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J. Biol. Chem., Vol. 283, Issue 16, 10347-10356, April 18, 2008

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Stimulated Efflux of Amino Acids and Glutathione from Cultured Hippocampal Slices by Omission of Extracellular Calcium

LIKELY INVOLVEMENT OF CONNEXIN HEMICHANNELS^*

Malin H. Stridh, Mattias Tranberg, Stephen G. Weber¹, Fredrik Blomstrand², and Mats Sandberg^¶13

From the Institute of Neuroscience and Physiology, University of Gothenburg, SE-40530 Gothenburg, Sweden, the Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, and the ^¶Institute of Biomedicine, University of Gothenburg, SE-40530 Gothenburg, Sweden

Omission of extracellular Ca²⁺ for 15 min from the incubation medium of cultured hippocampal slices stimulated the efflux of glutathione, phosphoethanolamine, hypotaurine, and taurine. The efflux was reduced by several blockers of gap junctions, i.e. carbenoxolone, flufenamic acid, and endothelin-1, and by the connexin43 hemichannel blocking peptide Gap26 but was unchanged by the P2X₇ receptor inhibitor oxidized ATP, a pannexin1 hemichannel blocking peptide and an inactive analogue of carbenoxolone. Pretreatment of the slices with the neurotoxin N-methyl-D -aspartate left the efflux by Ca²⁺ omission unchanged, indicating that the stimulated efflux primarily originated from glia. Elevated glutamate efflux was detected when Ca²⁺ omission was combined with the glutamate uptake blocker L-trans-pyrrolidine-2,4-dicarboxylate and when both Ca²⁺ and Mg²⁺ were omitted from the medium. Omission of Ca²⁺ for 15 min alone did not induce delayed toxicity, but in combination with blocked glutamate uptake, significant cell death was observed 24 h later. Our results indicate that omission of extracellular Ca²⁺ stimulates efflux of glutathione and specific amino acids including glutamate via opening of glial hemichannels. This type of efflux may have protective functions via glutathione efflux but can aggravate toxicity in situations when glutamate reuptake is impaired, such as following a stroke.

Received for publication, May 21, 2007 , and in revised form, December 22, 2007.

^* This work was supported by funds from the Swedish Research Council/Medicine (to M. S.), Parkinsonfonden, and Åhlén-stiftelsen. 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.

¹ Supported by National Institutes of Health Grant GM 44842.

² Supported by the Fredrik and Ingrid Thurings Foundation, the Edit Jacobsons Foundation, and the Magnus Bergvalls Foundation.

³ To whom correspondence should be addressed: Institute of Biomedicine, Box 420, 40530 Gothenburg, Sweden. Fax: 4631-786-3840; E-mail: mats.sandberg{at}anatcell.gu.se.

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