Pancreatic β-cell-specific ablation of TASK-1 channels augments glucose-stimulated calcium entry and insulin secretion, improving glucose tolerance

Abstract

Calcium entry through voltage-dependent Ca2+channels (VDCCs) is required for pancreatic β-cell insulin secretion. The 2-pore-domain acid-sensitive potassium channel (TASK-1) regulates neuronal excitability and VDCC activation by hyperpolarizing the plasma membrane potential (Δφp); however, a role for pancreatic β-cell TASK-1 channels is unknown. Here we examined the influence of TASK-1 channel activity on the β-cell Δφp and insulin secretion during secretagogue stimulation. TASK-1 channels were found to be highly expressed in human and rodent islets and localized to the Plasmamembraneofβ-cells. TASK-1-like currents of mouse andhumanβ-cells were blocked by the potent TASK-1 channel inhibitor, A1899 (250nM). Although inhibition of TASK-1 currents did not influence the β-cell Δφp in the presence of low (2mM) glucose, A1899 significantly enhanced glucose-stimulated(14mM) Δφpdepolarization ofhumanandmouseβ-cells. TASK-1 inhibition also resulted in greater secretagogue-stimulated Ca2+influx in both human and mouse islets. Moreover, conditional ablation of mouse β-cell TASK-1 channels reduced K2P currents, increased glucose- stimulated Δφp depolarization, and augmented secretagogue-stimulated Ca2+influx. The Δφp depolarization caused by TASK-1 inhibition resulted in a transient increase in glucose-stimulated mouse β-cell action potential (AP) firing frequency. However, secretagogue-stimulated β-cell AP duration eventually increased in the presence of A1899 as well as in β-cells without TASK-1, causing a decrease in AP firing frequency. Ablation or inhibition of mouse β-cell TASK-1 channels also significantly enhanced glucose-stimulated insulin secretion, which improved glucose tolerance. Conversely, TASK-1 ablation did not perturb β-cell Δφp, Ca2+influx, or insulin secretion under low-glucose conditions (2mM). These results reveal a glucose-dependent role for β-cell TASK-1 channels of limiting glucose-stimulated Δφp depolarization and insulin secretion, which modulates glucose homeostasis. Copyright