title: Acute and chronic hypoxic regulation of recombinant hNa(v)1.5 alpha subunits.
abstract: 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.
authors.affiliation: School of Biological Sciences, The University of Manchester, G.38 Stopford Building, Oxford Road, Manchester M13 9PT, UK. ian.fearon@manchester.ac.uk
authors.forename: Ian M
authors.initials: IM
authors.lastname: Fearon
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Brown
mesh_terms: D015687:Cell Hypoxia; D002460:Cell Line; D004553:Electric Conductivity; D006801:Humans; D007700:Kinetics; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D062554:NAV1.5 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; D021122:Protein Subunits; D011994:Recombinant Proteins; C568320:SCN5A protein, human; D015222:Sodium Channels