Biological science of headache channels

Several episodic neurological diseases, including familial hemiplegic migraine (FHM) and different types of epilepsy, are caused by mutations in ion channels, and hence classified as channelopathies. The classification of FHM as a channelopathy has introduced a new perspective in headache research and has strengthened the idea of migraine as a disorder of neural excitability. Here we review recent studies of the functional consequences of mutations in the CACNA1A and SCNA1A genes (encoding the pore-forming subunit of CaV2.1 and NaV1.1 channels) and the ATPA1A2 gene (encoding the α2 subunit of the Na+/K+ pump), responsible for FHM1, FHM3, and FHM2, respectively. These studies show that: (1) FHM1 mutations produce gain-of-function of the CaV2.1 channel and, as a consequence, increased glutamate release at cortical synapses and facilitation of induction and propagation of cortical spreading depression (CSD); (2) FHM2 mutations produce loss-of-function of the α2 Na+/K+-ATPase; and (3) the FHM3 mutation accelerates recovery from fast inactivation of NaV1.5 channels. These findings are consistent with the hypothesis that FHM mutations share the ability to render the brain more susceptible to CSD, by causing excessive synaptic glutamate release (FHM1) or decreased removal of K+ and glutamate from the synaptic cleft (FHM2) or excessive extracellular K+ (FHM3).