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A Novel Functional Role of TASK‐1 in Hypoxia

TASK‐1, a member of the two‐pore domain potassium channel family, is strongly expressed in the heart. However, little is known about the regulation and function of cardiac TASK‐1 channels. The present study was designed to explore whether cardiac TASK‐1 channels play an essential role in the cytoprotection against hypoxia and reoxygenation. A cellular model of hypoxia or hypoxia and oxygenation from rat heart‐derived H9c2 cells and HEK293T cells was employed. The advantage of using HEK293T cells is that they lack endogenous TASK‐1. Hypoxia was induced by incubating cells in an airtight chamber in which O2 was replaced by 95% N2 and 5% CO2 with the glucose‐free Tyrode solution. Trypan blue cell viability assay was utilized in combination with biochemical analysis and immunofluorescence microscopy. The cell viability assay revealed that TASK‐1 expression increased the number of viable cells in HEK293T cells subjected to 2 hours of hypoxia followed by 2 hours of reoxygenation (H/R). To dissect the protective role of TASK‐1, mitochondrial membrane potential (MMP) was assessed by tetramethylrhodamine (TMRE) fluorescence. Our data indicated that MMP was significantly decreased by H/R, but was maintained by TASK‐1 expression. Our work on the subcellular localization of TASK‐1 demonstrated that while TASK‐1 showed a strong plasma membrane localization, a small fraction of TASK‐1 colocalized with the mitochondrial marker MitoTracker in intact cells and/or isolated mitochondria. H/R decreased the expression of TASK‐1 along cell periphery but did not alter colocalization of TASK‐1 with MitoTracker in HEK293T cells and/or H9c2 cells. Western blot analysis further supported the notion that the total cellular TASK‐1 expression from H9c2 cells was significantly reduced by H/R. Moreover, our data showed that Cyclosporin A (CsA), an inhibitor of mitochondrial permeability transition pore (mPTP), prevented reduction in MMP by H/R, the effect was not further enhanced by expressing TASK‐1. In summary, we provided the evidence that TASK‐1 channels are protective against hypoxia and reoxygenation‐induced injury, possibly by their capacity of maintaining the mitochondrial membrane potential via inhibiting mPTP opening.