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The Journal of Neuroscience, October 26, 2005, 25(43):9960-9967; doi:10.1523/JNEUROSCI.2003-05.2005

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Neurobiology of Disease
Na⁺-Dependent Sources of Intra-Axonal Ca²⁺ Release in Rat Optic Nerve during In Vitro Chemical Ischemia

Maria A. Nikolaeva, Ballari Mukherjee, and Peter K. Stys

Division of Neuroscience, Ottawa Health Research Institute, University of Ottawa, Ottawa, Ontario, Canada K1Y 4K9

The contribution of intracellular stores to axonal Ca²⁺ overload during chemical ischemia in vitro was examined by confocal microscopy. Ca²⁺ accumulation was measured by fluo-4 dextran (low-affinity dye, K_D 4 µM) or by Oregon Green 488 BAPTA-1 dextran (highaffinity dye, K_D 450 nM). Axonal Na⁺ was measured using CoroNa Green. Ischemia in CSF containing 2 mM Ca²⁺ caused an 3.5-fold increase in fluo-4 emission after 30 min, indicating a large axonal Ca²⁺ rise well into the micromolar range. Axonal Na⁺ accumulation was enhanced by veratridine and reduced, but not abolished, by TTX. Ischemia in Ca²⁺-free (plus BAPTA) perfusate resulted in a smaller but consistent Ca²⁺ increase monitored by Oregon Green 488 BAPTA-1, indicating release from intracellular sources. This release was eliminated in large part when Na⁺ influx was reduced by replacement with N-methyl-D-glucamine (NMDG⁺; even in depolarizing high K⁺ perfusate), Li⁺, or by the application of TTX and significantly increased by veratridine. Intracellular release also was reduced significantly by neomycin or 1-(6-[(17-methoxyestra-1,3,5 [10]-trien-17-yl) amino] hexyl)-¹H-pyrrole-2,5-dione ( U73122) (phospholipase C inhibitors), heparin [inositol trisphosphate (IP₃) receptor blocker], or 7-chloro-5-(2-chlorophenyl)-1,5-dihydro-4,1-benzothiazepin-2(³H)-one (CGP37157 [GenBank] ; mitochondrial Na⁺/Ca²⁺ exchange inhibitor) as well as ryanodine. Combining CGP37157 with  U73122 or heparin decreased the response more than either agent alone and significantly improved electrophysiological recovery. Our conclusion is that intra-axonal Ca²⁺ release during ischemia in rat optic nerve is mainly dependent on Na⁺ influx. This Na⁺ accumulation stimulates three distinct intra-axonal sources of Ca²⁺: (1) the mitochondrial Na⁺/Ca²⁺ exchanger driven in the Na⁺ import/Ca²⁺ export mode, (2) positive modulation of ryanodine receptors, and (3) promotion of IP₃ generation by phospholipase C.

Key words: axon; Na/Ca exchanger; IP₃; ryanodine; endoplasmic reticulum; mitochondria; phospholipase C

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Received July 12, 2004; revised September 15, 2005; accepted September 17, 2005.

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