Substance-P receptor (UniProt P14600; also known as Neurokinin-1 receptor, NK-1 receptor, NK-1R, SPR, Tachykinin receptor 1) is encoded by the Tacr1 (also known as Nk1r, Tac1r) gene (Gene ID 24807) in rat species. NK-1, NK-2 and NK-3 are receptors that mediate the biological activities of tachykinins, including substance P (SP), neurokinin A (NKA), neurokinin B (NKB), ranakinin, kassinin, neuropeptide gamma, and eledoisin, widely distributed in the central and peripheral nervous systems. SP shows the highest affinity toward NK-1R (substance-P receptor) and exerts its biological activities via NK-1R, including addition, depression, chronic inflammation, and cancer progression. The involvement of NK-1R in acute pancreatitis through mediating neurogenic inflammation has also been reported. Upon stimulation by SP, the NK-1R interacts with multiple G proteins, including Gαs, Gαq/11, Gαi/o, Gα12, and Gα13, generating second messengers and activating downstream effector molecules. After binding NK-1R, SP induces a clathrin-dependent internalization of the receptor-ligand complex, SP is then degraded and the receptor is recycled to the cell surface. NK-1R is a 7-transmembrane (32-54, 65-86, 107-128, 149-169, 195-219, 249-270, 284-308) GPCR, having its N-terminal end (a.a. 1-31) at the extracelluar side and C-terminal end (a.a. 309-407) at the cytoplasmic side. There exist a second alternatively spliced human NK-1R isoform that lacks the C-terminal cytoplasmic domain (a.a. 312-407 missing). The full-length form enhances the growth of cancer cells and stimulates the production of cytokines, which up-regulate the truncated form. The truncated form mediates malignancy and is more abundant in colonic epithelial cells from patients with colitis-associated cancer. In cancer cells, the NK-1 receptor is mainly localized on the plasma membrane and in cytoplasm, and occasionally also in the nucleus.
