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Hypoxic depolarization of cerebellar granule neurons by specific inhibition of TASK-1

Plant, L. D., Kemp, Paul J., Peers, C., Henderson, Z. and Pearson, H. A. 2002. Hypoxic depolarization of cerebellar granule neurons by specific inhibition of TASK-1. Stroke 33 (9) , pp. 2324-2328. 10.1161/01.STR.0000027440.68031.B0

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Publisher: American Heart Association
ISSN: 0039-2499
Last Modified: 04 Jun 2017 06:39

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