Mucosal potassium efflux mediated via Kcnn4 channels provides the driving force for electrogenic anion secretion in colon.
Intermediate conductance K(+) (Kcnn4) channels are present in both mucosal and serosal membranes of colon. However, only serosal Kcnn4 channels have been shown to be essential for agonist-induced (cAMP and Ca(2+)) anion secretion. The present study sought to determine whether mucosal Kcnn4 channels also play a role in colonic anion secretion. Mucosal-to-serosal and serosal-to-mucosal unidirectional (86)Rb (K(+) surrogate) fluxes as well as short-circuit current (I(sc); a measure of anion secretion) were measured under voltage-clamp conditions in distal colon from rats fed either a standard or K(+)-free diet. 5,6-Dichloro-1-ethyl-1,3-dihydro-2H-benzimidazole-2-one (DC-EBIO) was used to activate Kcnn4 channels. Mucosal DC-EBIO both induced K(+) secretion and enhanced anion secretion in normal rat distal colon. The DC-EBIO-induced K(+) secretion was completely blocked by nonspecific (Ba(2+)) and Kcnn4-specific (TRAM-34) inhibitors, but was not blocked by the large-conductance K(+) (iberiotoxin), small-conductance K(+) (apamin), or KCNQ1 (chromanol 293B) specific blockers. Ba(2+) and TRAM-34 also inhibited DC-EBIO-enhanced anion secretion. The DC-EBIO-enhanced anion secretion was completely inhibited by the nonspecific anion channel blocker 5-nitro-2-(3-phenylpropyl-amino)benzoic acid, whereas it was only partially inhibited by CFTR [CFTR(inh)-172, glibenclamide]- and CaCC (niflumic acid)-specific Cl(-) channel blockers. In contrast, mucosal DC-EBIO-enhanced K(+) and anion secretion was not present in distal colon of dietary K-depleted rats, indicating absence of mucosal Kcnn4 channels. These observations indicate that mucosal Kcnn4 channels are capable of driving agonist-induced anion secretion mediated via CFTR and CaCC and likely contribute to stool K(+) losses that accompany diarrheal illnesses.
Nanda Kumar
N S
NS
Depts. of Biochemistry and Microbiology, West Virginia Univ. School of Medicine, Morgantown, 26506, USA.
Singh
Satish K
SK
Rajendran
Vazhaikkurichi M
VM
D000818:Animals; D000838:Anions / Q000378:metabolism*; D001562:Benzimidazoles / Q000494:pharmacology; D018118:Chloride Channels / Q000235:genetics / Q000378:metabolism; D003106:Colon / Q000502:physiology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism; D017097:Electric Impedance; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D011188:Potassium / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
C507351:5,6-dichloro-1-ethyl-1,3-dihydro-2H-benzimidazol-2-one; D000838:Anions; D001562:Benzimidazoles; D018118:Chloride Channels; C504023:Clca5 protein, rat; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C491575:Kcnn4 protein, rat; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D011188:Potassium