Intact colonic K_Ca1.1 channel activity in KCNMB2 knockout mice

Mammalian potassium homeostasis results from tightly regulated renal and colonic excretion, which balances the unregulated dietary K⁺ intake. Colonic K⁺ secretion follows the pump-leak model, in which the large conductance Ca²⁺-activated K⁺ channel (K_Ca1.1) is well established as the sole, but highly regulated apical K⁺ conductance. The physiological importance of auxiliary β and γ subunits of the pore-forming α-subunit of the K_Ca1.1 channel is not yet fully established. This study investigates colonic K⁺ secretion in a global knockout mouse of the K_Ca1.1-β2-subunit (KCNMB2^-/-), which apparently is the only β-subunit of the colonic enterocyte K_Ca1.1 channel. We can report that: (1) Neither K_Ca1.1 α- nor the remaining β-subunits were compensatory transcriptional regulated in colonic epithelia of KCNMB2^-/- mice. (2) Colonic epithelia from KCNMB2^-/- mice displayed equal basal and ATP-induced K_Ca1.1-mediated K⁺ conductance as compared to KCNMB2^+/+ (3) K⁺ secretion was increased in KCNMB2^-/- epithelia compared to wild-type epithelia from animals fed an aldosterone-inducing diet. (4) Importantly, the apical K⁺ conductance was abolished by the specific blocker of K_Ca1.1 channel iberiotoxin in both KCNMB2^+/+ and KCNMB2^-/- mice. Recently a novel family of auxiliary γ-subunits of the K_Ca1.1 channel has been described. (5) We detected the γ1-subunit (LRRC26) mRNA in colonic epithelia. To investigate the physiological role of the γ1-subunit of K_Ca1.1 channels in colonic K⁺ secretion, we acquired an LRRC26 knockout mouse. (6) Unexpectedly, LRRC26 mice had a perinatal lethal phenotype, thus preventing functional measurements. On this basis we conclude that colonic K⁺ secretion is intact or even increased in mice lacking the β2-subunit of K_Ca1.1 channel complex despite no additional compensatory induction of K_Ca1.1 β-subunits.