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Roles of G_i and G_q/11 in Mediating Desensitization of the Luteinizing Hormone/Choriogonadotropin Receptor in Porcine Ovarian Follicular Membranes¹

Departments of Cell and Molecular Biology (R.M.R.-G., S.M.) and Molecular Pharmacology and Biological Chemistry (H.H.) and the Neuroscience Institute, Northwestern University Medical School, Chicago, Illinois 60611; Department of Pharmacology and the Neurobiotechnology Center, Ohio State University (X.Z.), Columbus, Ohio 43210; the Department of Anesthesiology, University of California School of Medicine (M.B., L.B.), Los Angeles, California 90095; and the Department of Biochemistry, University of Illinois (Y.-K.H.) Chicago, Illinois 60612

Address all correspondence and requests for reprints to: Dr. Mary Hunzicker-Dunn, Department of Cell and Molecular Biology, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, Illinois 60611. E-mail: mhd{at}nwu.edu

Although desensitization of most guanine nucleotide-binding (G) protein receptors is triggered by phosphorylation of the receptor, desensitization of the LH/CG receptor (-R) in porcine follicular ovarian membranes appears to be independent of LH/CG-R phosphorylation. We therefore evaluated whether desensitization of the LH/CG-R reflected a direct inhibition of adenylyl cyclase (AC) activity by either the -subunit of G_i or ß-subunits derived from any of the membrane G proteins activated in response to LH/CG-R activation or whether desensitization reflected a competition between G_s and a G protein that activated phospholipase C for binding sites on the LH/CG-R. The results showed that follicular membrane AC activity was not inhibited upon activation of the LH/CG-R despite evidence that the ACs in follicular membranes, when maximally activated by forskolin, could be inhibited when membrane G proteins were activated by guanyl-5'-yl imidodiphosphate, and that pertussis toxin pretreatment of membranes raised forskolin-stimulated AC activity, consistent with a tonic inhibition of follicular membrane AC activity. Similarly, agonist-stimulated desensitization of LH/CG-R-stimulated AC activity was not inhibited by pertussis toxin. Therefore, desensitization is not the result of inhibition of AC mediated by an inhibitory G_i subunit. Follicular membrane AC was also not inhibited by Gß subunits freed with activation of G_s, G_q/11, or G₁₃, based on the inabilities of exogenous Gß to promote desensitization and of a protein that sequesters Gß to inhibit desensitization. Desensitization was also not inhibited by a G_q/11 C-terminal peptide or antiserum directed toward the C-terminus of G_q/11, nor was it reversed with the addition of Gß to membranes exhibiting desensitized LH/CG-R, suggesting that desensitization is independent of coupling of the LH/CG-R to G_q/11. These results indicate that agonist-dependent desensitization of LH/CG-R-stimulated AC activity is mediated by a unique mechanism.

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