doi: 10.1161/01.STR.0000027440.68031.B0
(Stroke. 2002;33:2324.)
© 2002 American Heart Association, Inc.
Original Contributions |
Hypoxic Depolarization of Cerebellar Granule Neurons by Specific Inhibition of TASK-1
From the School of Biomedical Sciences and Institute for Cardiovascular Research (C.P.), University of Leeds, Leeds, UK.
Correspondence to Dr H.A. Pearson, School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, UK. E-mail h.a.pearson{at}leeds.ac.uk
Background and Purpose— The mechanisms underlying neuronal excitotoxicity during hypoxic/ischemic episodes are not fully understood. One feature of such insults is a rapid and transient depolarization of central neurons. TASK-1, an open rectifying K+ leak channel, is significant in setting the resting membrane potential of rat cerebellar granule neurons by mediating a standing outward K+ current. In this study we investigate the theory that the transient neuronal depolarization seen during hypoxia is due to the inhibition of TASK-1.
Methods— Activity of TASK-1 in primary cultures of rat cerebellar granule neurons was investigated by the whole-cell patch-clamp technique. Discriminating pharmacological and electrophysiological maneuvers were used to isolate the specific channel types underlying acute hypoxic depolarizations.
Results— Exposure of cells to acute hypoxia resulted in a reversible and highly reproducible mean membrane depolarization of 14.2±2.6 mV (n=5; P<0.01). Two recognized means of inhibiting TASK-1 (decreasing extracellular pH to 6.4 or exposure to the TASK-1–selective inhibitor anandamide) abolished both the hypoxic depolarization and the hypoxic depression of a standing outward current, identifying TASK-1 as the channel mediating this effect.
Conclusions— Our data provide compelling evidence that hypoxia depolarizes central neurons by specific inhibition of TASK-1. Since this hypoxic depolarization may be an early, contributory factor in the response of central neurons to hypoxic/ischemic episodes, TASK-1 may provide a potential therapeutic target in the treatment of stroke.
Key Words: brain • ion channels • ischemia • potassium channels
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