Control of action potential-induced Ca2+ signaling in the soma of hippocampal neurons by Ca2+ release from intracellular stores.

Stimulus-induced increases in neuronal Ca2+ concentration are important signaling events for transcriptional regulation and neuronal plasticity. Electrical inputs are thought to mediate Ca2+ responses in the soma by triggering action potentials, which in turn open voltage-gated Ca2+ channels in the somatic plasma membrane. It is not yet known to what extent internal Ca2+ amplification contributes to the somatic Ca2+ responses. Here we used fluorescent Ca2+ measurements in cultured hippocampal neurons and report that the amplitude of the somatic Ca2+ increase triggered by field stimulation is independent of the extracellular Ca2+ concentration as long as the concentration is greater than 50 microM. Furthermore, significantly more La3+ has to be added extracellularly for blocking Ca2+ responses, as predicted from the reported La3+ dependence of voltage-gated Ca2+ channels. These measurements suggest that field stimulation-induced somatic Ca2+ responses in hippocampal neurons are largely attributable to Ca2+ release from intracellular stores. Only a small number of Ca2+ ions have to enter across the plasma membrane for this intracellular Ca2+ amplification process to occur. Rapid fluorescence-imaging measurements showed that the internal Ca2+ amplification occurs over 10-15 msec and linearly increases intracellular Ca2+ concentrations for up to 40 action potentials. At a fixed number of field pulses, frequencies of 40 Hz were optimal for somatic Ca2+ increases. Our studies suggest that the opening of intracellular Ca2+ release channels plays a crucial part in shaping the action potential-induced neuronal Ca2+ response.