Post-transcriptional control of human maxiK potassium channel activity and acute oxygen sensitivity by chronic hypoxia

Matthew E. Hartness, Stephen P. Brazier, Chris Peers, Alan N. Bateson, Michael L. J. Ashford, Paul J. Kemp

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    32 Citations (Scopus)

    Abstract

    Various cardiorespiratory diseases (e.g. congestive heart failure, emphysema) result in systemic hypoxia and patients consequently demonstrate adaptive cellular responses which predispose them to conditions such as pulmonary hypertension and stroke. Central to many affected excitable tissues is activity of large conductance, Ca2+-activated K+ (maxiK) channels. We have studied maxiK channel activity in HEK293 cells stably co-expressing the most widely distributed of the human a- and ß-subunits that constitute these channel following maneuvers which mimic severe hypoxia. At all [Ca2+]i, chronic hypoxia (~ 18 mm Hg, 72 h) increased K+ current density, most markedly at physiological [Ca2+]i K+ currents in cells cultured in normoxia showed a [Ca2+]i-dependent sensitivity to acute hypoxic inhibition ( ~ 25 mm Hg, 3 min). However, chronic hypoxia dramatically changed the Ca2+ sensitivity of this acute hypoxic inhibitory profile such that low [Ca2+]i could sustain an acute hypoxic inhibitory response. Chronic hypoxia caused no change in a-subunit immunoreactivity with Western blotting but evoked a 3-fold increase in ß-subunit expression. These observations were fully supported by immunocytochemistry, which also suggested that chronic hypoxia augmented a/ß-subunit co-localization at the plasma membrane. Using a novel nuclear run-on assay and RNase protection we found that chronic hypoxia did not alter mRNA production rates or steady-state levels, which suggests that this important environmental cue modulates maxiK channel function via post-transcriptional mechanisms.

    Original languageEnglish
    Pages (from-to)51422-51432
    Number of pages11
    JournalJournal of Biological Chemistry
    Volume278
    Issue number51
    DOIs
    Publication statusPublished - 2003

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