TY - JOUR
T1 - Impact of TASK-1 in human pulmonary artery smooth muscle cells
AU - Olschewski, Andrea
AU - Li, Yingji
AU - Tang, Bi
AU - Hanze, Jörg
AU - Eul, Bastian
AU - Bohle, Rainer M.
AU - Wilhelm, Jochen
AU - Morty, Rory E.
AU - Brau, Michael E.
AU - Weir, E. Kenneth
AU - Kwapiszewska, Grazyna
AU - Klepetko, Walter
AU - Seeger, Werner
AU - Olschewski, Horst
PY - 2006/4
Y1 - 2006/4
N2 - 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.
AB - 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.
KW - Hypoxic pulmonary vasoconstriction
KW - Potassium channels
KW - Pulmonary circulation
KW - TASK-1
KW - Treprostinil
UR - http://www.scopus.com/inward/record.url?scp=33646816053&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33646816053&partnerID=8YFLogxK
U2 - 10.1161/01.RES.0000219677.12988.e9
DO - 10.1161/01.RES.0000219677.12988.e9
M3 - Article
C2 - 16574908
AN - SCOPUS:33646816053
SN - 0009-7330
VL - 98
SP - 1072
EP - 1080
JO - Circulation research
JF - Circulation research
IS - 8
ER -