A new look at calcium channel α2δ subunits

The classical roles of α2δ proteins are as accessory calcium channel subunits, enhancing channel trafficking. They were thought to have type-I transmembrane topology, but we find that they can form GPI-anchored proteins. Moreover α2δ-1 and α2δ-3 have been shown to have novel functions in synaptogenesis, independent of their effect on calcium channels. In neurons, the α2δ-1 subunits are present mainly in presynaptic terminals. Peripheral sensory nerve injury results in the up-regulation of α2δ-1 in dorsal root ganglion (DRG) neurons, and there is a consequent increase in trafficking of α2δ-1 to their terminals. Furthermore, gabapentinoid drugs, which bind to α2δ-1 and α2δ-2, not only impair their trafficking, but also affect α2δ-1-dependent synaptogenesis. These drugs may interfere with α2δ function at several different levels.