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1 Department of Physiology & Biophysics, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
2 Department of Physiology, University of Toronto, Toronto, Ontario, Canada
3 Division of Cellular and Molecular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
* To whom correspondence should be addressed. E-mail: french{at}ucalgary.ca.
ATP-sensitive potassium (KATP) channels, incorporating Kir6.x and SUR subunits, are weak inward rectifiers that are thought to play a role in neuronal protection from ischemic insults. However, the involvement of Kir6.2-containing KATP channel in hippocampus and neocortex has not been tested directly. To delineate the physiological roles of Kir6.2 channels in the central nervous system (CNS), we used knockout (KO) mice that do not express Kir6.2. Immunocytochemical staining demonstrated that Kir6.2 protein was expressed robustly in hippocampal neurons of the wild type (WT) mice, and absent in the KO. To examine neuronal sensitivity to metabolic stress in vitro, and to ischemia in vivo, we (a) exposed hippocampal slices to transient oxygen and glucose deprivation (OGD), and (b) produced focal cerebral ischemia by middle cerebral artery occlusion (MCAO). Both slice and whole animal studies showed that neurons from the KO mice were severely damaged following anoxia or ischemia, whereas few injured neurons were observed in the WT, suggesting that Kir6.2 channels are necessary to protect neurons from ischemic insults. Membrane potential recordings from the WT CA1 pyramidal neurons showed a bi-phasic response to OGD; a brief hyperpolarization was followed by a small depolarization during OGD, with complete recovery within 30 min after returning to normoxic conditions. By contrast, CA1 pyramidal neurons from the KO mice were irreversibly depolarized by OGD exposure, without any preceding hyperpolarization. These data suggest that expression of Kir6.2 channels prevents prolonged depolarization of neurons resulting from acute hypoxic or ischemic insults, and thus protects these central neurons from the injury.
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