Abstract/Summary

α2δ proteins are well-established modulators of membrane expression 5 and biophysical properties of voltage-gated calcium channels. Moreover, they are 6 critical regulators of synapse formation and function and key players in transsynap- 7 tic signalling. The α2δ isoforms are highly glycosylated membrane-anchored pro- 8 teins with distinct structural features, some of which are also observed in a human 9 α2δ-like protein termed CACHD1. Accumulating evidence has underpinned the 10 involvement of α2δ proteins in neurological and neurodevelopmental disorders, 11 making them attractive novel therapeutic targets. Also, CACHD1, through its mod- 12 ulation of T-type currents, is an emerging potential drug target, particularly for epi- 13 lepsy and pain. Furthermore, α2δ proteins are targets of the widely prescribed 14 gabapentinoids. Among these, gabapentin and pregabalin, which have a high bind- 15 ing affinity for α2δ-1 and α2δ-2, have been administered particularly in the treatment 16 of neuropathic pain conditions, epilepsy, and restless leg syndrome. Extensive 17 efforts have been and are being made to understand the structure and functions of 18 α2δ proteins and how they interact with synaptic proteins. This is ultimately helping 19 to understand the contribution of the α2δ protein family to neurological and neuro- 20 developmental disorders and provides insight into potential novel treatment options.