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 ) and HCO₃ ^- 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_V7.1 is not involved in duodenal ion transport, while K_Ca3.1 selectively regulates duodenal I and HCO₃ ^- secretion in a Ca²⁺-mediated but not cAMP-mediated manner. Blockade of K_Ca3.1 increased the rate of HCO₃ ^- fluxes via cystic fibrosis transmembrane conductance regulator (CFTR) channels in SCBN cells. Jejunal I 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.