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J. Biol. Chem., Vol. 280, Issue 6, 4491-4497, February 11, 2005

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Exposure to Hypoxia Rapidly Induces Mitochondrial Channel Activity within a Living Synapse^*

Elizabeth A. Jonas¶||, John A. Hickman**, J. Marie Hardwick, and Leonard K. Kaczmarek¶

From the Departments of Pharmacology and Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, ^**Institut de Recherches Servier, 125 Chemin de Ronde, 78290 Croissy sur Sienne, France, Department of Molecular Microbiology and Immunology, Johns Hopkins University School of Public Health and Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, and ^¶Marine Biological Laboratory, Woods Hole, Massachusetts 02543

One of the earliest effects of hypoxia on neuronal function is to produce a run-down of synaptic transmission, and more prolonged hypoxia results in neuronal death. An increase in the permeability of the outer mitochondrial membrane, controlled by BCL-2 family proteins, occurs in response to stimuli that trigger cell death. By patch clamping mitochondrial membranes inside the presynaptic terminal of a squid giant synapse, we have now found that several minutes of hypoxia trigger the opening of large multiconductance channels. The channel activity is induced concurrently with the attenuation of synaptic responses that occurs under hypoxic conditions. Hypoxia-induced channels are inhibited by NADH, an agent that inhibits large conductance channels produced by a pro-apoptotic fragment of BCL-xL in these synaptic mitochondria. The appearance of hypoxia-induced channels was also prevented by the caspase/cysteine protease inhibitor benzyloxycarbonyl-VAD-fluoromethyl ketone (Z-VAD-fmk), which inhibits proteolysis of BCL-xL during hypoxia. Both NADH and Z-VAD-fmk reduced significantly the rate of decline of synaptic responses during hypoxia. Our results indicate that an increase in outer mitochondrial channel activity is a very early event in the response of neurons to hypoxia and suggest that this increase in activity may contribute to the decline in synaptic function during hypoxia.

Received for publication, September 16, 2004 , and in revised form, November 10, 2004.

^* This work was supported by Grants NS18496 (to L. K. K.), NS37402 (to J. M. H.), and NS45876 (to E. A. J.) from the National Institutes of Health and by an American Heart Association Established Investigator Award (to E. A. J.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Dept. of Internal Medicine (Endo), Yale University School of Medicine, 333 Cedar St., New Haven, CT 06520. Tel.: 203-785-3087; Fax: 203-785-6015; E-mail: elizabeth.jonas{at}yale.edu.

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