Unravelling the pathophysiology of calcium channel mutations causing neurological disorders

Voltage-gated calcium channels are molecules that play a key role in cell-to-cell communication and muscle contraction. They are divided into low voltage-activated (LVA or T-type) and high voltage-activated (HVA) channels, which may further be dissected into L, N, P/Q and R channels based on their sensitivity to drugs and toxins. Calcium channels constitute a heteromeric complex composed of a large pore-forming α1 subunit and four auxiliary subunits, α2/δ, β and γ. Genes encoding the different subunits of the calcium channels have now been identified. For instance, the α1A subunit of the neuronal calcium channel is encoded by the CACNL1A4 gene; it contains four internal repeats (DI to DIV), each of them composed of six transmembrane segments (S1 to S6). Recently, P/Q type channels were shown to be splice variants of the CACNL1A4 gene (Bourinet et al., 1999). These channels are involved in the release of neurotransmitters from nerve terminals by allowing an influx of calcium which stimulates the exocytosis of synaptic vesicles (Augustine et al., 1998).