Medizinische Universität Graz - Research portal
Selected Publication:
SHR Neuro Cancer Cardio Lipid Metab Microb
Tang, B; Li, Y; Nagaraj, C; Morty, RE; Gabor, S; Stacher, E; Voswinckel, R; Weissmann, N; Leithner, K; Olschewski, H; Olschewski, A.
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; 41(4): 476-483.
Doi: 10.1165/rcmb.2008-0412OC
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- Co-authors Med Uni Graz
- Chandran Nagaraj
- Gabor Sabine
- Leithner Katharina
- Li Yingji
- Olschewski Andrea
- Olschewski Horst
- Stacher-Priehse Elvira
- Tang Bi
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- Abstract:
- 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.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- Arachidonic Acids - pharmacology
- Drug Synergism -
- Endothelin-1 - pharmacology
- Humans -
- Lung - blood supply
- Membrane Potentials - drug effects
- Mice -
- Mice, Inbred C57BL -
- Myocytes, Smooth Muscle - drug effects
- Nerve Tissue Proteins - antagonists and inhibitors
- Patch-Clamp Techniques -
- Perfusion -
- Phosphorylation - drug effects
- Polyunsaturated Alkamides - pharmacology
- Potassium - metabolism
- Potassium Channels, Tandem Pore Domain - antagonists and inhibitors
- Pressure -
- Protein Processing, Post-Translational - drug effects
- Pulmonary Artery - cytology
- Signal Transduction - drug effects
- Vasoconstriction - drug effects
- Find related publications in this database (Keywords)
- endothelin-1
- TASK-1 channel
- membrane potential
- pulmonary hypertension