| First Author | Ahow M | Year | 2014 |
| Journal | Endocrinology | Volume | 155 |
| Issue | 11 | Pages | 4433-46 |
| PubMed ID | 25147978 | Mgi Jnum | J:218710 |
| Mgi Id | MGI:5618220 | Doi | 10.1210/en.2014-1304 |
| Citation | Ahow M, et al. (2014) KISS1R signals independently of Galphaq/11 and triggers LH secretion via the beta-arrestin pathway in the male mouse. Endocrinology 155(11):4433-46 |
| abstractText | Hypothalamic GnRH is the master regulator of the neuroendocrine reproductive axis, and its secretion is regulated by many factors. Among these is kisspeptin (Kp), a potent trigger of GnRH secretion. Kp signals via the Kp receptor (KISS1R), a Galphaq/11-coupled 7-transmembrane-spanning receptor. Until this study, it was understood that KISS1R mediates GnRH secretion via the Galphaq/11-coupled pathway in an ERK1/2-dependent manner. We recently demonstrated that KISS1R also signals independently of Galphaq/11 via beta-arrestin and that this pathway also mediates ERK1/2 activation. Because GnRH secretion is ERK1/2-dependent, we hypothesized that KISS1R regulates GnRH secretion via both the Galphaq/11- and beta-arrestin-coupled pathways. To test this hypothesis, we measured LH secretion, a surrogate marker of GnRH secretion, in mice lacking either beta-arrestin-1 or beta-arrestin-2. Results revealed that Kp-dependent LH secretion was significantly diminished relative to wild-type mice (P < .001), thus supporting that beta-arrestin mediates Kp-induced GnRH secretion. Based on this, we hypothesized that Galphaq/11-uncoupled KISS1R mutants, like L148S, will display Galphaq/11-independent signaling. To test this hypothesis, L148S was expressed in HEK 293 cells. and results confirmed that, although strongly uncoupled from Galphaq/11, L148S retained the ability to trigger significant Kp-dependent ERK1/2 phosphorylation (P < .05). Furthermore, using mouse embryonic fibroblasts lacking beta-arrestin-1 and -2, we demonstrated that L148S-mediated ERK1/2 phosphorylation is beta-arrestin-dependent. Overall, we conclude that KISS1R signals via Galphaq/11 and beta-arrestin to regulate GnRH secretion. This novel and important finding could explain why patients bearing some types of Galphaq/11-uncoupled KISS1R mutants display partial gonadotropic deficiency and even a reversal of the condition, idiopathic hypogonadotropic hypogonadism. |
