This Article Full Text Full Text (PDF) Supplemental Data Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via Google Scholar Google Scholar Articles by White, C. D. Articles by Lu, Z.-L. Search for Related Content PubMed PubMed Citation Articles by White, C. D. Articles by Lu, Z.-L.

A Crucial Role for G_q/11, But Not G_i/o or G_s, in Gonadotropin-Releasing Hormone Receptor-Mediated Cell Growth Inhibition

The Medical Research Council Human Reproductive Sciences Unit (C.D.W., M.C., K.M., R.P.M., Z.-L.L.), The Queen’s Medical Research Institute, Edinburgh EH16 4TJ, United Kingdom; The School of Physiology (C.A.F.), The University of Witwatersrand Medical School, Parktown, Johannesburg 2193, South Africa; and Receptor Biology Group (M.C., C.A.F., R.P.M.), Institute for Infectious Diseases and Molecular Medicine, Division of Medical Biochemistry, University of Cape Town, Observatory 7925, South Africa

Address all correspondence and requests for reprints to: Zhi-Liang Lu, The Medical Research Council Human Reproductive Sciences Unit, The Queen’s Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, United Kingdom. E-mail: z.lu{at}hrsu.mrc.ac.uk.

GnRH acts on its cognate receptor in pituitary gonadotropes to regulate the biosynthesis and secretion of gonadotropins. It may also have direct extrapituitary actions, including inhibition of cell growth in reproductive malignancies, in which GnRH activation of the MAPK cascades is thought to play a pivotal role. In extrapituitary tissues, GnRH receptor signaling has been postulated to involve coupling of the receptor to different G proteins. We examined the ability of the GnRH receptor to couple directly to G_q/11, G_i/o, and G_s, their roles in the activation of the MAPK cascades, and the subsequent cellular effects. We show that in G_q/11-negative cells stably expressing the GnRH receptor, GnRH did not induce activation of ERK, jun-N-terminal kinase, or P38 MAPK. In contrast to G_i or chimeric G_qi5, transfection of G_q cDNA enabled GnRH to induce phosphorylation of ERK, jun-N-terminal kinase, and P38. Furthermore, no GnRH-mediated cAMP response or inhibition of isoproterenol-induced cAMP accumulation was observed. In another cellular background, [³⁵S]GTPS binding assays confirmed that the GnRH receptor was unable to directly couple to G_i but could directly interact with G_q/11. Interestingly, GnRH stimulated a marked reduction in cell growth only in cells expressing G_q, and this inhibition could be significantly rescued by blocking ERK activation. We therefore provide direct evidence, in multiple cellular backgrounds, that coupling of the GnRH receptor to G_q/11, but not to G_i/o or G_s, and consequent activation of ERK plays a crucial role in GnRH-mediated cell death.