1 Department of Physiology and Biophysics, Faculty of Health Sciences, Aarhus University, Aarhus University2 Department of Biomedicine - Forskning og uddannelse, Vest, Department of Biomedicine, Health, Aarhus University3 University of Tübingen4 Hannover Medical School5 Department of Biomedicine - Forskning og uddannelse, Vest, Department of Biomedicine, Health, Aarhus University
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, Ca(2+)-activated K(Ca)1.1 (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 Ca(2+)-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 alpha-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.
Journal of Physiology, 2010, Vol 588, p. 1763-1777