Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Chandran, N.
Impact of TASK-1 in human pulmonary artery smooth muscle cells - Modulation of the two-pore domain channel by vasoactive agents
[ Dissertation ] Medical University of Graz; 2012. pp. 89
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- Autor*innen der Med Uni Graz:
- Chandran Nagaraj
- Betreuer*innen:
- Frank Sasa
- Olschewski Andrea
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- Abstract:
- The role of potassium (K+) channels in hypoxic pulmonary vasoconstriction has been intensively studied. There is a great interest among research investigators who work on the pulmonary circulation in defining the mechanisms responsible for hypoxic pulmonary vasoconstriction (HPV). HPV plays a large part in matching ventilation and perfusion in the lung. Oxygen-sensitive K+ channels are known to be a primary response element. However, the molecular mechanisms behind acute hypoxic inhibition of potassium channels, in particular TASK-1, have been frustratingly difficult to elucidate. We now provide novel finding that non-receptor Src family tyrosine kinases (SrcTK) are vital for the function of potassium channels and consequently for their contribution to the resting membrane potential of human pulmonary artery smooth muscle cells (hPASMCs) and pulmonary vascular tone. We show that the expression of SrcTK in human lung and in primary human PASMCs, is colocalized with the TASK-1 channels in the plasma membrane. Silencing of SrcTK inhibits the K+ channels, leading to the depolarization of resting membrane potential. Moderate hypoxia inhibits active phospho-SrcTK and reduces the co-localization of the TASK-1 channel and phospho-SrcTK in the cell membrane. The physiological effect of SrcTK inhibition is similar to that of hypoxia, where the TASK-1 current is also inhibited and leads to membrane depolarization. Given the ability of SrcTK to control the gating of these K+ channels in response to hypoxia, these kinases appear to be key regulatory molecules involved in the intracellular signalling cascade of HPV and setting the basal pulmonary vascular tone. Moreover, dasatinib, was proposed as a second-line therapy for patients with Chronic myelogenous leukemia (CML). Dasatinib a potent inhibitor of the Src family, has been reported to cause pulmonary arterial hypertension (PAH) in CML patients. This PAH tends to resolve rapidly after discontinuation of the dasatinib suggesting that it may not be primarily due to marked cellular proliferation but to chronic vasoconstriction. One can speculate that dasatinib-initiated pulmonary hypertension may relate to our finding that siRNA against SrcTK reduces K+ current and causes depolarization of hPASMCs and results in increased pulmonary arterial pressure. This study addresses an important physiological question, the cellular signaling responsible for hypoxic inhibition of K+ channels in human pulmonary artery smooth muscle cells and, by extrapolation, for part of the mechanism of hypoxic pulmonary vasoconstriction. The wider relevance of this work is shown by a recent report that a Src tyrosine kinase inhibitor, dasatinib, can cause reversible clinical pulmonary hypertension.