<p>We studied the effects of Semax on spontaneous fluctuations of intracellular calcium ion concentration [Ca²⁺]_i in pyramidal neurons on hippocampal slices and on proton-induced increase in [Ca²⁺]_i in cerebellar granule cells in cerebellar slices. Application of Semax (1 μM), significantly increased the frequency of spontaneous [Ca²⁺]_i fluctuations in the pyramidal layer cells of the hippocampal CA1 field, but had no significant effect on proton-stimulated increase in [Ca²⁺]_i in cerebellar granule cells. These data provide insight into the localization of cellular targets and elucidate the dynamics of the initial stages of interaction between the peptide and the hippocampal neuronal network. The primary mechanism of the neuroprotective effect of Semax appears to be unrelated to attenuation of calcium entry through acid-sensing ion channels in cerebellar granule cells.</p>