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Regulation of RGS3 and RGS10 Palmitoylation by GnRH

Oregon Regional Primate Research Center and Department of Physiology and Pharmacology (C.C.-F., J.A.J., S.P.B., P.M.C.), Oregon Health and Science University, Portland, Oregon 97201; Department of Pharmacology (R.A.F.), University of Iowa College of Medicine, Iowa City, Iowa 52242; and Department of Chemistry (T.H.J.), University of Kentucky, Lexington, Kentucky 40506

Address all correspondence and requests for reprints to: P. Michael Conn, 505 NW 185^th Avenue, Beaverton, Oregon 97006. E-mail: .

Regulators of G protein signaling (RGS) play a pivotal role in cellular signal transduction. RGS3 or RGS10 were overexpressed in GGH₃ cells [GH₃ cells stably expressing the GnRH receptor (GnRHR)]. Responsiveness to a GnRH agonist was assessed because RGS proteins attenuate production of inositol phosphates (IP) and/or cAMP, molecules believed to be involved in GnRH signaling. In addition, site-directed mutagenesis of a potentially palmitoylated Cys⁶⁰ residue of RGS10 was used to assess the significance of this site. We observed maximum inhibition of GnRH-stimulated IP responses by RGS3 and by the conserved domain of RGS10 at both 48 and 72 h after transfection, indicating their involvement in G_q mediated signaling. Significantly diminished cAMP production was observed at all times when cells overexpressed the conserved domain of RGS10; no effect was observed with RGS3 on G_s-mediated signaling. Palmitic acid incorporation into RGS3 was dependent on agonist occupancy of GnRHR, whereas palmitoylation of RGS10 was constitutive. Mutation of the conserved Cys⁶⁰ residue of RGS10 obviated its negative regulatory action on GnRH-stimulated responses, indicating that this site is crucial for its activity on this system. This study is the first demonstration of a role for palmitoylation of this conserved Cys⁶⁰ in mammalian G protein signaling.

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