Although L-type voltage-sensitive calcium channels (VSCCs) have been well characterized electrophysiologically, their role in synaptic physiology has remained unclear. To assess their involvement in synaptic regulation of gene expression, we have examined the effects of selective VSCC antagonists on basal, synaptically mediated activation of several transcription factor genes in cultured cortical neurons. Basal expression of c-fos, jun-B, zif268, and fos-B is rapidly suppressed by exposure to L-type VSCC antagonists and increased by (-)BayK-8644, a VSCC agonist. Although VSCC antagonists block kainate-induced rises in intracellular calcium and gene expression, these agents have little effect on spontaneous electrical activity or synaptically induced calcium transients in these neurons. These findings suggest that even though L-type VSCCs contribute a relatively minor component of synaptic calcium transients, they appear to play a key role in coupling synaptic excitation to activation of transcriptional events thought to contribute to neuronal plasticity.