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Impact of TASK-1 in human pulmonary artery smooth muscle cells.

Authors
  • Olschewski, Andrea
  • Li, Yingji
  • Tang, Bi
  • Hanze, Jörg
  • Eul, Bastian
  • Bohle, Rainer M
  • Wilhelm, Jochen
  • Morty, Rory E
  • Brau, Michael E
  • Weir, E Kenneth
  • Kwapiszewska, Grazyna
  • Klepetko, Walter
  • Seeger, Werner
  • Olschewski, Horst
Type
Published Article
Journal
Circulation Research
Publisher
Ovid Technologies Wolters Kluwer -American Heart Association
Publication Date
Apr 28, 2006
Volume
98
Issue
8
Pages
1072–1080
Identifiers
PMID: 16574908
Source
Medline
License
Unknown

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.

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