Neurokinin 1 Receptor

The tachykinin receptor 1 (TACR1) also known as neurokinin 1 receptor (NK1R) or substance P receptor (SPR) is a G protein coupled receptor found in the central nervous system and peripheral nervous system. The endogenous ligand for this receptor is Substance P, although it has some affinity for other tachykinins. The protein is the product of the TACR1 gene.

C14TKL-1
126088-92-4
FR 113680
126088-92-4
168266-51-1
168266-51-1
1703748-89-3
Fosnetupitant
1703748-89-3
SDZ NKT 343
180046-99-5
Hemokinin 1 (mouse)
208041-90-1
414910-30-8
Casopitant Mesylate
414910-30-8
Hemokinin 1 (human)
491851-53-7
522664-63-7
Ibodutant
522664-63-7
552292-58-7
Telmapitant
552292-58-7
579475-18-6
Orvepitant
579475-18-6
Orvepitant maleate
579475-24-4
860642-69-9
Serlopitant
860642-69-9
Spantide I
91224-37-2

Background


Neurokinin-1 receptor (NK-1R) belongs to a family of receptors known as tachykinin receptors, which have ligands known as tachykinins. The NK-1R binds substance P and hemokinin-1 with high affinity, while the neurokinin-2 receptor binds neurokinin A with high affinity and the neurokinin-3 receptor binds neurokinin B with high affinity. The tachykinin receptors are all G-protein coupled receptors, with seven transmembrane domains, an N-terminal extracellular tail and a C-terminal cytoplasmic tail. They couple through Gq to activate phospholipase C.

Physiologic and Pathophysiologic Effects of Substance P and the Neurokinin-1 Receptor

During the inflammatory response, NK-1R has specific effects on the vasculature, granulocytes, mast cells, lymphocytes, and monocytes/macrophages. Release of substance P from a site of inflammation causes effects in a variety of cell types that lead to extravasation, chemotaxis, and activation of leukocytes. NK-1R is expressed in the vascular endothelium and treatment of vascular endothelial cells with substance P causes migration and proliferation, a key step in angiogenesis which could provide increased blood flow and increased leukocyte migration to an inflamed area. In addition, substance P/NK-1R can mediate vasodilation through nitric oxide release and an increase in vascular permeability, which allows for circulating leukocytes to extravasate. Extravasation is also achieved, at least in part, through substance P-induced expression of E-selectin and intracellular adhesion molecule-1 in the vascular endothelium and through substance P-induced expression of CD11, a leukocyte adhesion protein, in granulocytes. Just as the in vitro results lead one to conclude that NK-1R can induce extravasation of granulocytes, pharmacological inhibition of NK-1R has been shown to inhibit in vivo granulocyte extravasation in several studies. Substance P can also cause mast cell activation and mediate granulocyte infiltration through the inflammatory mediators released by mast cells, as well as cause in vitro neutrophil chemotaxis and activation.

Neurokinin-1 Receptor Expression and Activity in Ulcerative Colitis and Cancers

The NK-1R has been identified in epithelial cells in rodent models of colonic inflammation and in patients with ulcerative colitis as well as Crohn’s Disease. Not all studies in human patients are in agreement regarding epithelial NK-1R expression in ulcerative colitis: some studies have shown an increase, while others have not. These results may due in part to technical differences between the studies combined with the expected variation within the general population. NK-1R plays a functional role in a rodent model of inflammation where treatment with an NK-1R antagonist can reduce inflammatory damage, although attempts to treat patients with NK-1R antagonists to alleviate symptoms of ulcerative colitis have not been effective.

Increased expression of the NK-1R has been identified in many tumors. Hennig et al. first reported binding of radiolabeled substance P to tissue samples from patients with a variety of cancers, including astrocytomas, glioblastomas, ganglioneuroblastomas, medullary thyroid carcinomas and breast carcinomas. Interestingly, Hennig et al did not find substance P binding in colon adenocarcinomas; however, they examined colon cancers without distinguishing between sporadic and colitis-associated cancers. Hennig also made the notable observation that all tumors had neovasculature that expressed NK-1R, providing evidence towards its potential role in promoting angiogenesis. Another study linked the presence of fl-NK-1R to pancreatic carcinoma and ovarian carcinoma but not colon adenocarcinoma; a third study showed increases in NK-1R expression in pancreatic carcinoma compared to normal controls. While the two studies above showed no NK-1R expression in colon adenocarcinomas, another study does show the presence of NK-1 R in colon tumors. All colon cancer studies did not specify between types of tumors, so they likely contained primarily cancers from the sporadic pathway as opposed to the inflammation-associated pathway. NK-1R has also been identified in skin and laryngeal cancers.

Reference:

Gillespie, E. (2013). Colonic epithelial genes in the transition from chronic inflammation to carcinoma in human colitis-associated cancer: Focus on the truncated neurokinin-1 receptor. Boston University.