Different functional roles for K(+) channel subtypes in regulating small intestinal glucose and ion transport

Although K(+) channels are important in mediating the driving force for colonic ion transport, their role in small intestinal transport is poorly understood. To investigate this, small intestinal short circuit currents (I(sc)) and HCO(3)(−) secretion were measured in mice, and intracellular pH (pH(i)) was measured in small intestinal epithelial SCBN cells. The expression and location of Kv subtypes were verified by RT-PCR, western blotting and immunohistochemistry. Diabetic mice were also used to investigate the role of Kv subtypes in regulating intestinal glucose absorption. We found that K(V)7.1 is not involved in duodenal ion transport, while K(Ca)3.1 selectively regulates duodenal I(sc) and HCO(3)(−) secretion in a Ca(2+)-mediated but not cAMP-mediated manner. Blockade of K(Ca)3.1 increased the rate of HCO(3)(−) fluxes via cystic fibrosis transmembrane conductance regulator (CFTR) channels in SCBN cells. Jejunal I(sc) was significantly stimulated by glucose, but markedly inhibited by 4-aminopyridine (4-AP) and tetraethylammonium (TEA). Moreover, both Kv1.1 and Kv1.3 were expressed in jejunal mucosae. Finally, 4-AP significantly attenuated weight gain of normal and diabetic mice, and both 4-AP and TEA significantly lowered blood glucose of diabetic mice. This study not only examines the contribution of various K(+) channel subtypes to small intestinal epithelial ion transport and glucose absorption, but also proposes a novel concept for developing specific K(+) channel blockers to reduce weight gain and lower blood glucose in diabetes mellitus.