2180-P: HERG2 Channel Plays a Key Role in Insulin Secretion

Abstract

Background: Glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells is mainly mediated by KATP channels. A problem commonly associated with drugs like the sulfonylureas, KATP channel inhibitor, is that KATP current inhibition is independent of the basal glucose levels and hypoglycemia is frequently observed. Nevertheless, the role of non-KATP K+ channels in insulin secretion is largely unknown. Here, we show that a voltage-gated K+ (Kv) channel, HERG2, plays a key role in insulin secretion. Aims: To investigate the effects of HERG2 channel in β-cells. Methods: Using TALEN-based method, we created Herg2 gene knock out (KO) mice. Patch-clamp experiments were performed to record Kv currents and action potential in primary cultured β-cells from wild type (WT) and KO mice. INS-1 cells, rat β-cell line, were transfected with shRNA of Herg2 gene or scramble shRNA to generated Herg2 transiently knock down (KD) or WT cells. Glucose-stimulated calcium levels were measured and GSIS experiments were performed in INS-1WT and INS-1KD cells. Results: The Kv currents of β-cells from the KO mice decreased approximately 37.6% compared with that of the WT mice, indicating HERG2 channel constitutes 37.6% of all Kv currents. The action potential duration was significantly prolonged in KO β-cells, whereas the action potential magnitude and resting potential remained unchanged compared with WT β-cells. INS-1KD showed enhanced glucose-induced elevation of the intracellular Ca2+ concentrations, the most important ion that triggers insulin secretion in β-cell. Consistently, Herg2 knockdown significantly enhanced insulin secretion at a high glucose concentration, but did not potentiate insulin secretion at basal glucose concentration, suggesting the glucose-dependent insulin secretion of HERG2 channel. Conclusions HERG2, as a non-KATP K+ channel, regulates the action potential duration of β-cells and plays a key role in insulin secretion. Inhibition of HERG2 currents leads to enhanced insulin secretion only in high glucose levels. Disclosure M. Zhao: None. J. Yang: None.