Gender-Related Differences of Tachykinin NK Receptor Expression and Activity in Human Colonic Smooth Muscle.

The tachykinin NK receptor plays a key role in gastrointestinal motor function. Enteric neurons release neurokinin A (NKA), which activates NK receptors on gastrointestinal smooth muscle, leading to contraction and increased motility. In patients with diarrhea-predominant irritable bowel syndrome, the NK receptor antagonist ibodutant had a greater therapeutic effect in females than males. The present study aimed to determine whether gender influences the expression and activity of NK receptors in human colonic smooth muscle. In vitro functional studies were performed to examine the contractile responses of colonic muscle strips to NKA and the selective NK receptor agonist [Lys,MeLeu,Nle]NKA(4-10). Contractions were also measured in the presence of ibodutant to determine its antagonistic potency. The signal transduction pathways coupled to NK receptor activation were investigated using second messenger inhibitors. Western blot and fluorescent immunohistochemistry were conducted to determine the protein expression and localization of NK receptors. NK receptor-mediated contractility was greater in females compared with males. When against NKA, ibodutant was more potent in females. NK receptor expression increased with age in females, but not in males. Phospholipase C-mediated signaling was less prominent in females compared with males, whereas Ca sensitization via Rho kinase and protein kinase C appeared to be the dominant pathway in both genders. The distribution of NK receptors in the human colon did not differ between the genders. Overall, gender differences exist in the expression and activity of NK receptors in colonic smooth muscle. These gender distinctions should be considered in the therapeutic development of NK receptor agents. SIGNIFICANCE STATEMENT: The tachykinin NK receptor has been identified as a therapeutic target for the treatment of bowel and bladder dysfunctions. The present study has revealed gender-related variations in NK receptor activity, signaling transduction pathways, antagonist potency, and changes in expression with age. These factors may underlie the gender differences in the treatment of diarrhea-predominant irritable bowel syndrome with NK receptor antagonists. Our findings highlight that gender differences should be considered in the therapeutic development of NK receptor agents.