Two-Pore-Domain TASK-1 Potassium Channels Modulate Pancreatic Islet Glucagon Secretion

Abstract

Glucose regulation of pancreatic alpha-cell Ca2+ entry through voltage-dependent Ca2+ channels is essential for normal glucagon secretion and becomes defective during the pathogenesis of diabetes mellitus. The two-pore-domain potassium (K2P) channel, TASK-1, is an important modulator of membrane voltage and Ca2+ entry, however, its role in alpha-cells has not been determined. Therefore, we addressed how TASK-1 channels modulate alpha-cell electrical activity, calcium entry and glucagon secretion. We find that TASK-1 channels are expressed in human and rodent alpha-cells. Furthermore, alpha-cell K2P currents are blocked by the specific and potent TASK-1 channel inhibitor A1899. Alpha-cell K2P currents are also significantly reduced following ablation of mouse alpha-cell TASK-1 channels. Inhibition of TASK-1 channels with A1899 causes membrane potential depolarization in both the human and mouse alpha-cells, which results in increased Ca2+ influx. While A1899 augments alpha-cell Ca2+ influx under low (1 mM) and high (14 mM) glucose conditions, treatment of mouse and human islets with A1899 only increases glucagon secretion under elevated (14 mM) glucose conditions. Therefore, these data suggest an important role for TASK-1 channels in limiting alpha-cell excitability and glucagon secretion during glucose stimulation. Interestingly, we also find that TASK-1 expression is reduced during the progression of type-2 diabetes mellitus in human islets. Thus, decreased TASK-1 channel activity may exacerbate the defective glucose inhibition of glucagon secretion observed in type-2 diabetes mellitus.