Neurokinin A

NKA binds all three tachykinin receptors (NK1, NK2, NK3) but has highest affinity for NK2R. NK2R is a Gq-coupled GPCR that activates PLC, IP3, and intracellular calcium release in smooth muscle, causing contraction. In airways, NK2R activation on bronchial smooth muscle produces bronchoconstriction. In the GI tract, NK2R drives smooth muscle contraction, increasing motility and contributing to visceral pain.

Like substance P, NKA is stored in and released from sensory nerve endings (C-fibers and Adelta fibers) in peripheral tissues and the spinal cord. Co-release of NKA and substance P amplifies neurogenic inflammation through NK1 and NK2 receptor activation on blood vessels, mast cells, and immune cells, producing vasodilation, plasma extravasation, and immune cell recruitment.

Inhaled NKA produces dose-dependent bronchoconstriction in asthmatic patients at concentrations that do not affect healthy subjects, validating airway NK2R hypersensitivity in asthma. NK2R antagonists (saredutant, nepadutant) were evaluated in Phase II asthma trials but did not show sufficient clinical efficacy versus existing bronchodilators, despite proof-of-concept for the mechanism.

NK2R in the GI tract mediates visceral hypersensitivity. NK2R antagonism reduces visceral pain responses in colorectal distension models. The potential for NK2R antagonism in IBS-related visceral pain motivated early clinical evaluation, though phase II results were mixed.

IV NKA infusion in humans produces vasodilation and hypotension mediated by NK2R on vascular smooth muscle and NK1R-mediated endothelial NO release. These hemodynamic effects distinguish NKA from the predominantly vasoconstrictive effects of substance P and have been used to study tachykinin vascular pharmacology.