AUTHOR=Melnyk Mariia I. , Dryn Dariia O. , Al Kury Lina T. , Dziuba Dmytro O. , Zholos Alexander V. 

TITLE=Suppression of mICAT in Mouse Small Intestinal Myocytes by General Anaesthetic Ketamine and its Recovery by TRPC4 Agonist (-)-englerin A

JOURNAL=Frontiers in Pharmacology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2020.594882

DOI=10.3389/fphar.2020.594882

ISSN=1663-9812

ABSTRACT=<p>A better understanding of the negative impact of general anesthetics on gastrointestinal motility requires thorough knowledge of their molecular targets. In this respect the muscarinic cationic current (mI<sub>CAT</sub> carried mainly via TRPC4 channels) that initiates cholinergic excitation-contraction coupling in the gut is of special interest. Here we aimed to characterize the effects of one of the most commonly used “dissociative anesthetics”, ketamine, on mI<sub>CAT</sub>. Patch-clamp and tensiometry techniques were used to investigate the mechanisms of the inhibitory effects of ketamine on mI<sub>CAT</sub> in single mouse ileal myocytes, as well as on intestinal motility. Ketamine (100 µM) strongly inhibited both carbachol- and GTPγS-induced mI<sub>CAT</sub>. The inhibition was slow (time constant of about 1 min) and practically irreversible. It was associated with altered voltage dependence and kinetics of mI<sub>CAT</sub>. In functional tests, ketamine suppressed both spontaneous and carbachol-induced contractions of small intestine. Importantly, inhibited by ketamine mI<sub>CAT</sub> could be restored by direct TRPC4 agonist (-)-englerin A. We identified mI<sub>CAT</sub> as a novel target for ketamine. Signal transduction leading to TRPC4 channel opening is disrupted by ketamine mainly downstream of muscarinic receptor activation, but does not involve TRPC4 <italic>per se</italic>. Direct TRPC4 agonists may be used for the correction of gastrointestinal disorders provoked by general anesthesia.</p>