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

Abstract

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.

The Impact of Heterozygous KCNK3 Mutations Associated With Pulmonary Arterial Hypertension on Channel Function and Pharmacological Recovery

“…KCNK3 currents contribute to the resting potential of native PASMCs, and the downregulation or inhibition of KCNK3 causes PASMC depolarization, excessive proliferation, and pulmonary arterial constriction 5, 7, 8, 9. Cultured PASMCs have been used previously to study overexpressed potassium channel activity, regulation, and pharmacology in the context of PAH 19, 20.…”

“…The voltage‐insensitivity of KCNK3 renders the channel open across all voltages, leading to potassium efflux from cells expressing the channel, which contributes to the negative resting potential. KCNK3 is widely expressed in the human body, including in the central nervous system, heart, and pulmonary artery smooth muscle cells (PASMCs) 6, 7…”

Potassium channels in pulmonary arterial hypertension

“…Because the K 2P channels are typically open at negative membrane potential, they have been strongly implicated in establishing the background K + conductance known to stabilise the negative resting membrane potential and counterbalance depolarisation [78]. KCNK3 (also called TASK1) encodes a pH-sensitive K 2P channel, which has been shown to be expressed by PASMCs and to contribute significantly to the resting membrane potential [79]. Indeed, TASK1 knockdown in human PASMCs caused a depolarisation of the resting membrane potential [80].…”

Functional evidence of a role for two‐pore domain potassium channels in rat mesenteric and pulmonary arteries

“…Furthermore, Kindler et al (2000) showed that the same antibody was specific for TASK-1 when used to probe sections taken from various regions of the rat central nervous system. Recently, this antibody was also used to probe rabbit pulmonary artery myocytes (Gurney et al, 2003). The anti-TASK-2 antibody used also binds specifically to TASK-2 in rat tissue (Gabriel et al, 2002) as well as in cultured Ehrlich cells (Niemeyer et al, 2001).…”

“…Although none of the channel modulators used should be regarded as selective, the results collectively suggest that TASK-1 channels in particular are of functional significance. Of note is the evidence that the potassium current designated I KN (Gurney et al, 2002) is carried by TASK-1 in pulmonary myocytes derived from rabbit pulmonary arteries (Gurney et al, 2003). This current, which is reduced in chronic pulmonary hypoxia and is important in setting resting membrane potential in pulmonary vessels (Evans et al, 1998), implicates TASK-1 in hypoxic disease states.…”