We studied the modulation of the intracellular free calcium concentrations ([Ca2+]i) by kainate/AMPA receptor activation in synaptosomes isolated from whole rat hippocampus, or from its CA1, CA3 or dentate gyrus subregions. The receptor was activated either by 100 microM S-alpha-amino-3-hydroxy-5-methyl-4-isoxazolopropionic acid (AMPA) (EC50 = 26.6 +/- 4.9 microM) or by 100 microM kainate (EC50 = 0.81 +/- 0.1 microM), but the effects of these agonists were not additive. The response to either AMPA or kainate was competitively inhibited by 10 microM 6-cyano-7-nitroquinoxaline-2,3-dioxine. Higher [Ca2+]i responses to 100 microM AMPA or to 100 microM kainate were observed in the CA3 subregion (43.2 +/- 2.5 nM or 42.8 +/- 2.3 nM, respectively) than in the whole hippocampus (22.4 +/- 1.1 nM or 22.4 +/- 1.6, respectively), in the CA1 subregion (26.4 +/- 1.1 nM or 26.6 +/- 2.6 nM, respectively) or in dentate gyrus (24.6 +/- 1.4 nM or 21.5 +/- 1.0 nM, respectively). These results indicate that the CA3 subregion of the hippocampus is enriched in a presynaptic high-affinity kainate receptor which modulates the [Ca2+]i in nerve terminals.