Hypoxic Depolarization of Cerebellar Granule Neurons by Specific Inhibition of TASK-1

Publisher Website
Google Scholar
Abstract
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 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.