Role for voltage gated calcium channels in calcitonin gene-related peptide release in the rat trigeminovascular system

Clinical and genetic studies have suggested a role for voltage gated calcium channels (VGCCs) in the pathogenesis of migraine. Release of calcitonin gene-related peptide (CGRP) from trigeminal neurons has also been implicated in migraine. The VGCCs are located presynaptically on neurons and are involved in the release of these peptides to different stimuli. We have examined the presence and importance of VGCCs in controlling the CGRP release from rat dura mater, freshly isolated trigeminal ganglion (TG) and trigeminal nucleus caudalis (TNC). Each of the four VGCCs, P/Q-, N-, and L- and T-type are abundantly found in TG and TNC relative to the dura mater and each mediates a significant fraction of high potassium concentration induced CGRP release. In dura mater, blockade of P/Q-, N- and L-type VGCCs by ω-agatoxin TK, ω-conotoxin GVIA and nimodipine at 1 μM respectively, significantly decreased the potassium induced CGRP release. In the absence of calcium ions (Ca2+) and in the presence of a cocktail of blockers, the stimulated CGRP release from dura mater was reduced almost to the same level as basal CGRP release. In the TG ω-conotoxin GVIA inhibited the potassium induced CGRP release significantly. In the absence of Ca2+ and in the presence of a cocktail of blockers the stimulated CGRP release was significantly reduced. In the TNC only the cocktail of blockers and the absence of Ca2+ could reduce the potassium induced release significantly. These results suggest that depolarization by high potassium releases CGRP, and the release is regulated by Ca2+ ions and voltage-gated calcium channels.

Research Highlights▶ VGCCs are present in rat dura mater, TG and TNC. ▶ Release of CGRP in rat dura mater, TG and TNC is inhibited in calcium-free media. ▶ Blockade of P/Q-, N- and L-type VGCCs inhibited CGRP release in dura mater. ▶ Blockade of N-type VGCC inhibited CGRP release in trigeminal ganglion. ▶ A cocktail of four VGCC blockers inhibit CGRP release in dura mater, TG and TNC.