Invertebrate modeling of a migraine channelopathy

Migraine is a chronic episodic disorder that has been linked to abnormalities in serotonin signaling and abnormal function of a presynaptic voltage-gated calcium channel, CACNA1A. Although the importance of serotonin to migraine tendency suggests a link between serotonergic signaling and CACNA1A function, the nature of this connection remains unclear in vertebrate studies. This article reviews findings, based on an invertebrate model of CACNA1A dysfunction, which suggest a potential connection between serotonergic and calcium channel abnormalities in migraine. Neurons of the invertebrate species Caenorhabditis elegans express a voltage-gated calcium channel, UNC-2, which is the closest ortholog in C. elegans of human CACNA1A. Mutations in unc-2, the gene that encodes this invertebrate channel, cause the animals to be lethargic and uncoordinated. By identifying the genes that could be altered in such a way as to suppress the lethargic phenotype of unc-2, a signaling pathway has been identified through which UNC-2 calcium channel function antagonizes a transforming growth factor-beta (TGF-beta) pathway modulating locomotion. In C. elegans, serotonergic signaling can inhibit the rate of movement. The UNC-2/transforming growth factor-beta pathway identified regulates the expression of a gene encoding the rate-limiting enzyme for serotonin synthesis, tryptophan hydroxylase. The evolutionary and functional relationship between the UNC-2 channel and the migraine-associated CACNA1A channel was further confirmed through experiments showing that transgenic expression of human CACNA1A can suppress the lethargic and serotonin-deficient phenotypes of unc-2 mutant animals. The findings in this invertebrate model constitute the first direct demonstration of how CACNA1A function might affect the levels of serotonin, a neurotransmitter known to be important in migraine.