Mucosal potassium efflux mediated via Kcnn4 channels provides the driving force for electrogenic anion secretion in colon

Abstract

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.

Molecular basis of potassium channels in pancreatic duct epithelial cells

“…Moreover, stimulation of the rat pancreas with secretin caused a marked increase in K + concentrations in the pancreatic juice, which was equal to twice that in the plasma, indicating that K + was secreted 25 . K + efflux was also shown to be mediated via mucosal K Ca 3.1 channels in other epithelia, such as the distal colon, and provided, in part, the driving force for agonist-induced anion secretion 26 . Another example is salivary acini, in which both K Ca 1.1 and K Ca 3.1 were shown to be expressed on the apical membrane and contribute to optimal secretion 27 .…”

Trafficking of Intermediate (KCa3.1) and Small (KCa2.x) Conductance, Ca2+‐Activated K+ Channels: a Novel Target for Medicinal Chemistry Efforts?

“…KCa3.1a appears to be found in smooth muscle [49] . Further, Kumar et al reported that agonist-dependent activation of KCa3.1c stimulated anion secretion in the rat distal colon and suggested that KCa3.1c may contribute to the stool K + losses associated with diarrheal illnesses [50] . Additional physiological roles of the splice variants of KCa3.1 will be unraveled by further investigations.…”

Mechanistic insight into the heme-independent interplay between iron and carbon monoxide in CFTR and Slo1 BKCa channels

“…Later in 2011, CORM-2, a CO donor, was also found to evoke chloride and HCO 3 − currents across the apical membrane of rat distal colon, which is blocked by another nonspecific anion blocker glibenclamide 14 . Given that HO-1 is ubiquitously distributed and apical CFTR is present in rat distal colon 40–43 , endogenous CO might be a physiological modulator of CFTR channel currents. It is interesting to employ CFTR-specific inhibitor CFTRinh172 to examine whether the CO gas increases CFTR activity by releasing inhibitive Fe 3+ from the ICL3-R interface and whether the CO effect is repeated and whether CO enhances Cl − secretion of CF-causing mutants by airway epithelial cells (Figure 1) 44 .…”