Tachykinin NK2 receptor expression and activity in human colonic smooth muscle: an insight into the influence of gender, sex hormones and diverticular disease

The tachykinin NK2 receptor (NK2R) plays a key role in mediating colonic motor function. Enteric motor neurons release neurokinin A (NKA) which activates NK2R on smooth muscle cells, leading to contraction and increased colonic motility. In patients with diarrhoea-predominant irritable bowel syndrome, the NK2R antagonist ibodutant had a greater therapeutic effect in females compared to males. The present study aimed to determine whether gender and sex hormones influence the expression and activity of NK2R in human colonic smooth muscle. In addition, altered NK2R function was explored in colonic diverticular disease (DD). In vitro functional studies were performed to examine the contractile responses induced by NKA and the selective NK2R agonist [Lys5,MeLeu9,Nle10]NKA(4-10) (LMN-NKA) in human colonic smooth muscle strips from control and DD patients. In control strips, contractions were also measured in the presence of ibodutant to determine its dissociation constant. The signal transduction pathways coupled to NK2R activation were investigated using second messenger signalling inhibitors. The acute effects of estrogen, progesterone and testosterone on NK2R-mediated contractions were also examined. Western blot and fluorescent immunohistochemistry were conducted to determine the protein expression and localisation of NK2R in control and DD. In control strips, NK2R-mediated contractility was greater in females compared to males. When against NKA, ibodutant was more potent in females. NK2R protein expression increased with age in females, but not in males. Phospholipase C-mediated signalling was less prominent in females compared to males, while Ca2+ sensitisation via Rho kinase and protein kinase C appeared to be the dominant pathway in both genders. Estrogen, progesterone and testosterone, applied separately, reduced NK2R-mediated contractions in both genders. The distribution of NK2R in the human colon did not differ between the genders. In DD, NK2R was upregulated. In male DD strips, contractions evoked by LMN-NKA were more pronounced compared to controls. Overall, gender differences exist in the expression and activity of NK2R in human colonic smooth muscle. These gender distinctions may be due to the influence of sex hormones and should be considered in the therapeutic development of NK2R agents. In addition, upregulation of NK2R and altered NK2R activity is present in DD