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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 Gαq/11, Gαi/o, and Gαs, their roles in the activation of the MAPK cascades, and the subsequent cellular effects. We show that in Gαq/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 Gαi or chimeric Gαqi5, transfection of Gαq 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]GTPγS binding assays confirmed that the GnRH receptor was unable to directly couple to Gαi but could directly interact with Gαq/11. Interestingly, GnRH stimulated a marked reduction in cell growth only in cells expressing Gαq, 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 Gαq/11, but not to Gαi/o or Gαs, and consequent activation of ERK plays a crucial role in GnRH-mediated cell death.

A Crucial Role for Gαq/11, But Not Gαi/o or Gαs, in Gonadotropin-Releasing Hormone Receptor-Mediated Cell Growth Inhibition