Ca_v2.1 channelopathies and genetic approaches for investigatings Ca_v2.1 channel function and dysfunction

Voltage-gated Ca²⁺ (Ca_v) channels allow the entry of Ca²⁺ into a cell when the membrane is depolarized. In the nervous system, Ca_v channels control a broad array of functions including neurotransmitter release, neurite outgrowth, synaptogenesis, neuronal excitability, activity-dependent gene expression, and neuron survival, differentiation, and plasticity. Ca_v2.1 (P/Q-type) channels have a dominant, specific role in synaptic transmission at central excitatory synapses. In CACNA1A gene mutations, changes to the pore-forming a1 subunit of the Ca_v2.1 channel cause several autosomal-dominant neurological disorders in humans including familial hemiplegic migraine type 1 (FHM1), episodic ataxia type 2 (EA2), spinocerebellar ataxia type 6 (SCA6), and epilepsy. Mice with mutations in the Cacna1a gene are a useful tool for obtaining insights into disease processes and defining channel functions. Mouse Ca_v2.1 mutants include FHM1 model strains, including R192Q and S218L knockin mice, a SCA6 model strain carrying additional CAG repeats in the cacna1a locus of knockin mice, a knockout strain lacking Ca_v2.1 currents, and spontaneous strains that include rocker, tottering, rolling Nagoya, leaner, tottering-4j, tottering-5j, and wobbly mice. This chapter summarizes the human disease phenotypes and functional consequences of disease-causing mutations expressed in cell culture models, and overviews the results that Ca_v2.1 mutant mice have provided regarding the disease mechanisms of Ca_v2.1 channelopathy and the functions of Ca_v2.1 channels.