Abstract-Pulmonary vascular tone is strongly influenced by the resting membrane potential of smooth muscle cells, depolarization promoting Ca 2ϩ influx, and contraction. The resting potential is determined largely by the activity of K ϩ -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 ϩ channel, TASK-1, mediates a noninactivating, background K ϩ 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 2ϩ (100 to 200 mol/L) and anandamide (10 mol/L), but insensitive to cytoplasmic Ca 2ϩ . 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.
1. The molecular identity of the K channels giving rise to the negative membrane potential of pulmonary artery smooth muscle cells has yet to be determined. 2. To date, most studies have focused on voltage-gated, delayed rectifier channels and their roles in mediating hypoxia-induced membrane depolarization. There is, however, strong evidence that an outwardly rectifying K+ conductance distinct from the classical delayed rectifier is involved. 3. Growing evidence that TASK-like channels can sense hypoxia and are present in pulmonary artery smooth muscle cells suggests that they may be responsible for the resting K+ conductance and resting potential. 4. The present review considers the evidence that particular K channels maintain the resting membrane potential of pulmonary artery smooth muscle cells and mediate the depolarizing response to hypoxia.
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