Ca2+ entry via P/Q-type Ca2+ channels and the Na+/Ca2+ exchanger in rat and human neocortical synaptosomes
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Rat or human neocortical synaptosomes were used to study the role of voltage-gated Ca2+ channels and the Na+/Ca2+ exchanger in 45Ca2+ influx into nerve terminals. K+ depolarization-induced 45Ca2+ influx through voltage-gated Ca2+ channels into rat or human synaptosomes was completely blocked by mibefradil 30 µM or Cd2+ 100 µM but was not affected by tetrodotoxin 1 µM. It was reduced by ω-agatoxin IVA 0.2 µM by 68% in synaptosomes of either species, whereas ω-conotoxin GVIA 0.1 µM and nifedipine 1 µM had no effect. Veratridine-induced 45Ca2+ entry into rat neocortical synaptosomes was completely blocked by mibefradil 30 µM, reduced by 80% by Cd2+ 100 µM, by 90% by tetrodotoxin 1 µM and by 53% by ω-agatoxin IVA 0.2 µM but not by ω-conotoxin GVIA 0.1 µM or nifedipine 1 µM. Na+/Ca2+ exchanger-mediated 45Ca2+ uptake into rat neocortical synaptosomes evoked by replacement of Na+ by choline+ in the incubation buffer was reduced by KB-R7943 (3–50 µM), an inhibitor of the Na+/Ca2+ exchanger, in a concentration-dependent manner (maximal inhibition by 46% at 50 µM; IC23%=7.1 µM). Mibefradil also inhibited the Na+/Ca2+ exchanger-mediated Ca2+ uptake, although at 3.7 times lower potency (IC23%=26 µM). It is concluded that in rat and human neocortical nerve terminals Ca2+ entry is mediated under physiological conditions by P/Q-type, but not by N- or L-type Ca2+ channels or the Na+/Ca2+ exchanger. If the cytosolic Na+ concentration is increased, Ca2+ is also taken up via the Na+/Ca2+ exchanger. In addition to the ability of mibefradil to block all voltage-operated Ca2+ channels, this drug is a low potency inhibitor of the Na+/Ca2+ exchanger.
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