Activation of electrogenic K secretion requires BK channels in guinea pig distal colon

A variety of hormones and neurotransmitters activate electrogenic K+ secretion in guinea pig distal colon, generally together with Cl− secretion. Blockers of BK channels (KCa1.1, Kcnma1), iberiotoxin (IbTx) and paxilline, inhibited the short‐circuit current (Isc) associated with K+ secretion. Consistent with this K+ secretion occurring via apical membrane BK, mucosal addition of IbTx inhibited epinephrine (epi) activation with an IC50 for Isc (epiIsc) and for transepithelial conductance (epiGt) of ~200 nM. However, maximal inhibition was only ~50%. Mucosally added paxilline [10 μM] also inhibited epiIsc and epiGt by ~50%. IbTx and paxilline each inhibited Isc activated by mucosal ATP, supporting apical BK as an absolute requirement for this K+ secretion. Sensitivity to IbTx and paxilline demonstrated K+ secretion during activation of Cl− secretion by prostaglandin‐E2 and a cholinergic agonist. Distal colonic epithelial cells expressed BKα mRNA with the ZERO splice variant and 3 splice variants for the C‐terminus. These cells also expressed the regulatory β‐subunits BKβ1 and BKβ4. Immuno‐localization demonstrated BKα in apical and basolateral membranes of surface and crypt cells. Together these results support a cellular mechanism for electrogenic K+ secretion involving activation of apical membrane BK, but epi activated K+ secretion also required opening of other K+ channel types. [NIH DK65845]