{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n KISS1R (also known as GPR54) is a critical G protein–coupled receptor that mediates the actions of kisspeptin on the reproductive axis. Activation of KISS1R in hypothalamic gonadotropin‐releasing hormone (GnRH) neurons triggers a robust intracellular signaling cascade—most notably via phospholipase C activation, IP₃ production, and subsequent Ca²⁺ mobilization—which results in membrane depolarization through modulation of potassium and nonselective cation channels. This signaling underlies the potent stimulatory effect on pulsatile GnRH secretion that is essential for the onset of puberty, proper sexual maturation, and maintenance of fertility. Indeed, loss‐of‐function mutations or targeted deletion of KISS1R in both humans and mice leads to hypogonadotropic hypogonadism, delayed or absent pubertal development, and impaired gonadal steroidogenesis. Conversely, re‐expression of KISS1R exclusively in GnRH neurons is sufficient to rescue reproductive function, underscoring the cell‐autonomous role of this receptor in the hypothalamic–pituitary–gonadal axis. Moreover, KISS1R signaling is integrated with other neuromodulatory systems—including nitric oxide pathways and metabolic cues—which helps coordinate reproductive competence with overall physiological homeostasis. Collectively, these findings designate KISS1R as a pivotal molecular “switch” in linking kisspeptin signals to the neuroendocrine regulation of reproduction."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Electrophysiological studies further demonstrate that kisspeptin binding to KISS1R initiates a phospholipase C–IP₃–dependent calcium cascade that modulates both inward and outward currents, leading to the sustained depolarization of GnRH neurons."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " In mouse models, GnRH neuron–specific deletion of KISS1R results in infertility and the absence of pulsatile luteinizing hormone secretion, whereas targeted re–expression of the receptor in these neurons restores pubertal progression and reproductive capability."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " In addition to its central role, kisspeptin–KISS1R signaling contributes to the proper sexual differentiation of neural circuits underlying reproductive behavior"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": ", with comprehensive reviews emphasizing its fundamental role as the gatekeeper of the GnRH system."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, interactions between kisspeptin, acting via KISS1R, and other regulatory molecules such as neuronal nitric oxide synthase help integrate environmental and metabolic signals with the reproductive neuroendocrine network."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " In summary, KISS1R is indispensable for initiating and sustaining the neuroendocrine signals that control puberty and fertility, providing a molecular nexus that links kisspeptin signaling to the broader regulation of reproductive physiology.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Stephanie B Seminara, Sophie Messager, Emmanouella E Chatzidaki, et al. 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