Voltage‐Gated N‐Type and T‐Type Calcium Channels and Excitability Disorders

Calcium (Ca2þ) is a ubiquitous signaling molecule involved in a diverse array of cellular processes ranging from control of membrane excitability to gene transcription, all of which require that intracellular levels be tightly regulated. In particular, voltage-gated Ca2þ channels (Cav) regulate transmembrane fluxes of calcium in response to membrane depolarization. Ca2þ currents can generally be grouped into two major classes of Cav channels: high voltage activated (HVA) and low voltage activated (LVA or “T-type”). Based on their pharmacological and biophysical properties, the HVA class can be further subdivided into L-, N-, P/Q-, and R-type channels. The main pore-forming a subunits of the Cav channels are encoded by 10 different genes, CACNA1A, CACNA1B, CACNA1C, CACNA1D, CACNA1E, CACNA1F, CACNA1G,CACNA1H, CACNA1I, and CACNA1S, with a greater variety of subtypes for each class arising from a substantial degree of alternative splicing.Associatedwith the pore-forming subunit of HVA channels are several accessory subunits, a2d (four genes inmammals),b (four genes inmammals), and g (up to eight genes inmammals), although the precise complement is not well determined biochemically for all of the HVA channel types. Further, HVA channel complexity occurs as a result of the