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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 2-pore domain K channel, TWIK-related acid-sensitive K channel 1 (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 regulate [alpha]-cell electrical activity, Ca2 entry, and glucagon secretion. We find that TASK-1 channels expressed in human and rodent [alpha]-cells are blocked by the TASK-1 channel inhibitor A1899. Alpha-cell 2-pore domain K currents were also significantly reduced after ablation of mouse [alpha]-cell TASK-1 channels. Inhibition of TASK-1 channels with A1899 caused plasma membrane potential depolarization in both human and mouse [alpha]-cells, which resulted in increased electrical excitability. Moreover, ablation of [alpha]-cell TASK-1 channels increased [alpha]-cell electrical excitability under elevated glucose (11mM) conditions compared with control [alpha]-cells. This resulted in significantly elevated [alpha]-cell Ca2 influx when TASK-1 channels were inhibited in the presence of high glucose (14mM). However, there was an insignificant change in [alpha]-cell Ca2 influx after TASK-1 inhibition in low glucose (1mM). Glucagon secretion from mouse and human islets was also elevated specifically in high (11mM) glucose after acute TASK-1 inhibition. Interestingly, mice deficient for [alpha]-cell TASK-1 showed improvements in both glucose inhibition of glucagon secretion and glucose tolerance, which resulted from the chronic loss of [alpha]-cell TASK-1 currents. Therefore, these data suggest an important role for TASK-1 channels in limiting [alpha]-cell excitability and glucagon secretion during glucose stimulation.

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