Molecular and functional characterization of Kv7 K+ channel in murine gastrointestinal smooth muscles.
Members of the K(v)7 voltage-gated K(+) channel family are important determinants of cardiac and neuronal membrane excitability. Recently, we and others have shown that K(v)7 channels are also crucial regulators of smooth muscle activity. The aim of the present study was to assess the K(v)7 expression in different parts of the murine gastrointestinal (GI) tract and to assess their functional roles by use of pharmacological agents. Of KCNQ/K(v)7 members, both KCNQ4/K(v)7.4 and KCNQ5/K(v)7.5 genes and proteins were the most abundantly expressed K(v)7 channels in smooth muscles throughout the GI tract. Immunohistochemical staining also revealed that K(v)7.4 and K(v)7.5 but not K(v)7.1 were expressed in the circular muscle layer of the colon. In segments of distal colon circular muscle exhibiting spontaneous phasic contractions, the nonselective K(v)7 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 K(v)7.1-selective blocker chromanol 293B had no effect in either type of segment. These data show that K(v)7.x especially K(v)7.4 and K(v)7.5 are expressed in different regions of the murine gastrointestinal tract and blockers of K(v)7 channels augment inherent contractile activity. Drugs that selectively block K(v)7.4/7.5 might be promising therapeutics for the treatment of motility disorders such as constipation associated with irritable bowel syndrome.
Jepps
Thomas A
TA
Division of Basic Medical Sciences, St George's, University of London, London, United Kingdom.
Greenwood
Iain A
IA
Moffatt
James D
JD
Sanders
Kenton M
KM
Ohya
Susumu
S
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D015153:Blotting, Western; D002219:Carbamates / Q000494:pharmacology; D002839:Chromans / Q000494:pharmacology; D003106:Colon / Q000378:metabolism; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000378:metabolism*; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology; D051656:KCNQ Potassium Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051657:KCNQ1 Potassium Channel / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism*; D009213:Myography; D010655:Phenylenediamines / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology
C112297:10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone; D000873:Anthracenes; D002219:Carbamates; D002839:Chromans; D007211:Indoles; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; C506326:KCNQ5 channel, mouse; C496910:Kcnq1 protein, mouse; C492167:Kcnq4 protein, mouse; D010655:Phenylenediamines; D026902:Potassium Channel Blockers; D011725:Pyridines; D013449:Sulfonamides; C101866:ezogabine; C103474:6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethylchromane; C061017:linopirdine