Gender-Related Differences of Tachykinin NK₂ Receptor Expression and Activity in Human Colonic Smooth Muscle

The tachykinin NK₂ receptor plays a key role in gastrointestinal motor function. Enteric neurons release neurokinin A (NKA), which activates NK₂ receptors on gastrointestinal smooth muscle, leading to contraction and increased motility. In patients with diarrhea-predominant irritable bowel syndrome, the NK₂ 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 NK₂ 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 NK₂ receptor agonist [Lys⁵,MeLeu⁹,Nle¹⁰]NKA(4-10). Contractions were also measured in the presence of ibodutant to determine its antagonistic potency. The signal transduction pathways coupled to NK₂ receptor activation were investigated using second messenger inhibitors. Western blot and fluorescent immunohistochemistry were conducted to determine the protein expression and localization of NK₂ receptors. NK₂ receptor-mediated contractility was greater in females compared with males. When against NKA, ibodutant was more potent in females. NK₂ receptor expression increased with age in females, but not in males. Phospholipase C-mediated signaling was less prominent in females compared with males, whereas Ca²⁺ sensitization via Rho kinase and protein kinase C appeared to be the dominant pathway in both genders. The distribution of NK₂ receptors in the human colon did not differ between the genders. Overall, gender differences exist in the expression and activity of NK₂ receptors in colonic smooth muscle. These gender distinctions should be considered in the therapeutic development of NK₂ receptor agents. SIGNIFICANCE STATEMENT: The tachykinin NK₂ 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 NK₂ 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 NK₂ receptor antagonists. Our findings highlight that gender differences should be considered in the therapeutic development of NK₂ receptor agents.