title: TASK-1 Potassium Channels Limit Pancreatic α-Cell Calcium Influx and Glucagon Secretion.
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.
authors: Department of Molecular Physiology and Biophysics (P.K.D., N.C.V., D.A.J.), Vanderbilt University, Nashville, Tennessee 37232-0615; and University of Oklahoma College of Medicine (B.L.), Oklahoma City, Oklahoma 73104-5042.
authors: Prasanna K
authors: PK
authors: Dadi
authors: Brooke
authors: B
authors: Luo
authors: Nicholas C
authors: NC
authors: Vierra
authors: David A
authors: DA
authors: Jacobson
mesh_terms: D000818:Animals; D020013:Calcium Signaling; D002478:Cells, Cultured; D005260:Female; D015870:Gene Expression; D005934:Glucagon / Q000378:metabolism*; D050416:Glucagon-Secreting Cells / Q000378:metabolism*; D005947:Glucose / Q000502:physiology; D006801:Humans; D008297:Male; D053078:Membrane Potential, Mitochondrial; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000502:physiology*; D024683:Potassium Channels, Tandem Pore Domain / Q000502:physiology*
chemical_list: D009419:Nerve Tissue Proteins; D024683:Potassium Channels, Tandem Pore Domain; C420132:potassium channel subfamily K member 3; D005934:Glucagon; D005947:Glucose