Zinc inhibits Ca2+ transport by rat brain Na+/Ca2+ exchanger

CALCIUM transport by the Na+/Ca2+ exchanger was measured in plasma membranes vesicles purified from rat brain and in primary rat cortical cell culture. Sodium-loaded vesicles rapidly accumulate Ca2+ via Na+/Ca2+ exchange (Na-i(+)-dependent Ca2+ uptake). Extravesicular zinc inhibited Na+/Ca2+ exchange as evidenced by a reduction of the initial velocity of Ca2+ uptake. Significant inhibition of Ca2+ uptake was seen at concentrations of zinc as low as 3 mu M. Lineweaver-Burk analysis of the data was consistent with noncompetitive inhibition with respect to extravesicular Ca2+ concentration. The K-i for zinc inhibition of Ca2+ uptake determined from a Dixon plot was 14.5 mu M. This is within the range of zinc concentrations thought to be obtained extracellularly after excitation. When vesicles were preloaded with Ca2+, extravesicular zinc also inhibited reversal of Na+/Ca2+ exchange (Na-o(+)-dependent Ca2+ release) although its potency was much less: concentrations of greater than or equal to 30 mu M zinc were required. Zinc inhibition of Ca2+ release was not Na+ dependent. Na-i(+)-dependent calcium uptake by rat cortical cells in primary culture also was inhibited by zinc. The extent of inhibition was similar to that seen for inhibition of Na-i(+)-dependent Ca2+ uptake in membrane vesicles, but the potency was less. The results suggest that Ca2+ transport by the Na+/Ca2+ exchanger is inhibited by concentrations of zinc thought to be attained extracellularly after excitation. NeuroReport 9: 3091-3096 (C) 1998 Lippincott Williams & Wilkins.