| First Author | Dadi PK | Year | 2014 |
| Journal | Endocrinology | Volume | 155 |
| Issue | 10 | Pages | 3757-68 |
| PubMed ID | 24932805 | Mgi Jnum | J:218356 |
| Mgi Id | MGI:5617333 | Doi | 10.1210/en.2013-2051 |
| Citation | Dadi PK, et al. (2014) Pancreatic beta-cell-specific ablation of TASK-1 channels augments glucose-stimulated calcium entry and insulin secretion, improving glucose tolerance. Endocrinology 155(10):3757-68 |
| abstractText | Calcium entry through voltage-dependent Ca(2+) channels (VDCCs) is required for pancreatic beta-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 (Deltapsip); however, a role for pancreatic beta-cell TASK-1 channels is unknown. Here we examined the influence of TASK-1 channel activity on the beta-cell Deltapsip 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 beta-cells. TASK-1-like currents of mouse and human beta-cells were blocked by the potent TASK-1 channel inhibitor, A1899 (250nM). Although inhibition of TASK-1 currents did not influence the beta-cell Deltapsip in the presence of low (2mM) glucose, A1899 significantly enhanced glucose-stimulated (14mM) Deltapsip depolarization of human and mouse beta-cells. TASK-1 inhibition also resulted in greater secretagogue-stimulated Ca(2+) influx in both human and mouse islets. Moreover, conditional ablation of mouse beta-cell TASK-1 channels reduced K2P currents, increased glucose-stimulated Deltapsip depolarization, and augmented secretagogue-stimulated Ca(2+) influx. The Deltapsip depolarization caused by TASK-1 inhibition resulted in a transient increase in glucose-stimulated mouse beta-cell action potential (AP) firing frequency. However, secretagogue-stimulated beta-cell AP duration eventually increased in the presence of A1899 as well as in beta-cells without TASK-1, causing a decrease in AP firing frequency. Ablation or inhibition of mouse beta-cell TASK-1 channels also significantly enhanced glucose-stimulated insulin secretion, which improved glucose tolerance. Conversely, TASK-1 ablation did not perturb beta-cell Deltapsip, Ca(2+) influx, or insulin secretion under low-glucose conditions (2mM). These results reveal a glucose-dependent role for beta-cell TASK-1 channels of limiting glucose-stimulated Deltapsip depolarization and insulin secretion, which modulates glucose homeostasis. |
