neurokinin1

Neurokinin-1 (NK1) receptor is a G protein–coupled receptor for the neuropeptide substance P. It is encoded by the TACR1 gene in humans.

NK1 receptors are widely distributed in the central nervous system and peripheral tissues, including the dorsal horn of the spinal cord, brainstem, limbic regions, and sensory neurons of the gut. They contribute to pain signaling and neurogenic inflammation, regulate mood and stress responses, and participate in the emetic reflex.

Signaling: Upon binding of substance P, NK1 receptors activate Gq/11 proteins, stimulating phospholipase C, generating IP3 and DAG, and increasing intracellular calcium. This leads to neuronal excitation and the release of second messengers that modulate synaptic transmission and inflammatory processes.

Clinical significance: NK1 receptor antagonists block substance P signaling and are approved for prevention of chemotherapy-induced nausea and vomiting and postoperative nausea and vomiting. Examples include aprepitant, fosaprepitant, rolapitant, and netupitant (often given with palonosetron). Research has explored NK1 antagonists for anxiety, depression, migraine, and pruritus, with varying results.

Pharmacology and genetics: NK1 receptor ligands are primarily metabolized by hepatic enzymes such as CYP3A4; interactions with inhibitors or inducers can alter drug exposure. Common adverse effects include fatigue, dizziness, and infusion reactions. The TACR1 gene encodes the NK1 receptor, and genetic variation may influence expression or drug response.