Aldosterone and β‐Adrenergic Activation of Colonic K + Secretion Requires BK Channels (K Ca 1.1)

Abstract

Aldosterone (aldo) and epinephrine (epi) activate electrogenic K+ secretion in distal colon via a cellular mechanism involving apical membrane K+ channels and basolateral Cl- channels. Epi [10 μM] activated a short-circuit current (epiIsc) in ex vivo mouse distal colon (C57BL/6) consistent with transient Cl- secretion and sustained K+ secretion. Prior addition of peptide-YY [0.3 μM] suppressed transient epiIsc revealing sustained epiIsc within 5 min after epi addition. Aldo [1 μM] activated a sustained Isc consistent with K+ secretion after a delay of ~20 min; subsequent epi addition further stimulated Isc in a non-additive manner suggesting that epi alone produced maximal K+ secretion. Secretory activation also was measured in age-matched litter-mates lacking the slo-gene product (BK-knockout). epiIsc in BKKO distal colon was a small transient with a steady-state similar to basal, and aldoIsc remained similar to pre-stimulation Isc. Addition of the BK blockers paxilline or iberiotoxin (IbTx) inhibited epiIsc in wild-type colon supporting a requirement for this channel in the apical membrane. Low sensitivity to IbTx suggests involvement of the β-subunits kcnmb1 or kcnmb4. Basal Isc was more positive in BKKO colon than wildtype consistent with Cl- secretion. Addition of the Ca++-activated Cl- channel blocker CaCCinh-A01 [30 μM] in wild-type increased basalIsc with a resulting Isc similar to basalIsc in BKKO. Partial inhibition of basalIsc by the CFTR Cl- channel blocker CFTRinh-172 [30 μM] suggests an unmasking of basal Cl- secretion in BKKO colon. These results indicate a near complete dependence of electrogenic K+ secretion on the presence of the BK K+ channel in the apical membrane of the mouse distal colonic epithelium. [WSU-BSoM Seed Grant]