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The Journal of Neuroscience, September 17, 2008, 28(38):9463-9472; doi:10.1523/JNEUROSCI.2286-08.2008

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Neurobiology of Disease
Ischemia Enhances Activation by Ca²⁺ and Redox Modification of Ryanodine Receptor Channels from Rat Brain Cortex

Ricardo Bull,^1,2 José Pablo Finkelstein,² Jorge Gálvez,² Gina Sánchez,³ Paulina Donoso,^1,4 María Isabel Behrens,^1,5 and Cecilia Hidalgo^1,4

¹Centro de Estudios Moleculares de la Célula, Fondo de Investigación Avanzada en Áreas Prioritarias, ²Programa de Fisiología y Biofísica, Instituto de Ciencias Biomédicas, ³Programa de Patología, Instituto de Ciencias Biomédicas, ⁴Programa de Biología Celular y Molecular, Instituto de Ciencias Biomédicas, Facultad de Medicina, and ⁵Departamento de Neurología y Neurocirugía, Hospital Clínico, Universidad de Chile, Santiago 7, Chile

Correspondence should be addressed to Dr. Ricardo Bull, Programa de Fisiología y Biofísica, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Casilla 70005, Santiago 7, Chile. Email: rbull{at}med.uchile.cl

Cerebral ischemia stimulates Ca²⁺ influx and thus increases neuronal intracellular free [Ca²⁺]. Using a rat model of cerebral ischemia without recirculation, we tested whether ischemia enhances the activation by Ca²⁺ of ryanodine receptor (RyR) channels, a requisite feature of RyR-mediated Ca²⁺-induced Ca²⁺ release (CICR). To this aim, we evaluated how single RyR channels from endoplasmic reticulum vesicles, fused into planar lipid bilayers, responded to cytoplasmic [Ca²⁺] changes. Endoplasmic reticulum vesicles were isolated from the cortex of rat brains incubated without blood flow for 5 min at 37°C (ischemic) or at 4°C (control). Ischemic brains displayed increased oxidative intracellular conditions, as evidenced by a lower ratio (130:1) of reduced/oxidized glutathione than controls (200:1). Single RyR channels from ischemic or control brains displayed the same three responses to Ca²⁺ reported previously, characterized by low, moderate, or high maximal activity. Relative to controls, RyR channels from ischemic brains displayed with increased frequency the high activity response and with lower frequency the low activity response. Both control and ischemic cortical vesicles contained the RyR2 and RyR3 isoforms in a 3:1 proportion, with undetectable amounts of RyR1. Ischemia reduced [³H]ryanodine binding and total RyR protein content by 35%, and increased at least twofold endogenous RyR2 S-nitrosylation and S-glutathionylation without affecting the corresponding RyR3 endogenous levels. In vitro RyR S-glutathionylation but not S-nitrosylation favored the emergence of high activity channels. We propose that ischemia, by enhancing RyR2 S-glutathionylation, allows RyR2 to sustain CICR; the resulting amplification of Ca²⁺ entry signals may contribute to cortical neuronal death.

Key words: endoplasmic reticulum; Ca²⁺ release channels; Ca²⁺-induced Ca²⁺ release; sulfhydryl oxidation; oxygen deprivation; oxidative stress

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Received May 21, 2008; revised July 7, 2008; accepted Aug. 4, 2008.

Correspondence should be addressed to Dr. Ricardo Bull, Programa de Fisiología y Biofísica, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Casilla 70005, Santiago 7, Chile. Email: rbull{at}med.uchile.cl

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