• Dadi PK, Luo B, Vierra NC, Jacobson DA. TASK-1 potassium channels limit pancreatic alpha-cell calcium influx and glucagon secretion. Molecular endocrinology (Baltimore, Md.). 2015 Apr 7. me20141321. PMID: 25849724 [PubMed].

Abstract 

Glucose regulation of pancreatic α-cell Ca(2+) entry through voltage-dependent Ca(2+) 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 Ca(2+) entry, however, its role in α-cells has not been determined. Therefore, we addressed how TASK-1 channels regulate α-cell electrical activity, Ca(2+) entry, and glucagon secretion. We find that TASK-1 channels expressed in human and rodent α-cells are blocked by the TASK-1 channel inhibitor A1899. Alpha-cell K2P currents were also significantly reduced following ablation of mouse α-cell TASK-1 channels. Inhibition of TASK-1 channels with A1899 caused plasma membrane potential depolarization in both human and mouse α-cells, which resulted in increased electrical excitability. Moreover, ablation of α-cell TASK-1 channels increased α-cell electrical excitability under elevated glucose (11 mM) conditions compared to control α-cells. This resulted in significantly elevated α-cell Ca(2+) influx when TASK-1 channels were inhibited in the presence of high glucose (14 mM), however, there was an insignificant change in α-cell Ca(2+) influx following TASK-1 inhibition in low glucose (1 mM). Glucagon secretion from mouse and human islets was also elevated specifically in high (11 mM) glucose following acute TASK-1 inhibition. Interestingly, mice deficient for α-cell TASK-1 showed improvements in both glucose inhibition of glucagon secretion and glucose tolerance, which resulted from the chronic loss of α-cell TASK-1 currents. Therefore, these data suggest an important role for TASK-1 channels in limiting α-cell excitability and glucagon secretion during glucose stimulation.