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

Andrea Olschewski, Yingji Li, Bi Tang, Jörg Hanze, Bastian Eul, Rainer M. Bohle, Jochen Wilhelm, Rory E. Morty, Michael E. Brau, E. Kenneth Weir, Grazyna Kwapiszewska, Walter Klepetko, Werner Seeger, Horst Olschewski

Research output: Contribution to journalArticlepeer-review

137 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1072-1080
Number of pages9
JournalCirculation research
Volume98
Issue number8
DOIs
StatePublished - Apr 2006

Keywords

  • Hypoxic pulmonary vasoconstriction
  • Potassium channels
  • Pulmonary circulation
  • TASK-1
  • Treprostinil

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