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J. Biol. Chem., Vol. 279, Issue 25, 26314-26322, June 18, 2004

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RGS17/RGSZ2, a Novel Regulator of G_i/o, G_z, and G_q Signaling^*

Helen Mao, Qingshi Zhao¶, Mireille Daigle, Mohammad H. Ghahremani, Peter Chidiac¶||, and Paul R. Albert**

From the Department of Neuroscience, Ottawa Health Research Institute, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada and ^¶Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario N6A 5C1, Canada

To identify novel regulators of G_o, the most abundant G-protein in brain, we used yeast two-hybrid screening with constitutively active G_o as bait and identified a new regulator of G-protein signaling (RGS) protein, RGS17 (RGSZ2), as a novel human member of the RZ (or A) subfamily of RGS proteins. RGS17 contains an amino-terminal cysteine-rich motif and a carboxyl-terminal RGS domain with highest homology to hRGSZ1- and hRGS-G-interacting protein. RGS17 RNA was strongly expressed as multiple species in cerebellum and other brain regions. The interactions between hRGS17 and active forms of G_i1–3, G_o, G_z, or G_q but not G_s were detected by yeast two-hybrid assay, in vitro pull-down assay, and co-immunoprecipitation studies. Recombinant RGS17 acted as a GTPase-activating protein (GAP) on free G_i2 and G_o under pre-steady-state conditions, and on M2-muscarinic receptor-activated G_i1, G_i2, G_i3, G_z, and G_o in steady-state GTPase assays in vitro. Unlike RGSZ1, which is highly selective for G_z, RGS17 exhibited limited selectivity for G_o among G_i/G_o proteins. All RZ family members reduced dopamine-D2/G_i-mediated inhibition of cAMP formation and abolished thyrotropin-releasing hormone receptor/G_q-mediated calcium mobilization. RGS17 is a new RZ member that preferentially inhibits receptor signaling via G_i/o, G_z, and G_q over G_s to enhance cAMP-dependent signaling and inhibit calcium signaling. Differences observed between in vitro GAP assays and whole-cell signaling suggest additional determinants of the G-protein specificity of RGS GAP effects that could include receptors and effectors.

Received for publication, February 18, 2004 , and in revised form, April 9, 2004.

^* This research was supported by grants from the Ontario Mental Health Foundation (to P. R. A.) and the Canadian Institutes of Health Research (to P. R. A. and P. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

|| To whom correspondence should be addressed. Tel.: 519-661-3318; Fax: 519-661-3827; E-mail: peter.chidiac{at}fmd.uwo.ca. ^** To whom correspondence should be addressed. Tel.: 613-562-5800, ext. 8307; Fax: 613-562-5403; E-mail: palbert{at}uottawa.ca.

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