Two-Pore Domain K Channel, TASK-1, in Pulmonary Artery Smooth Muscle Cells

Abstract

Pulmonary vascular tone is strongly influenced by the resting membrane potential of smooth muscle cells, depolarization promoting Ca 2+ influx, and contraction. The resting potential is determined largely by the activity of K + -selective ion channels, the molecular nature of which has been debated for some time. In this study, we provide strong evidence that the two-pore domain K + channel, TASK-1, mediates a noninactivating, background K + current ( I KN ), which sets the resting membrane potential in rabbit pulmonary artery smooth muscle cells (PASMCs). TASK-1 mRNA was found to be present in PASMCs, and the membranes of PASMCs contained TASK-1 protein. Both I KN and the resting potential were found to be exquisitely sensitive to extracellular pH, acidosis inhibiting the current and causing depolarization. Moreover, I KN and the resting potential were enhanced by halothane (1 mmol/L), inhibited by Zn 2+ (100 to 200 μmol/L) and anandamide (10 μmol/L), but insensitive to cytoplasmic Ca 2+ . These properties are all diagnostic of TASK-1 channels and add to previously identified features of I KN that are shared with TASK-1, such as inhibition by hypoxia, low sensitivity to 4-aminopyridine and quinine and insensitivity to tetraethylammonium ions. It is therefore concluded that TASK-1 channels are major contributors to the resting potential in pulmonary artery smooth muscle. They are likely to play an important role in mediating pulmonary vascular responses to changes in extracellular pH, and they could be responsible for the modulatory effects of pH on hypoxic pulmonary vasoconstriction.