L-type voltage-gated calcium channels modulate kainic acid neurotoxicity in cerebellar granule cells

This study reports on the regulation of kainate neurotoxicity in cerebellar granule cells by calcium entry through voltage-gated calcium channels and by calcium release from internal cellular stores. Kainate neurotoxicity was prevented by the AMPA selective antagonist LY 303070 (10 mu M). Kainate ne urotoxicity was potentiated by cadmium, a general voltage-gated calcium cha nnel blocker, and the L-type voltage-gated calcium channel blocker nifedipi ne. The antagonists of intracellular Ca2+ ([Ca2+](i)) release, thapsigargin and ryanodine, were also able to potentiate kainate neurotoxicity. Kainate treatment elevated [Ca2+](i) concentration with a rapid initial increase t hat peaked at 1543 nM and then declined to plateau at similar to 400 nM. Ni fedipine lowered the peak response to 764 nM and the plateau response to si milar to 90 nM. Thapsigargin also lowered the kainate-induced increase in [ Ca2+](i) (640 nM peak, 125 nM plateau). The ryanodine receptor agonist caff eine eliminated the kainate-induced increase in [Ca2+](i), and reduced kain ate neurotoxicity. Kainate neurotoxicity potentiated by nifedipine was not prevented by RNA or protein synthesis inhibitors, nor by the caspase inhibi tors WAD-CHO and DEVD-CHO. Neither DNA laddering nor the number of apoptoti c nuclei were increased following treatment with kainate and nifedipine. In creased nuclear staining with the membrane impermeable dye propidium iodide was observed immediately following kainate treatment, indicating a loss of plasma membrane integrity. Thus, kainate neurotoxicity is prevented by cal cium entry through L-type calcium channels. (C) 1999 Elsevier Science B.V. All rights reserved.