Increased Activation of L-Type Voltage-Dependent Calcium Channels Is Associated with Glycine Enhancement of N-Methyl-d-Aspartate-Stimulated Dopamine Release in Global Cerebral Ischemia/Reperfusion

Abstract: We investigated the relationships among N -methyl- d -aspartate, glycine, L-type voltage-dependent calcium channels, and [³H]dopamine release in a canine model of global cerebral ischemia/reperfusion. The binding of [³H]PN200-110 ([³H]isradipine) to L-type voltage-dependent calcium channels, that open as a consequence of N -methyl- d -aspartate-induced changes in membrane potential, was approximately doubled in striatal membranes prepared from ischemic animals relative to controls, and remained significantly elevated at 30 min and 2 h of reperfusion. These changes coincided temporally with changes in the ability of the voltage-sensitive calcium channel blocker nitrendipine to inhibit glycine enhancement of N -methyl- d -aspartate-stimulated [³H]dopamine release in striatal slices prepared from the same animals. Compared with nonischemic controls, N -methyl- d -aspartate-stimulated [³H]dopamine release was increased in ischemic animals and remained increased throughout reperfusion up to at least 24 h. Glycine enhanced N -methyl- d -aspartate-stimulated release in all treatment groups. The enhancement of N -methyl- d -aspartate-stimulated dopamine release by glycine was reduced by the inclusion of nitrendipine in striatal slices from ischemic and 30-min reperfused animals. These data suggest that glycine may facilitate opening of the voltage-dependent calcium channels activated by N -methyl- d -aspartate and that this facilitation is blocked by the antagonist nitrendipine.