The role of intracellular Na super(+) and mitochondria in buffering of kainate-induced intracellular free Ca super(2+) changes in rat forebrain neurones

* 1 We have examined the mechanisms by which cultured central neurones from embryonic rat brain buffer intracellular Ca super(2+) loads following kainate receptor activation using fluorescent indicators of [Ca super(2+)] sub(i) and [Na super(+)] sub(i). * 2 Stimulation of cultured forebrain neurones with 100 mu m kainate produced a rapid increase in [Ca super(2+)] sub(i) that displayed a variable rate of recovery. Kainate also increased [Na super(+)] sub(i) with a response that was slightly slower in onset and markedly slower in recovery. * 3 The recovery of [Ca super(2+)] sub(i) to baseline was not very sensitive to the [Na super(+)] sub(i). The magnitude of the increase in [Na super(+)] sub(i) in response to kainate did not correlate well with the [Ca super(2+)] sub(i) recovery time, and experimental manipulations that altered [Na super(+)] sub(i) did not have a large impact on the rate of recovery of [Ca super(2+)] sub(i). * 4 The recovery of [Ca super(2+)] sub(i) to baseline was accelerated by the mitochondrial Na super(+)-Ca super(2+) exchange inhibitor CGP-37157, suggesting that the recovery rate is influenced by release of Ca super(2+) from a mitochondrial pool and also that variation in the recovery rate is related to the extent of mitochondrial Ca super(2+) loading. Kainate did not alter the mitochondrial membrane potential. * 5 These studies reveal that mitochondria have a central role in buffering neuronal [Ca super(2+)] sub(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 Ca super(2+) loading. However, unlike NMDA receptor-mediated Ca super(2+) loads, kainate receptor activation has minimal effects on mitochondrial function.