| Tachykinin-3, encoded by the TAC3 gene, is synthesized as a secreted prepropeptide that undergoes proteolytic processing to generate neurokinin B, a member of the conserved tachykinin neuropeptide family characterized by a C‑terminal consensus motif that confers high affinity and selectivity toward the G protein‑coupled neurokinin‑3 receptor (NK3R) while retaining lower affinity for other tachykinin receptors. The mature peptide is predominantly produced in discrete neuronal populations of the central and peripheral nervous systems, including hypothalamic circuits that control gonadotropin‑releasing hormone (GnRH) secretion, establishing tachykinin‑3 as a key central regulator of gonadal function and reproductive neuroendocrine output, with additional expression reported in peripheral tissues such as the placenta, where it associates with pregnancy‑related vascular and hypertensive phenotypes. Engagement of NK3R by tachykinin‑3 activates heterotrimeric G proteins of the Gq/11 family, leading to stimulation of phospholipase C, hydrolysis of phosphatidylinositol bisphosphate, and generation of inositol trisphosphate and diacylglycerol, which in turn mobilize intracellular calcium stores and activate protein kinase C, providing a rapid route to regulate neuronal excitability, neurotransmitter release, and smooth muscle contractility in target tissues. These proximal signals converge with additional NK3R‑driven cascades that modulate downstream effectors such as L‑type calcium channels and other ion channels, supporting robust calcium‑dependent transcriptional responses and synaptic integration in circuits where tachykinin‑3–NK3R signaling shapes rhythmic GnRH pulse generation, neuroendocrine feedback, and autonomic outputs. Structural determinants within the C‑terminal region of tachykinin‑3, including the conserved motif and neighboring aromatic and charged residues, are critical for high‑affinity NK3R recognition and for discriminating receptor subtype preference, and structure–activity analyses using neurokinin B analogs show that specific substitutions can markedly enhance NK3R binding and agonist potency while reducing off‑target activation of NK1R and NK2R, illustrating how subtle peptide modifications influence receptor coupling and signaling strength. Within NK3R‑expressing neurons, sustained tachykinin‑3 stimulation not only drives classical calcium and PKC signaling but also engages nuclear programs that remodel chromatin through histone acetylation, linking this peptide–receptor pair to epigenetic control of gene expression and suggesting that repeated or chronic activation can durably adjust transcriptional profiles associated with neuronal plasticity and neuroendocrine state. Physiologically, tachykinin‑3 signaling participates in the integration of inputs from kisspeptin and dynorphin networks in the hypothalamus, contributing to the timing and amplitude of GnRH pulses, regulation of luteinizing hormone release, and thus downstream gonadal steroid production, while in peripheral organs the same ligand–receptor module contributes to smooth muscle responses, vasodilation, and secretory functions that influence vascular tone and organ perfusion. Loss‑of‑function mutations in TAC3 or disruption of neurokinin B production result in normosmic hypogonadotropic hypogonadism and infertility, underscoring the non‑redundant requirement for intact tachykinin‑3 signaling in human reproductive axis development and maintenance, whereas altered expression in placental tissue has been associated with pregnancy‑induced hypertension and preeclampsia, consistent with its vasoactive and endocrine regulatory properties. |
