Tityustoxin (TsTX), a toxin obtained from the venom of the Brazilian scorpion Tityus serrulatus, stimulates Na+ influx through tetrodotoxin (TTX)-sensitive Na+ channels which, in turn, promotes both Ca(2+)-dependent and Ca(2+)-independent release of glutamate from rat cerebrocortical synaptosomes. The level of Ca(2+)-dependent glutamate release after addition of 0.5 microM TsTX is greater than that produced by a maximally depolarizing concentration of KCl. This effect of TsTX, which is entirely dependent on Na+ entry, suggests that Na+ has a role in modulating Ca2+ entry and glutamate release that is not simply related to membrane depolarization. In order to investigate possible modulatory role(s) of Na+ on Ca(2+)-dependent glutamate release, we compared the effects of TsTX with those of KCl and the Na+ ionophore gramicidin D. When used alone, 100 nM gramicidin D produced a larger increase in intrasynaptosomal free Na+ than did 0.5 microM TsTX, and a similar rise in intrasynaptosomal free Ca2+, but was much less effective in promoting glutamate release. Even the combination of membrane depolarization (by 33 mM KCl) and elevation of intrasynaptosomal free Na+ (by 100 nM gramicidin) was still less effective than TsTX at causing Ca(2+)-dependent glutamate release. These data suggest that localized Na+ entry, through TTX-sensitive Na+ channels, exerts a modulatory role on Ca(2+)-dependent glutamate release from nerve endings in the cerebral cortex.

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