Faithful relay of information depends on the precisely adjusted spatial arrangement between presynaptic release sites and postsynaptic receptor signaling complex (Biederer et al., 2017; Haas et al., 2018; Tang et al., 2016). However, the molecular mechanism responsible for the pre- and post-synaptic alignment is not known. The α2δ proteins (α2δ1-4) are the only extracellular portion of the entire voltage-gated calcium channel (VGCC) complex, which is the central organizer of the presynaptic releasing machinery across the entire nervous system. Given that α2δs are multidomain proteins capable of mediating different protein-protein interactions and that all four members of α2δs have been recently shown as critical players for the formation and function of different synapses (Eroglu et al., Cell 2009; Fell et al., J Neurosci 2016; Pirone et al., J Neurosci  2014; Wang et al., Neuron 2017), we hypothesize that extracellular α2δ proteins serve as an universal mechanism underlying synaptic efficiency by ensuring the precise pre- and post-synaptic alignment.

Cryo-EM structure of α2δ1 protein (Wu 2016 Nature) demonstrates the extracellular, multidomain nature of α2δ proteins. α2δ4, the only retina specific α2δ protein, is enriched at synaptic layers of mouse retina. Absence of α2δ4 leads to massive photoreceptor synaptic deficits and at least part of these deficits is due to its interaction with cell adhesion molecule ELFN1 (Wang et al., Neuron 2017).