Gender-Related Differences of Tachykinin NK₂Receptor Expression and Activity in Human Colonic Smooth Muscle

Abstract

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 diarrhoea-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 [Lys 5 ,MeLeu 9 ,Nle 10 ]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 to 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 signalling was less prominent in females compared to males, while Ca 2+ 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.

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“…Neurokinin 2 receptor (NK 2 R) peptide agonists: NK 2 Rs are heavily expressed in detrusor and colorectal smooth muscle (Drimousis et al 2020, Warner et al 2003 (Palea et al 1996, Parlani et al 1990, the bile ducts (Patacchini et al 1997), bronchus, and reproductive organs (Fisher & Pennefather 1999, Magraner et al 1998, Patacchini et al 2002. Finally, NK 2 Rs are also found on primary afferent neurons (Drimousis et al 2020, Sculptoreanu et al 2009. The distribution of NK 2 Rs in the colorectum and bladder are quite similar across species, including humans.…”