| 16763288 |
Dong H, Smith A, Hovaida M, Chow JY: Role of Ca2+-activated K+ channels in duodenal mucosal ion transport and bicarbonate secretion. Am J Physiol Gastrointest Liver Physiol. 2006 Dec;291(6):G1120-8. Epub 2006 Jun 8.
Stimulation of muscarinic receptors in the duodenal mucosa raises cytosolic free Ca (2+) concentration ([Ca (2+)](cyt)), thereby regulating duodenal epithelial ion transport. However, little is known about the downstream molecular targets that account for this Ca (2+)-mediated biological action. Ca (2+)-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 Ca (2+)-mediated duodenal epithelial ion transport. Two selective blockers of intermediate-conductance Ca (2+)-activated K (+) (IK (Ca)) channels, clotrimazole (30 muM) and 1-[(2-chlorophenyl) diphenylmethyl]-1H-pyrazole (TRAM-34; 10 muM), 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 BaCl (2) failed to inhibit CCh-induced I (sc) and DMBS. A-23187 (10 muM), a Ca (2+) 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- 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 [Ca (2+)](cyt) to mediate duodenal epithelial ion transport. |
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