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

Endocrinology. 2014 Oct;155(10):3757-68. doi: 10.1210/en.2013-2051. Epub 2014 Jun 16.


Calcium entry through voltage-dependent Ca(2+) 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 (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 (250nM). Although inhibition of TASK-1 currents did not influence the β-cell Δψp in the presence of low (2mM) glucose, A1899 significantly enhanced glucose-stimulated (14mM) 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 (2mM). 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Calcium / metabolism*
  • Calcium Signaling / drug effects
  • Cells, Cultured
  • Female
  • Glucose / pharmacology*
  • Glucose Intolerance / genetics*
  • Glucose Intolerance / metabolism
  • Humans
  • Insulin / metabolism*
  • Insulin Secretion
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism*
  • Male
  • Membrane Potentials / drug effects
  • Membrane Potentials / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • Organ Specificity / genetics
  • Potassium Channels, Tandem Pore Domain / genetics*
  • Potassium Channels, Tandem Pore Domain / metabolism


  • Insulin
  • Nerve Tissue Proteins
  • Potassium Channels, Tandem Pore Domain
  • potassium channel subfamily K member 3
  • Glucose
  • Calcium