title: KISS1R signals independently of Gαq/11 and triggers LH secretion via the β-arrestin pathway in the male mouse.
abstract: 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 Gαq/11-coupled 7-transmembrane-spanning receptor. Until this study, it was understood that KISS1R mediates GnRH secretion via the Gαq/11-coupled pathway in an ERK1/2-dependent manner. We recently demonstrated that KISS1R also signals independently of Gαq/11 via β-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 Gαq/11- and β-arrestin-coupled pathways. To test this hypothesis, we measured LH secretion, a surrogate marker of GnRH secretion, in mice lacking either β-arrestin-1 or β-arrestin-2. Results revealed that Kp-dependent LH secretion was significantly diminished relative to wild-type mice (P < .001), thus supporting that β-arrestin mediates Kp-induced GnRH secretion. Based on this, we hypothesized that Gαq/11-uncoupled KISS1R mutants, like L148S, will display Gαq/11-independent signaling. To test this hypothesis, L148S was expressed in HEK 293 cells. and results confirmed that, although strongly uncoupled from Gαq/11, L148S retained the ability to trigger significant Kp-dependent ERK1/2 phosphorylation (P < .05). Furthermore, using mouse embryonic fibroblasts lacking β-arrestin-1 and -2, we demonstrated that L148S-mediated ERK1/2 phosphorylation is β-arrestin-dependent. Overall, we conclude that KISS1R signals via Gαq/11 and β-arrestin to regulate GnRH secretion. This novel and important finding could explain why patients bearing some types of Gαq/11-uncoupled KISS1R mutants display partial gonadotropic deficiency and even a reversal of the condition, idiopathic hypogonadotropic hypogonadism.
authors.affiliation: The Children's Health Research Institute (M.A., M.P., A.V.B.), London, Ontario, Canada; Lawson Health Research Institute (M.A., M.P., A.V.B.), London, Ontario, Canada; Departments of Obstetrics and Gynaecology (M.P., A.V.B.), Physiology and Pharmacology (M.A., M.B., A.V.B.), and Oncology (M.B.), The University of Western Ontario, London, Ontario, Canada N6C 2V5; Division of Endocrinology, Diabetes, and Hypertension (L.M., J.W., K.S., R.S.C., U.B.K.), Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115; Department of Biomedical Sciences (C.N., S.A.T.), Colorado State University, Fort Collins, Colorado 80523; and Department of Reproductive Medicine (C.A.G.-K., P.L.M.), Center for Reproductive Science and Medicine, University of California, San Diego, La Jolla, California 92093.
authors.forename: Maryse
authors.initials: M
authors.lastname: Ahow
authors.forename: Le
authors.initials: L
authors.lastname: Min
authors.forename: Macarena
authors.initials: M
authors.lastname: Pampillo
authors.forename: Connor
authors.initials: C
authors.lastname: Nash
authors.forename: Junping
authors.initials: J
authors.lastname: Wen
authors.forename: Kathleen
authors.initials: K
authors.lastname: Soltis
authors.forename: Rona S
authors.initials: RS
authors.lastname: Carroll
authors.forename: Christine A
authors.initials: CA
authors.lastname: Glidewell-Kenney
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Mellon
authors.forename: Moshmi
authors.initials: M
authors.lastname: Bhattacharya
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Tobet
authors.forename: Ursula B
authors.initials: UB
authors.lastname: Kaiser
authors.forename: Andy V
authors.initials: AV
authors.lastname: Babwah
mesh_terms: D000818:Animals; D019390:Arrestins / Q000235:genetics / Q000502:physiology*; D002064:Buserelin / Q000494:pharmacology; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D007986:Luteinizing Hormone / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D000074502:Receptors, Kisspeptin-1; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D000071559:beta-Arrestin 1; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C000605253:ARRB1 protein, human; C000605254:ARRB2 protein, human; C000605255:Arrb1 protein, mouse; C000605258:Arrb2 protein, mouse; D019390:Arrestins; C492248:Kiss1r protein, mouse; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; D000071559:beta-Arrestin 1; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D007986:Luteinizing Hormone; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D002064:Buserelin