Endothelin-1 inhibits background two-pore domain channel TASK-1 in primary human pulmonary artery smooth muscle cells

Am J Respir Cell Mol Biol. 2009 Oct;41(4):476-83. doi: 10.1165/rcmb.2008-0412OC. Epub 2009 Feb 2.


Endothelin (ET)-1 causes long-lasting vasoconstriction and vascular remodeling by interacting with specific G-protein-coupled receptors in pulmonary artery smooth muscle cells (PASMCs), and thus plays an important role in the pathophysiology of pulmonary arterial hypertension. The two-pore domain K(+) channel, TASK-1, controls the resting membrane potential in human PASMCs (hPASMCs), and renders these cells sensitive to a variety of vasoactive factors, as previously shown. ET-1 may exert its vasoconstrictive effects in part by targeting TASK-1. To clarify this, we analyzed the ET-1 signaling pathway related to TASK-1 in primary hPASMCs. We employed the whole-cell patch-clamp technique combined with TASK-1 small interfering RNA (siRNA) in hPASMC and the isolated, perfused, and ventilated mouse lung model. We found that ET-1 depolarized primary hPASMCs by phosphorylating TASK-1 at clinically relevant concentrations. The ET sensitivity of TASK-1 required ET(A) receptors, phospholipase C, phosphatidylinositol 4,5-biphosphate, diacylglycerol, and protein kinase C in primary hPASMCs. The ET-1 effect on membrane potential and TASK-1 was abrogated using TASK-1 siRNA. This is the first time that the background K(+) channel, TASK-1, has been identified in the ET-1-mediated depolarization in native hPASMC, and might represent a novel pathologic mechanism related to pulmonary arterial hypertension.

MeSH terms

  • Animals
  • Arachidonic Acids / pharmacology
  • Drug Synergism
  • Endocannabinoids
  • Endothelin-1 / pharmacology*
  • Endothelin-1 / physiology
  • Humans
  • Lung / blood supply
  • Lung / drug effects
  • Lung / metabolism
  • Membrane Potentials / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Myocytes, Smooth Muscle / drug effects*
  • Myocytes, Smooth Muscle / metabolism
  • Nerve Tissue Proteins / antagonists & inhibitors*
  • Nerve Tissue Proteins / metabolism
  • Patch-Clamp Techniques
  • Perfusion
  • Phosphorylation / drug effects
  • Polyunsaturated Alkamides / pharmacology
  • Potassium / metabolism
  • Potassium Channels, Tandem Pore Domain / antagonists & inhibitors*
  • Potassium Channels, Tandem Pore Domain / metabolism
  • Pressure
  • Protein Processing, Post-Translational / drug effects
  • Pulmonary Artery / cytology*
  • Pulmonary Artery / drug effects
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Vasoconstriction / drug effects*
  • Vasoconstriction / physiology


  • Arachidonic Acids
  • Endocannabinoids
  • Endothelin-1
  • Nerve Tissue Proteins
  • Polyunsaturated Alkamides
  • Potassium Channels, Tandem Pore Domain
  • potassium channel subfamily K member 3
  • Potassium
  • anandamide