KISS1R signals independently of Gɑ<sub>q/11</sub> and triggers LH secretion via the ß-arrestin pathway in the male mouse — ASN Events
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  2. Poster Session 1 - Neuroendocrinology of Reproduction I
  3. KISS1R signals independently of Gɑq/11 and triggers LH secretion via the ß-arrestin pathway in the male mouse

KISS1R signals independently of Gɑq/11 and triggers LH secretion via the ß-arrestin pathway in the male mouse (#211)

Andy V Babwah 1 , Maryse Ahow 2 , Le Min 3 , Macarena Pampillo 2 , Connor Nash 4 , Junping Wen 3 , Kathleen Soltis 3 , Rona S Carroll 3 , Christine A Glidewell-Kenney 5 , Pamela L Mellon 5 , Moshmi Bhattacharya 2 , Stuart A Tobet 4 , Ursula B Kaiser 3
  1. Obstetrics and Gynaecology, The University of Western Ontario, London, ON, Canada
  2. University of Western Ontario, London, ON, Canada
  3. Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
  4. Department of Biomedical Sciences , Colorado State University, Fort Collins, CO, USA
  5. Department of Reproductive Medicine, Center for Reproductive Science and Medicine , University of California, San Diego, La Jolla, CA, USA

Hypothalamic GnRH is the master regulator of the neuroendocrine reproductive axis and its secretion is regulated by many factors. Among these is kisspeptin which is recognized as a potent trigger of GnRH secretion. Kisspeptin signals via KISS1R, a Gɑq/11-coupled seven transmembrane-spanning receptor. Prior to this study, it was understood that KISS1R mediates GnRH secretion via the Gɑq/11-coupled pathway in an ERK-dependent manner. We recently demonstrated that KISS1R also signals independently of Gɑq/11 via ß-arrestin and that this pathway also involves ERK activation. Since GnRH secretion is an ERK-dependent process, we hypothesized that KISS1R regulates GnRH secretion via both the Gɑq/11- and ß-arrestin-coupled pathways. To test this hypothesis, we measured LH secretion, a surrogate marker of GnRH secretion, in mice lacking either ß-arrestin-1 or ß-arrestin-2. The results revealed that Kp-dependent LH secretion was significantly diminished relative to WT mice (P < 0.001), thus supporting that ß-arrestin mediates Kp-induced GnRH secretion. Based on this finding, we hypothesized Gɑq/11-uncoupled KISS1R mutants like L148S will display Gɑq/11-independent signaling. To test this hypothesis, L148S was expressed in HEK 293 cells and results confirmed that, while strongly uncoupled from Gɑq/11, L148S retained the ability to trigger significant ERK activation following Kp-treatment (P < 0.05). Taken together with the ß-arrestin knockout results, we conclude that KISS1R signals via both Gɑq/11 and ß-arrestin to regulate GnRH secretion. This novel and important finding could explain why patients bearing some types of Gɑq/11-uncoupled KISS1R mutants display partial gonadotropic deficiency.