Hypoxia inhibits human recombinant large conductance, Ca2+-activated K+ (maxi-K) channels by a mechanism which is membrane delimited and Ca2+ sensitive

Anthony Lewis, C. Peers, M. Ashford, P. Kemp

Research output: Contribution to journalArticlepeer-review

Abstract

Large conductance, Ca2+-activated K+ (maxi-K) channel activity was recorded in excised, inside-out patches from HEK 293 cells stably co-expressing the α- and β-subunits of human brain maxi-K channels. At +50 mV, and in the presence of 300 nm, single channel activity was acutely and reversibly suppressed upon reducing PO2 from 150 to > 40 mmHg by over 30 %. The hypoxia-evoked reduction in current was due predominantly to suppression in NPo, although a minor component was attributable to reduced unitary conductance of 8–12 %. Hypoxia caused an approximate doubling of the time constant for activation but was without effect on deactivation. At lower levels of (30 and 100 nm), hypoxic inhibition did not reach significance. In contrast, 300 nm and 1 μmboth sustained significant hypoxic suppression of activity over the entire activating voltage range. At these two levels, hypoxia evoked a positive shift in the activating voltage (by ∼10 mV at 300 nm and ∼25 mV at 1 μm). At saturating [Ca2+]i (100 μm), hypoxic inhibition was absent. Distinguishing between hypoxia-evoked changes in voltage- and/or -sensitivity was achieved by evoking maximal channel activity using high depolarising potentials (up to +200 mV) in the presence of 300 nm or 100 μm or in its virtual absence (> 1 nm). Under these experimental conditions, hypoxia caused significant channel inhibition only in the presence of 300 nm. Thus, since regulation was observed in excised patches, maxi-K channel inhibition by hypoxia does not require soluble intracellular components and, mechanistically, is voltage independent and sensitive.
Original languageEnglish
Pages (from-to)771-780
Number of pages10
JournalThe Journal of Physiology
Volume540
Issue number3
DOIs
Publication statusPublished - 2002

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