Endocytosis of KATP Channels Drives Glucose-Stimulated Excitation of Pancreatic β Cells

Abstract

Summary: Insulin secretion from pancreatic β cells in response to high glucose (HG) critically depends on the inhibition of KATP channel activity in HG. It is generally believed that HG-induced effects are mediated by the increase in intracellular ATP, but here, we showed that, in INS-1 cells, endocytosis of KATP channel plays a major role. Upon HG stimulation, resting membrane potential depolarized by 30.6 mV (from −69.2 to −38.6 mV) and KATP conductance decreased by 91% (from 0.243 to 0.022 nS/pF), whereas intracellular ATP was increased by only 47%. HG stimulation induced internalization of KATP channels, causing a significant decrease in surface channel density, and this decrease was completely abolished by inhibiting endocytosis using dynasore, a dynamin inhibitor, or a PKC inhibitor. These drugs profoundly inhibited HG-induced depolarization. Our results suggest that the control of KATP channel surface density plays a greater role than ATP-dependent gating in regulating β cell excitability. : Pancreatic β cells secrete insulin when blood glucose is high because of the presence of KATP channels, which are inhibited by glucose. The mechanism of KATP channel inhibition by glucose is believed to be mediated by ATP increase, but Han et al. show that KATP channel endocytosis is a major mechanism. Keywords: pancreatic β-cells, KATP channels, endocytosis, high glucose, ATP, excitability, depolarization, protein kinase C, channel gating, channel trafficking