Acute and chronic hypoxic regulation of recombinant hNa(v)1.5 alpha subunits

Acute and chronic hypoxic regulation of ion channels is involved in both cell physiology and pathology. Voltage-dependent Na(+) channels play a dominant role in the upstroke of the action potential in excitable cells, while non-inactivating (persistent or sustained) Na(+) currents contribute to action potential shape and duration. In cardiac myocytes, hypoxic augmentation of persistent Na(+) currents has been proposed to underlie cardiac arrhythmias via prolonging action potential duration. Here, we demonstrate that acute hypoxia (P(O2), 20mm Hg) augmented persistent Na(+) currents in HEK293 cells stably expressing human Na(v)1.5 alpha subunits. Hypoxia also inhibited peak Na(+) currents in a voltage-dependent manner, and the kinetics of activation and inactivation of Na(+) currents were significantly slowed during hypoxia. We further demonstrate that exposure to chronic hypoxia (6% O(2) for 24h) augmented peak Na(+) channel current, which given the exogenous promoter driving expression of the channel occurs most probably via a post-transcriptional mechanism. These effects of acute and chronic hypoxia likely play an arrhythmogenic role during both short- and long-term hypoxic/ischaemic episodes. The HEK293 expression system provides a useful paradigm in which to examine the mechanisms of O(2) sensing by the Na(+) channel.