Cav2.1 Channels and Migraine

Abstract

Migraine is a common disabling brain disorder whose key manifestations are recurrent attacks of unilateral headache that may be preceded by transient neurological aura symptoms. Missense mutations in CACNA1A, the gene that encodes the pore-forming a 1 subunit of human voltage-gated Ca v 2.1 (P/Q-type) calcium channels, cause a rare form of migraine with aura (familial hemiplegic migraine type 1: FHM1). This chapter, first, briefly summarizes current understanding of the pathophysiological mechanisms that underlie migraine headache, migraine aura, and the onset of a migraine attack. Then, the chapter describes and discusses (i) the functional consequences of FHM1 mutations on the biophysical properties of recombinant human Ca v 2.1 channels and native Ca v 2.1 channels in neurons of knockin mouse models carrying the mild R192Q or severe S218L mutations in the orthologous gene, and (ii) the functional consequences of these mutations on neurophysiological processes in the cerebral cortex and trigeminovascular system thought to be involved in the pathophysiology of migraine (including cortical spreading depression, cortical synaptic transmission, and several trigeminal ganglion neuron functions) and the insights into migraine mechanisms obtained from the alterations of these processes in FHM1 knockin mice.

Anatomy and Physiology of Headache

“…Voltage gated calcium channels (VGCCs) play a unique role in migraine, as missense mutations in the CACNA1A gene of Cav2.1 (P/Q-type) cause familial hemiplegic migraine type 1 (FHM 1), characterized by abnormal cortical excitation. 55 56 Some mutations of FHM 1 also result in hyperexcitability of TG neurons. 57 P/Q-, L-, and N-type VGCCs in trigeminal nucleus caudalis (TNC) are important for CGRP release 58 59 and postsynaptic action potentials.…”