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 (K _Ca 1.1, Kcnma1 ), iberiotoxin (IbTx) and paxilline, inhibited the short-circuit current (I _sc ) associated with K ⁺ secretion. Consistent with this K ⁺ secretion occurring via apical membrane BK, mucosal addition of IbTx inhibited epinephrine (epi) activation with an IC ₅₀ for I _sc ( ^epi I _sc ) and for transepithelial conductance ( ^epi G _t ) of ~200 nM. However, maximal inhibition was only ~50%. Mucosally added paxilline [10 μM] also inhibited ^epi I _sc and ^epi G _t by ~50%. IbTx and paxilline each inhibited I _sc 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-E ₂ 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.