A new look at calcium channel α2δ subunits

The classical roles of alpha(2)delta 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 alpha(2)delta-1 and alpha(2)delta-3 have been shown to have novel functions in synaptogenesis, independent of their effect on calcium channels. In neurons, the alpha(2)delta-1 subunits are present mainly in presynaptic terminals. Peripheral sensory nerve injury results in the up-regulation of alpha(2)delta-1 in dorsal root ganglion (DRG) neurons, and there is a consequent increase in trafficking of alpha(2)delta-1 to their terminals. Furthermore, gabapentinoid drugs, which bind to alpha(2)delta-1 and alpha(2)delta-2, not only impair their trafficking, but also affect alpha(2)delta-1-dependent synaptogenesis. These drugs may interfere with alpha(2)delta function at several different levels.