Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Olschewski, A; Li, Y; Tang, B; Hanze, J; Eul, B; Bohle, RM; Wilhelm, J; Morty, RE; Brau, ME; Weir, EK; Kwapiszewska, G; Klepetko, W; Seeger, W; Olschewski, H.
Impact of TASK-1 in human pulmonary artery smooth muscle cells.
Circ Res. 2006; 98(8):1072-1080
Doi: 10.1161/01.RES.0000219677.12988.e9
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- Führende Autor*innen der Med Uni Graz
- Olschewski Andrea
- Co-Autor*innen der Med Uni Graz
- Kwapiszewska-Marsh Grazyna
- Li Yingji
- Olschewski Horst
- Tang Bi
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- Abstract:
- The excitability of pulmonary artery smooth muscle cells (PASMC) is regulated by potassium (K+) conductances. Although studies suggest that background K+ currents carried by 2-pore domain K+ channels are important regulators of resting membrane potential in PASMC, their role in human PASMC is unknown. Our study tested the hypothesis that TASK-1 leak K+ channels contribute to the K+ current and resting membrane potential in human PASMC. We used the whole-cell patch-clamp technique and TASK-1 small interfering RNA (siRNA). Noninactivating K+ current performed by TASK-1 K+ channels were identified by current characteristics and inhibition by anandamide and acidosis (pH 6.3), each resulting in significant membrane depolarization. Moreover, we showed that TASK-1 is blocked by moderate hypoxia and activated by treprostinil at clinically relevant concentrations. This is mediated via protein kinase A (PKA)-dependent phosphorylation of TASK-1. To further confirm the role of TASK-1 channels in regulation of resting membrane potential, we knocked down TASK-1 expression using TASK-1 siRNA. The knockdown of TASK-1 was reflected by a significant depolarization of resting membrane potential. Treatment of human PASMC with TASK-1 siRNA resulted in loss of sensitivity to anandamide, acidosis, alkalosis, hypoxia, and treprostinil. These results suggest that (1) TASK-1 is expressed in human PASMC; (2) TASK-1 is hypoxia-sensitive and controls the resting membrane potential, thus implicating an important role for TASK-1 K+ channels in the regulation of pulmonary vascular tone; and (3) treprostinil activates TASK-1 at clinically relevant concentrations via PKA, which might represent an important mechanism underlying the vasorelaxing properties of prostanoids and their beneficial effect in vivo.
- Find related publications in this database (using NLM MeSH Indexing)
- Cells, Cultured -
- DNA Primers -
- Gene Expression Regulation -
- Humans -
- Muscle, Smooth, Vascular - cytology Muscle, Smooth, Vascular - physiology
- Nerve Tissue Proteins -
- Patch-Clamp Techniques -
- Potassium - physiology
- Potassium Channels - physiology
- Potassium Channels, Tandem Pore Domain - genetics Potassium Channels, Tandem Pore Domain - physiology
- Pulmonary Artery - cytology Pulmonary Artery - physiology
- RNA, Messenger - genetics
- Find related publications in this database (Keywords)
- pulmonary circulation
- potassium channels
- TASK-1
- treprostinil
- hypoxic pulmonary vasoconstriction