The calcitonin gene-related peptide (CGRP) and P/Q voltage-gated calcium channel genes have been implicated in the underlying pathophysiology of migraine headaches. CGRP levels are elevated during migraine, then are restored to normal coincident with headache relief following treatment with the serotonergic drug sumatriptan. Patients with the rare familial hemiplegic migraine disorder have mutations in a subunit of the P/Q-type calcium channel. However, whether there is a connection between calcium and CGRP expression in the sensory neurons that are activated during migraine is not known. The approach that we have taken is to study the regulation of CGRP gene expression in primary cultures of rat trigeminal neurons. We have previously demonstrated that CGRP secretion from these cultures is increased by depolarization and inflammatory signals and decreased by treatment with 5-HT₁ agonists, including sumatriptan. We now report that the CGRP promoter is activated by depolarization and inflammatory signals. These signals cause a transient increase in calcium and activation of MAP kinase pathways. The stimulation requires a helix-loop-helix regulatory element within a cell-specific 18 bp enhancer that is sufficient to target expression of a reporter gene preferentially to neurons. The MAP kinase-stimulated CGRP promoter activity was markedly reduced by treatment with sumatriptan. Sumatriptan regulation of CGRP gene expression did not couple to a G_i/G_o pathway but rather caused a prolonged increase in intracellular calcium. The sustained elevation in calcium was shown to be sufficient to repress MAP kinase stimulation of the CGRP promoter. Finally, we provide evidence that the inhibitory effects of sumatriptan are probably mediated via induction of serine/threonine protein phosphatases. This raises the possibility of using the cell-specific CGRP enhancer for targeted expression of a therapeutic phosphatase. Based on our results, we propose that the CGRP promoter is sensitive to the amplitude and duration of a calcium signal, such that transient calcium signals increase CGRP gene expression during migraine while prolonged calcium signals induced by serotonergic migraine drugs could reduce CGRP levels. While the role of the P/Q calcium channels in this model remains completely speculative, we suggest that channel mutations may alter the calcium dynamics in the trigeminal neurons so as to result in increased levels of CGRP.