Pancreatic beta-cell specific ablation of TASK-1 channels augments glucose-stimulated calcium entry and insulin secretion, improving glucose tolerance.
AUTHORS
- PMID: 24932805 [PubMed].
ABSTRACT
Calcium entry through voltage dependent Ca(2+) channels (VDCCs) is required for pancreatic β-cell insulin secretion. The two-pore-domain potassium (K2P) channel, TASK-1, regulates neuronal excitability and VDCC activation by hyperpolarizing the plasma membrane potential (Δψp); 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 Δψp and insulin secretion during secretagogue stimulation. TASK-1 channels were found to be highly expressed in human and rodent islets and localized to the plasma membrane of β-cells. TASK-1-like currents of mouse and human β-cells were blocked by the potent TASK-1 channel inhibitor, A1899 (250 nM). While inhibition of TASK-1 currents did not influence the β-cell Δψp in the presence of low (2mM) glucose, A1899 significantly enhanced glucose-stimulated (14 mM) Δψp depolarization of human and mouse β-cells. TASK-1 inhibition also resulted in greater secretagogue-stimulated Ca(2+) influx in both human and mouse islets. Moreover, conditional ablation of mouse β-cell TASK-1 channels reduced K2P currents, increased glucose-stimulated Δψp depolarization and augmented secretagogue-stimulated Ca(2+) influx. The Δψp 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 Δψp, Ca(2+) influx or insulin secretion under low glucose conditions (2 mM). These results reveal a glucose-dependent role for β-cell TASK-1 channels of limiting glucose-stimulated Δψp depolarization and insulin secretion, which modulates glucose homeostasis.
Calcium entry through voltage dependent Ca(2+) channels (VDCCs) is required for pancreatic β-cell insulin secretion. The two-pore-domain potassium (K2P) channel, TASK-1, regulates neuronal excitability and VDCC activation by hyperpolarizing the plasma membrane potential (Δψp); 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 Δψp and insulin secretion during secretagogue stimulation. TASK-1 channels were found to be highly expressed in human and rodent islets and localized to the plasma membrane of β-cells. TASK-1-like currents of mouse and human β-cells were blocked by the potent TASK-1 channel inhibitor, A1899 (250 nM). While inhibition of TASK-1 currents did not influence the β-cell Δψp in the presence of low (2mM) glucose, A1899 significantly enhanced glucose-stimulated (14 mM) Δψp depolarization of human and mouse β-cells. TASK-1 inhibition also resulted in greater secretagogue-stimulated Ca(2+) influx in both human and mouse islets. Moreover, conditional ablation of mouse β-cell TASK-1 channels reduced K2P currents, increased glucose-stimulated Δψp depolarization and augmented secretagogue-stimulated Ca(2+) influx. The Δψp 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 Δψp, Ca(2+) influx or insulin secretion under low glucose conditions (2 mM). These results reveal a glucose-dependent role for β-cell TASK-1 channels of limiting glucose-stimulated Δψp depolarization and insulin secretion, which modulates glucose homeostasis.
Tags: 2014