Calcium channel αδ subunits in epilepsy and as targets for antiepileptic drugs

The αδ proteins are accessory subunits of voltage-gated calcium channel subunits. As such, they enhance calcium channel trafficking and insertion in the plasma membrane, but also influence the biophysical properties of the channels. However, αδ-1 and αδ-3 have now been shown to be involved in synaptogenesis, apparently independently of their effect on calcium channel function. In neurons, αδ-1 is mainly localized to presynaptic terminals. In terms of pathophysiology, αδ-1 is involved in neuropathic pain that develops after peripheral sensory nerve injury, which involves an increase in αδ-1 gene expression. The αδ-2 subunit may be particularly important in relation to epilepsy. Mice bearing mutations in αδ-2, as well as αδ-2 knockout mice, exhibit both spike-wave epilepsy and, in some mouse strains, tonic-clonic seizures. Furthermore, αδ-1 and αδ-2 are the targets for the gabapentinoid drugs (gabapentin and pregabalin). These drugs are used in the therapy of certain forms of epilepsy, and are also efficacious in alleviation of neuropathic pain. Despite binding to these αδ subunits, gabapentin and pregabalin produce little acute inhibition of calcium channel currents. However, they do produce inhibition when applied chronically, and impair trafficking of the αδ subunits, which may represent the mechanism of inhibition of synaptic transmission.