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HORMONES AND SIGNALING

Role of Ca²⁺-activated K⁺ channels in duodenal mucosal ion transport and bicarbonate secretion

Division of Gastroenterology, Department of Medicine, School of Medicine, University of California, San Diego, California

Submitted 16 December 2005 ; accepted in final form 21 May 2006

Stimulation of muscarinic receptors in the duodenal mucosa raises cytosolic free Ca²⁺ concentration ([Ca²⁺]_cyt), thereby regulating duodenal epithelial ion transport. However, little is known about the downstream molecular targets that account for this Ca²⁺-mediated biological action. Ca²⁺-activated K⁺ (K_Ca) channels are candidates, but the expression and function of duodenal K_Ca channels are poorly understood. Therefore, we determined whether K_Ca channels are expressed in the duodenal mucosa and investigated their involvement in Ca²⁺-mediated duodenal epithelial ion transport. Two selective blockers of intermediate-conductance Ca²⁺-activated K⁺ (IK_Ca) channels, clotrimazole (30 µM) and 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34; 10 µM), significantly inhibited carbachol (CCh)-induced duodenal short-circuit current (I_sc) and duodenal mucosal bicarbonate secretion (DMBS) in mice but did not affect responses to forskolin and heat-stable enterotoxin of Escherichia coli. Tetraethylammonium, 4-aminopyridine, and BaCl₂ failed to inhibit CCh-induced I_sc and DMBS. A-23187 (10 µM), a Ca²⁺ ionophore, and 1-ethyl-2-benzimidazolinone (1-EBIO; 1 mM), a selective opener of K_Ca channels, increased both I_sc and DMBS. The effect of 1-EBIO was more pronounced with serosal than mucosal addition. Again, both clotrimazole and TRAM-34 significantly reduced A23187 [GenBank] - or 1-EBIO-induced I_sc and DMBS. Moreover, clotrimazole (20 mg/kg ip) significantly attenuated acid-stimulated DMBS of mice in vivo. Finally, the molecular identity of IK_Ca channels was verified as KCNN4 (SK4) in freshly isolated murine duodenal mucosae by RT-PCR and Western blotting. Together, our results suggest that the IK_Ca channel is one of the downstream molecular targets for [Ca²⁺]_cyt to mediate duodenal epithelial ion transport.

cytosolic free Ca²⁺; mouse duodenum; KCNN4

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