title: Src tyrosine kinase is crucial for potassium channel function in human pulmonary arteries.
abstract: 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.
authors.affiliation: Ludwig Boltzmann Institute for Lung Vascular Research, Medical University of Graz, Austria.
authors.forename: Chandran
authors.initials: C
authors.lastname: Nagaraj
authors.forename: Bi
authors.initials: B
authors.lastname: Tang
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Bálint
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Wygrecka
authors.forename: Andelko
authors.initials: A
authors.lastname: Hrzenjak
authors.forename: Grazyna
authors.initials: G
authors.lastname: Kwapiszewska
authors.forename: Elvira
authors.initials: E
authors.lastname: Stacher
authors.forename: Joerg
authors.initials: J
authors.lastname: Lindenmann
authors.forename: E Kenneth
authors.initials: EK
authors.lastname: Weir
authors.forename: Horst
authors.initials: H
authors.lastname: Olschewski
authors.forename: Andrea
authors.initials: A
authors.lastname: Olschewski
mesh_terms: D002478:Cells, Cultured; D006801:Humans; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D015221:Potassium Channels / Q000502:physiology*; D011651:Pulmonary Artery / Q000166:cytology / Q000201:enzymology / Q000502:physiology*; D019061:src-Family Kinases / Q000502:physiology*
chemical_list: D015221:Potassium Channels; D019061:src-Family Kinases