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.