title: Enhanced K(+) secretion in dextran sulfate-induced colitis reflects upregulation of large conductance apical K(+) channels (BK; Kcnma1).
abstract: Defective colonic Na(+) and Cl(-) absorption is a feature of active ulcerative colitis (UC), but little is known about changes in colonic K(+) transport. We therefore investigated colonic K(+) transport in a rat model of dextran sulfate-induced colitis. Colitis was induced in rat distal colon using 5% dextran sulfate sodium (DSS). Short-circuit current (Isc, indicating electrogenic ion transport) and (86)Rb (K(+) surrogate) fluxes were measured in colonic mucosa mounted in Ussing chambers under voltage-clamp conditions in the presence of mucosal orthovanadate (a P-type ATPase inhibitor). Serum aldosterone was measured by immunoassay. Control animals exhibited zero net K(+) flux. By contrast, DSS-treated animals exhibited active K(+) secretion, which was inhibited by 98, 76, and 22% by Ba(2+) (nonspecific K(+) channel blocker), iberiotoxin (IbTX; BK channel blocker), and TRAM-34 (IK channel blocker), respectively. Apical BK channel α-subunit mRNA abundance and protein expression, and serum aldosterone levels in DSS-treated animals, were enhanced 6-, 3-, and 6-fold respectively, compared with controls. Increasing intracellular Ca(2+) with carbachol (CCH), or intracellular cAMP with forskolin (FSK), stimulated both active Cl(-) secretion and active K(+) secretion in controls but had no or little effect in DSS-treated animals. In DSS-induced colitis, active K(+) secretion involves upregulation of apical BK channel expression, which may be aldosterone-dependent, whereas Cl(-) secretion is diminished. Since similar ion transport abnormalities occur in patients with UC, diarrhea in this disease may reflect increased colonic K(+) secretion (rather than increased Cl(-) secretion), as well as defective Na(+) and Cl(-) absorption.
authors.affiliation: Department of Biochemistry and Molecular Biology, West Virginia University School of Medicine, Morgantown, West Virginia; and.
authors.forename: Basalingappa M
authors.initials: BM
authors.lastname: Kanthesh
authors.forename: Geoffrey I
authors.initials: GI
authors.lastname: Sandle
authors.forename: Vazhaikkurichi M
authors.initials: VM
authors.lastname: Rajendran
mesh_terms: D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism*; D016264:Dextran Sulfate / Q000633:toxicity*; D017136:Ion Transport / Q000187:drug effects / Q000502:physiology; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000096:biosynthesis*; D008297:Male; D009924:Organ Culture Techniques; D011188:Potassium / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
chemical_list: C494842:Kcnma1 protein, rat; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D016264:Dextran Sulfate; D011188:Potassium
keywords: aldosterone; chloride secretion; colitis; potassium channels; potassium secretion