{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTachykinin receptor 3 (TACR3) encodes the neurokinin‐3 receptor (NK3R), a G protein–coupled receptor broadly expressed in both the central nervous system and peripheral tissues. In peripheral systems, NK3R mediates diverse actions including the regulation of platelet aggregation via calcium mobilization, as evidenced by its role in triggering platelet activation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Genetic studies have also implicated TACR3 in gastrointestinal motility disorders such as slow transit constipation"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "and in modulating contractile responses in human airway smooth muscle through inositol phosphate signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Although association studies in neuropsychiatric conditions like schizophrenia have not revealed a definitive link"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ", NK3R is also implicated in substance‐related behaviors – with preclinical pharmacological evidence indicating that NK3R activation can influence responses to alcohol and cocaine."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nA pivotal function of TACR3 is its role in the neuroendocrine regulation of reproduction. Loss‐of‐function mutations in TACR3 disrupt the normal pulsatile release of gonadotropin‐releasing hormone (GnRH), leading to congenital hypogonadotropic hypogonadism and pubertal failure."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "10"}]}, {"type": "t", "text": " Studies in affected individuals and kindreds have underscored the essential role of the neurokinin B–NK3R signaling pathway in maintaining gonadal steroidogenesis and proper sexual maturation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": " Moreover, TACR3 messenger RNA has been detected throughout the female genital tract, suggesting localized reproductive functions"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": ", and genetic variant analyses in patients with pubertal disorders have further supported TACR3’s involvement in both delayed and precocious pubertal phenotypes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "13", "end_ref": "16"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its established reproductive role, emerging evidence highlights additional functions of TACR3. Variations in TACR3 have been associated with altered learning and memory performance—possibly by modulating acetylcholine release in key brain areas"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": ", while structure–function studies have revealed that mutations in specific transmembrane and intracellular domains impair NK3R trafficking and G protein coupling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": " In vascular and reproductive pathologies, aberrant activation of NK3R in the placenta has been linked to preeclampsia"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": ", and cross‐species examinations have documented marked differences in NK3R localization."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "20"}]}, {"type": "t", "text": " Recent work has focused on the design of novel peptide ligands targeting NK3R for therapeutic interventions"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": ", while direct ovarian actions of neurokinin B via NK3R have been shown to stimulate estrogen production—raising the possibility that impaired signaling may contribute to polycystic ovary syndrome."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "22"}]}, {"type": "t", "text": " TACR3 expression in the central nervous system has also been implicated in the pathogenesis of oral squamous cell carcinoma"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "24"}]}, {"type": "t", "text": "and may influence vasomotor symptoms during menopause."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "26"}]}, {"type": "t", "text": " Additional studies have explored its potential involvement in nonobstructive azoospermia"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "27"}]}, {"type": "t", "text": "and, in the context of addiction, preclinical reviews have emphasized NK3R’s modulation of drug‐related behaviors."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "28"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Gwenda J Graham, Joanne M Stevens, Nigel M Page, et al. 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