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Progression of hypoxic pulmonary hypertension is thought to be due, in part, to suppression of voltage-gated potassium channels (Kv) in pulmonary arterial smooth muscle cells (Archer et al. 2004; Michelakis et al. 2004) that is mediated by the inhibition of mitochondrial oxidative phosphorylation (Firth et al. 2009). We sought to determine the role in this process of the AMP-activated protein kinase (AMPK), which is intimately coupled to mitochondrial function due to its activation by LKB1-dependent phosphorylation in response to increases in the cellular AMP:ATP and/or ADP:ATP ratios. Inhibition of complex I of the mitochondrial electron transport chain using phenformin activated AMPK and inhibited Kv currents in pulmonary arterial myocytes, consistent with previously reported effects of mitochondrial inhibitors (Firth et al. 2008). Myocyte Kv currents were also markedly inhibited upon AMPK activation by A769662, AICAR and C13 and by intracellular dialysis from a patch-pipette of activated (thiophosphorylated) recombinant AMPK heterotrimers (α2β2γ1 or α1β1γ1). Hypoxia and inhibitors of mitochondrial oxidative phosphorylation reduced AMPK-sensitive K+ currents, which were also blocked by the selective Kv1.5 blocker DPO-1 but unaffected by the presence of the BKCa channel blocker paxilline. Moreover, recombinant human Kv1.5 channels were phosphorylated by AMPK in cell-free assays, and K+ currents carried by Kv1.5 stably expressed in HEK 293 cells were inhibited by intracellular dialysis of AMPK heterotrimers and by A769662, the effects of which were blocked by compound C. We conclude that AMPK mediates Kv channel inhibition by hypoxia in pulmonary arterial myocytes, at least in part, through phosphorylation of Kv1.5 and/or an associated protein.
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