The Presynaptic α2δ Protein Family and Their Therapeutic Potential

α2δ proteins are well-established modulators of membrane expression and biophysical properties of voltage-gated calcium channels. Moreover, they are critical regulators of synapse formation and function and key players in transsynaptic signalling. The α2δ isoforms are highly glycosylated membrane-anchored proteins with distinct structural features, some of which are also observed in a human α2δ-like protein termed CACHD1. Accumulating evidence has underpinned the involvement of α2δ proteins in neurological and neurodevelopmental disorders, making them attractive novel therapeutic targets. Also, CACHD1, through its modulation of T-type currents, is an emerging potential drug target, particularly for epilepsy and pain. Furthermore, α2δ proteins are targets of the widely prescribed gabapentinoids. Among these, gabapentin and pregabalin, which have a high binding affinity for α2δ-1 and α2δ-2, have been administered particularly in the treatment of neuropathic pain conditions, epilepsy, and restless leg syndrome. Extensive efforts have been and are being made to understand the structure and functions of α2δ proteins and how they interact with synaptic proteins. This is ultimately helping to understand the contribution of the α2δ protein family to neurological and neurodevelopmental disorders and provides insight into potential novel treatment options.