Doctor of Philosophy
Dr. Andy Babwah
Hypothalamic GnRH-releasing hormone (Gnrh) is the master regulator of the neuroendocrine reproductive axis and its secretion is regulated by many Gnrh neuronal-based signaling systems. Among these are Gαq/11-coupled receptors and their ligands.In most cases examined to date, activation of these receptors lead to Gnrh neuronal membrane depolarization and Gnrh secretion. The most potent trigger of Gnrh secretion is kisspeptin (Kp), a ligand for the Kiss1r Gαq/11-coupled receptor. Studies have shown that Kiss1r signaling is essential for attaining and maintaining fertility. We recently demonstrated that in addition to signaling via Gαq/11, Kiss1r also couples to and signals via the b-arrestin pathway. This led us to investigate the role of b-arrestin signaling in Kiss1r-dependent Gnrh secretion. Using mice lacking b-arrestin, we determined that Kiss1r triggers significant Gnrh secretion via the b-arrestin pathway. Thus, mice use both the Kiss1r-coupled Gαq/11 and b-arrestin signaling pathways to regulate Gnrh secretion and thereby, fertility. It is likely that in addition to using the b-arrestin-coupled pathway, Kiss1r uses other Gαq/11-independent signaling pathways to regulate fertility. To test whether these pathways are sufficient to attain and maintain fertility, we created Gnrh neuronal-specific Gαq/11 knockout mice and characterized their reproductive development and capacity to trigger Gnrh secretion following Kp administration. We observed that there was sufficient Kiss1r-Gαq/11-independent signaling in these mice to attain and maintain fertility. Our findings therefore show that Kiss1r signals via both Gαq/11-dependent and -independent signaling pathways to regulate Gnrh secretion and thereby, fertility.
Ahow, Maryse R., "Pathway-Specific Signaling and its Impact on Fertility: A Focus on the Kisspeptin Receptor, Kiss1r" (2014). Electronic Thesis and Dissertation Repository. 2537.