A1
Grant Proposal PI: Richard Neubig, M.D., Ph.D.
Assay Implementation: Zhihong Lin Ph.D., Joseph Babcock, Shunyou Long M.S., and Meng Wu Ph.D.
HTS execution: Joseph Babcock, Zhihong Lin Ph.D., Shunyou Long M.S., Xiaofang Huang M.S., Owen McManus Ph.D., and Meng Wu Ph.D.
Signal transduction pathways mediated by G protein-coupled receptors (GPCRs) are major therapeutic targets with many known pharmacologic modulators. The regulators of G protein signaling (RGS proteins) are a key family of modulators and scaffolds for GPCRs which have been identified by many authors as appealing drug targets [1-5]. RGS proteins bind to activated G proteins and strongly inhibit their signals by catalyzing the hydrolysis of bound GTP [6-7]. Consistent with this mode of action, genetic deletion of RGS greatly enhances receptor signaling [8-10]. Furthermore, RGS proteins display isoform-specific tissue distribution [11-14] and their expression is altered in pathophysiological states including Parkinson's disease , neuropathic pain [16-17], schizophrenia, hypertension, and congestive heart failure . An activator of RGS action would be expected to suppress the function of GPCR agonists such as vasoactivators, inflammatory mediators, endogenous neurotransmitters, or catecholamines such as L-DOPA. It has recently been established that loss of function of RGS2 causes hypertensive symptoms in mice  and may contribute to vasoactive disorders in humans as well [20-22]. Also, reduced expression of RGS4 has been correlated with schizophrenia [23-24]. Consequently, compounds that could either enhance the function of RGS proteins or could increase their expression might be of therapeutic benefit. The identification of selective modulators of RGS proteins would also greatly facilitate experimental studies of this sizeable protein family (with 20-30 members) by permitting rapid and specific chemical potentiation. Such RGS modulators would be particularly useful to determine which RGS proteins modulate particular receptor signaling pathways.
The goal of this project is to identify inhibitors of the regulator of G protein signaling 4 (RGS4), using a receptor-stimulated cell-based Ca++ assay.
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. Jeong, S.W., and Ikeda, S.R. 2000. Endogenous regulator of G-protein signaling proteins modify N-type calcium channel modulation in rat sympathetic neurons. J Neurosci 20:4489-4496. PMID: 10844018.
. Clark, M.J., Neubig, R.R., and Traynor, J.R. 2004. Endogenous regulator of G protein signaling proteins suppress Galphao-dependent, mu-opioid agonist-mediated adenylyl cyclase supersensitization. J Pharmacol Exp Ther 310:215-222. PMID: 15014136.
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. Tekumalla, P.K., Calon, F., Rahman, Z., Birdi, S., Rajput, A.H., Hornykiewicz, O., Di Paolo, T., Bedard, P.J., and Nestler, E.J. 2001. Elevated levels of DeltaFosB and RGS9 in striatum in Parkinson's disease. Biol Psychiatry 50:813-816. PMID: 11720701.
. Garnier, M., Zaratin, P.F., Ficalora, G., Valente, M., Fontanella, L., Rhee, M.H., Blumer, K.J., and Scheideler, M.A. 2003. Up-regulation of regulator of G protein signaling 4 expression in a model of neuropathic pain and insensitivity to morphine. J Pharmacol Exp Ther 304:1299-1306. PMID: 12604710.
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. Mittmann C, Chung CH, Hoppner G, Michalek C, Nose M, Schuler C, Schuh A, Eschenhagen T, Weil J, Pieske B, Hirt S, Wieland T. 2002. Expression of ten RGS proteins in human myocardium: functional characterization of an upregulation of RGS4 in heart failure. Cardiovasc Res 55:778-786. PMID: 12176127.
. Heximer SP, Knutsen RH, Sun X, Kaltenbronn KM, Rhee MH, Peng N, Oliveira-dos-Santos A, Penninger JM, Muslin AJ, Steinberg TH, Wyss JM, Mecham RP, Blumer KJ. 2003. Hypertension and prolonged vasoconstrictor signaling in RGS2-deficient mice. J Clin Invest 111:445-452. PMID: 12697745.
. Bodenstein, J., Sunahara, R.K., and Neubig, R.R. 2007. N-terminal residues control proteasomal degradation of RGS2, RGS4, and RGS5 in human embryonic kidney 293 cells. Mol Pharmacol 71:1040-1050. PMID: 17220356.
. Gu, S., Tirgari, S., and Heximer, S.P. 2008. The RGS2 gene product from a candidate hypertension allele shows decreased plasma membrane association and inhibition of Gq. Mol Pharmacol 73:1037-1043. PMID: 18230714.
. Yang J, Kamide K, Kokubo Y, Takiuchi S, Tanaka C, Banno M, Miwa Y, Yoshii M, Horio T, Okayama A, Tomoike H, Kawano Y, Miyata T. 2005. Genetic variations of regulator of G-protein signaling 2 in hypertensive patients and in the general population. J Hypertens 23:1497-1505. PMID: 16003176.
. Chowdari KV, Mirnics K, Semwal P, Wood J, Lawrence E, Bhatia T, Deshpande SN, B K T, Ferrell RE, Middleton FA, Devlin B, Levitt P, Lewis DA, Nimgaonkar VL. 2002. Association and linkage analyses of RGS4 polymorphisms in schizophrenia. Hum Mol Genet 11:1373-1380. PMID: 12023979.
. Mirnics, K., Middleton, F.A., Stanwood, G.D., Lewis, D.A., and Levitt, P. 2001. Disease-specific changes in regulator of G-protein signaling 4 (RGS4) expression in schizophrenia. Mol Psychiatry 6:293-301. PMID: 11326297.
RGS4, M3 receptor, HTS assay, 384, primary, antagonist, inhibitors, allosteric, FDSS, calcium, fluorescence, Kinetic, Fluo-4-AM, JHICC, Johns Hopkins, MLSMR, Molecular Libraries Probe Production Centers Network, MLPCN.