TASK-1 Potassium Channels Limit Pancreatic α-Cell Calcium Influx and Glucagon Secretion.
AUTHORS
- PMID: 25849724 [PubMed].
- PMCID: PMC4415209.
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 2-pore domain K(+) channel, TWIK-related acid-sensitive K(+) channel 1 (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 2-pore domain K(+) currents were also significantly reduced after 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 with 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 after TASK-1 inhibition in low glucose (1 mM). Glucagon secretion from mouse and human islets was also elevated specifically in high (11 mM) glucose after 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.
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 2-pore domain K(+) channel, TWIK-related acid-sensitive K(+) channel 1 (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 2-pore domain K(+) currents were also significantly reduced after 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 with 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 after TASK-1 inhibition in low glucose (1 mM). Glucagon secretion from mouse and human islets was also elevated specifically in high (11 mM) glucose after 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.
Tags: 2015