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The role of intracellular Na⁺ and mitochondria in buffering of kainate-induced intracellular free Ca²⁺ changes in rat forebrain neurones

Kari R. Hoyt, Amy K. Stout, Jamie M. Cardman and Ian J. Reynolds

1. We have examined the mechanisms by which cultured central neurones from embryonic rat brain buffer intracellular Ca²⁺ loads following kainate receptor activation using fluorescent indicators of [Ca²⁺]_i and [Na⁺]_i.

2. Stimulation of cultured forebrain neurones with 100 µM kainate produced a rapid increase in [Ca²⁺]_i that displayed a variable rate of recovery. Kainate also increased [Na⁺]_i with a response that was slightly slower in onset and markedly slower in recovery.

3. The recovery of [Ca²⁺]_i to baseline was not very sensitive to the [Na⁺]_i. The magnitude of the increase in [Na⁺]_i in response to kainate did not correlate well with the [Ca²⁺]_i recovery time, and experimental manipulations that altered [Na⁺]_i did not have a large impact on the rate of recovery of [Ca²⁺]_i.

4. The recovery of [Ca²⁺]_i to baseline was accelerated by the mitochondrial Na⁺-Ca²⁺ exchange inhibitor CGP-37157, suggesting that the recovery rate is influenced by release of Ca²⁺ from a mitochondrial pool and also that variation in the recovery rate is related to the extent of mitochondrial Ca²⁺ loading. Kainate did not alter the mitochondrial membrane potential.

5. These studies reveal that mitochondria have a central role in buffering neuronal [Ca²⁺]_i changes mediated by non-N-methyl-D-aspartate (NMDA) glutamate receptors, and that the variation in recovery times following kainate receptor activation reflects a variable degree of mitochondrial Ca²⁺ loading. However, unlike NMDA receptor-mediated Ca²⁺ loads, kainate receptor activation has minimal effects on mitochondrial function.

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