Adrenaline-induced colonic K+secretion is mediated by KCa1.1 (BK) channels

Colonic epithelial K+ secretion is a two-step transport process with initial K+ uptake over the basolateral membrane followed by K+ channel-dependent exit into the lumen. In this process the large-conductance, Ca2+-activated KCa1.1 (BK) channel has been identified as the only apparent secretory K+ channel in the apical membrane of the murine distal colon. The BK channel is responsible for both resting and Ca2+-activated colonic K+ secretion and is up-regulated by aldosterone. Agonists (e.g. adrenaline) that elevate cAMP are potent activators of distal colonic K+ secretion. However, the secretory K+ channel responsible for cAMP-induced K+ secretion remains to be defined. In this study we used the Ussing chamber to identify adrenaline-induced electrogenic K+ secretion. We found that the adrenaline-induced electrogenic ion secretion is a compound effect dominated by anion secretion and a smaller electrically opposing K+ secretion. Using tissue from (i) BK wildtype (BK+/+) and knockout (BK−/−) and (ii) cystic fibrosis transmembrane regulator (CFTR) wildtype (CFTR+/+) and knockout (CFTR−/−) mice we were able to isolate the adrenaline-induced K+ secretion. We found that adrenaline-induced K+ secretion: (1) is absent in colonic epithelia from BK−/− mice, (2) is greatly up-regulated in mice on a high K+ diet and (3) is present as sustained positive current in colonic epithelia from CFTR−/− mice. We identified two known C-terminal BK α-subunit splice variants in colonic enterocytes (STREX and ZERO). Importantly, the ZERO variant known to be activated by cAMP is differentially up-regulated in enterocytes from animals on a high K+ diet. In summary, these results strongly suggest that the adrenaline-induced distal colonic K+ secretion is mediated by the BK channel and probably involves aldosterone-induced ZERO splice variant up-regulation.