The gonadotropin-releasing hormone (GnRH) is the master regulator of fertility and kisspeptin (KP) is a potent trigger of GnRH secretion from GnRH neurons. KP signals via KISS1R, a Gα_q/11-coupled receptor, and mice bearing a global deletion of Kiss1r (Kiss1r^−/−) or a GnRH neuron-specific deletion of Kiss1r (Kiss1r^d/d) display hypogonadotropic hypogonadism and infertility. KISS1R also signals via β-arrestin, and in mice lacking β-arrestin-1 or -2, KP-triggered GnRH secretion is significantly diminished. Based on these findings, we hypothesized that ablation of Gα_q/11 in GnRH neurons would diminish but not completely block KP-triggered GnRH secretion and that Gα_q/11-independent GnRH secretion would be sufficient to maintain fertility. To test this, Gnaq (encodes Gα_q) was selectively inactivated in the GnRH neurons of global Gna11 (encodes Gα₁₁)-null mice by crossing Gnrh-Cre and Gnaq^fl/fl;Gna11^−/− mice. Experimental Gnaq^fl/fl;Gna11^−/−;Gnrh-Cre (Gnaq^d/d) and control Gnaq^fl/fl;Gna11^−/− (Gnaq^fl/fl) littermate mice were generated and subjected to reproductive profiling. This process revealed that testicular development and spermatogenesis, preputial separation, and anogenital distance in males and day of vaginal opening and of first estrus in females were significantly less affected in Gnaq^d/d mice than in previously characterized Kiss1r^−/− or Kiss1r^d/d mice. Additionally, Gnaq^d/d males were subfertile, and although Gnaq^d/d females did not ovulate spontaneously, they responded efficiently to a single dose of gonadotropins. Finally, KP stimulation triggered a significant increase in gonadotropins and testosterone levels in Gnaq^d/d mice. We therefore conclude that the milder reproductive phenotypes and maintained responsiveness to KP and gonadotropins reflect Gα_q/11-independent GnRH secretion and activation of the neuroendocrine-reproductive axis in Gnaq^d/d mice.

SIGNIFICANCE STATEMENT The gonadotropin-releasing hormone (GnRH) is the master regulator of fertility. Over the last decade, several studies have established that the KISS1 receptor, KISS1R, is a potent trigger of GnRH secretion and inactivation of KISS1R on the GnRH neuron results in infertility. While KISS1R is best understood as a Gα_q/11-coupled receptor, we previously demonstrated that it could couple to and signal via non-Gα_q/11-coupled pathways. The present study confirms these findings and, more importantly, while it establishes Gα_q/11-coupled signaling as a major conduit of GnRH secretion, it also uncovers a significant role for non-Gα_q/11-coupled signaling in potentiating reproductive development and function. This study further suggests that by augmenting signaling via these pathways, GnRH secretion can be enhanced to treat some forms of infertility.