Abstract
Gastrointestinal (GI) motility disorders such as irritable bowel syndrome (IBS) can occur when coordinated smooth muscle contractility is disrupted. Potassium (K+) channels regulate GI smooth muscle tone and are key to GI tract relaxation, but their molecular and functional phenotypes are poorly described. Here we define the expression and functional roles of mechano-gated K2P channels in mouse ileum and colon. Expression and distribution of the K2P channel family were investigated using quantitative RT-PCR (qPCR), immunohistochemistry and confocal microscopy. The contribution of mechano-gated K2P channels to mouse intestinal muscle tension was studied pharmacologically using organ bath. Multiple K2P gene transcripts were detected in mouse ileum and colon whole tissue preparations. Immunohistochemistry confirmed TREK-1 expression was smooth muscle specific in both ileum and colon, whereas TREK-2 and TRAAK channels were detected in enteric neurons but not smooth muscle. In organ bath, mechano-gated K2P channel activators (Riluzole, BL-1249, flufenamic acid, and cinnamyl 1-3,4-dihydroxy-alpha-cyanocinnamate) induced relaxation of KCl and CCh pre-contracted ileum and colon tissues and reduced the amplitude of spontaneous contractions. These data reveal the specific expression of mechano-gated K2P channels in mouse ileum and colon tissues and highlight TREK-1, a smooth muscle specific K2P channel in GI tract, as a potential therapeutic target for combating motility pathologies arising from hyper-contractility.
Highlights
Gastrointestinal motility is a highly complex physiological process involving the coordinated contractions of the tunica muscularis, a layer of the outer wall of the alimentary canal formed of two sheets of circularly and longitudinally orientated smooth muscle cells
Gene transcripts encoding for TRAAK (KCNK4), TASK-3 (KCNK9), TREK-2 (KCNK10), THIK-2 (KCNK12), TASK-5 (KCNK15), and TALK-1 (KCNK16) appeared barely detectable when normalized to housekeeping gene GAPDH and may be suggestive of cell specific expression patterns or broad tissue expression at low levels
Of the Two pore-domain potassium (K2P) channels described to date, the mechano-gated TREK subfamily of K2P channels are appearing as important regulators of smooth muscle contractility (Parelkar et al, 2010; Lembrechts et al, 2011; Monaghan et al, 2011; Lei et al, 2014) and importantly, details of several activators and inhibitors for this subfamily are emerging (Vivier et al, 2016)
Summary
Gastrointestinal motility is a highly complex physiological process involving the coordinated contractions of the tunica muscularis, a layer of the outer wall of the alimentary canal formed of two sheets of circularly and longitudinally orientated smooth muscle cells. The process of smooth muscle cell excitation-contraction coupling occurs predominantly via calcium influx through plasma membrane voltage-dependent calcium channels (VDCC). The activity of VDCC is intimately linked to cell membrane potential (Sanders, 2008; Jepps et al, 2009), which is set primarily by potassium-selective (K+) channels (Koh et al, 2012). A multitude of voltage-dependent and voltageindependent K1P channels have been shown to be expressed, both molecularly and functionally, in smooth muscles of the gastrointestinal tract (for review see Koh et al, 2012)
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