Molecular and functional characterization of Kv7 K+ channel in murine gastrointestinal smooth muscles

Abstract

Members of the Kv7 voltage-gated K+ channel family are important determinants of cardiac and neuronal membrane excitability. Recently, we and others have shown that Kv7 channels are also crucial regulators of smooth muscle activity. The aim of the present study was to assess the Kv7 expression in different parts of the murine gastrointestinal (GI) tract and to assess their functional roles by use of pharmacological agents. Of KCNQ/Kv7 members, both KCNQ4/Kv7.4 and KCNQ5/Kv7.5 genes and proteins were the most abundantly expressed Kv7 channels in smooth muscles throughout the GI tract. Immunohistochemical staining also revealed that Kv7.4 and Kv7.5 but not Kv7.1 were expressed in the circular muscle layer of the colon. In segments of distal colon circular muscle exhibiting spontaneous phasic contractions, the nonselective Kv7 blockers XE991 and linopirdine increased the integral of tension. Increases in the integral of tension were also observed under conditions of neuronal blockade. Similar effects, although less marked, were observed in the proximal colon. As expected, the Kv7.1-selective blocker chromanol 293B had no effect in either type of segment. These data show that Kv7.x especially Kv7.4 and Kv7.5 are expressed in different regions of the murine gastrointestinal tract and blockers of Kv7 channels augment inherent contractile activity. Drugs that selectively block Kv7.4/7.5 might be promising therapeutics for the treatment of motility disorders such as constipation associated with irritable bowel syndrome.