The
potassium channel TWIK-related
acid sensitive
potassium (TASK)-1 channel, together with other
potassium channels, controls the low resting tone of pulmonary arteries. The
Src family tyrosine kinase (SrcTK) may control
potassium channel function in human pulmonary artery smooth muscle cells (hPASMCs) in response to changes in
oxygen tension and the clinical use of a SrcTK inhibitor has resulted in partly reversible
pulmonary hypertension. This study aimed to determine the role of SrcTK in
hypoxia-induced inhibition of
potassium channels in hPASMCs. We show that SrcTK is co-localised with the TASK-1 channel. Inhibition of SrcTK decreases
potassium current density and results in considerable depolarisation, while activation of SrcTK increases
potassium current in patch-clamp recordings. Moderate
hypoxia and the SrcTK inhibitor decrease the
tyrosine phosphorylation state of the TASK-1 channel.
Hypoxia also decreases the level of phospho-SrcTK (tyr419) and reduces the co-localisation of the TASK-1 channel and phospho-SrcTK. Corresponding to this,
hypoxia reduces TASK-1 currents before but not after SrcTK inhibition and, in the isolated perfused mouse lung, SrcTK inhibitors increase pulmonary arterial pressure. We propose that the SrcTK is a crucial factor controlling
potassium channels, acting as a cofactor for setting a negative resting membrane potential in hPASMCs and a low resting pulmonary vascular tone.