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MUCOSAL BIOLOGY

Active K⁺ secretion through multiple K_Ca-type channels and regulation by IK_Ca channels in rat proximal colon

Departments of ¹Pharmacology, ²Cellular and Molecular Physiology, and ³Internal Medicine, Yale University, New Haven, Connecticut 06520; ⁴Center for Oral Biology, Aab Institute for Biomedical Research, University of Rochester Medical Center, Rochester, New York 14642

Submitted 13 August 2002 ; accepted in final form 15 February 2003

Colonic K⁺ secretion stimulated by cholinergic agents requires activation of muscarinic receptors and the release of intracellular Ca²⁺. However, the precise mechanisms by which this rise in Ca²⁺ leads to K⁺ efflux across the apical membrane are poorly understood. In the present study, Northern blot analysis of rat proximal colon revealed the presence of transcripts encoding rSK2 [small conductance (SK)], rSK4 [intermediate conductance (IK)], and rSlo [large conductance (BK)] Ca²⁺-activated K⁺ channels. In dietary K⁺-depleted animals, only rSK4 mRNA was reduced in the colon. On the basis of this observation, a cDNA encoding the K⁺ channel rSK4 was cloned from a rat colonic cDNA library. Transfection of this cDNA into Chinese hamster ovary (CHO) cells led to the expression of Ca²⁺-activated K⁺ channels that were blocked by the IK channel inhibitor clotrimazole (CLT). Confocal immunofluorescence confirmed the presence of IK channels in proximal colonic crypts, and Western blotting demonstrated that IK protein sorted to both the apical and basolateral surfaces of colonic epithelia. In addition, transcellular active K⁺ secretion was studied on epithelial strips of rat proximal colon using unidirectional ⁸⁶Rb⁺ fluxes. The addition of thapsigargin or carbachol to the serosal surface enhanced net ⁸⁶Rb⁺ secretion. The mucosal addition of CLT completely inhibited carbachol-induced net ⁸⁶Rb⁺ secretion. In contrast, only partial inhibition was observed with the BK and SK channel inhibitors, iberiotoxin and apamin, respectively. Finally, in parallel with the reduction in SK4 message observed in animals deprived of dietary K⁺, carbachol-induced ⁸⁶Rb⁺ secretion was abolished in dietary K⁺-depleted animals. These results suggest that the rSK4 channel mediates K⁺ secretion induced by muscarinic agonists in the rat proximal colon and that transcription of the rSK4 channel is downregulated to prevent K⁺ loss during dietary K⁺ depletion.

intermediate conductance Ca²⁺-activated K⁺ channel; intermediate-conductance channel; carbachol; clotrimazole; ⁸⁶RB⁺ flux; K⁺ depletion

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