α₂δ2 Controls the Function and Trans-Synaptic Coupling of Ca_v1.3 Channels in Mouse Inner Hair Cells and Is Essential for Normal Hearing

The Auxiliary Calcium Channel Subunit α2δ4 Is Required for Axonal Elaboration, Synaptic Transmission, and Wiring of Rod Photoreceptors

“…Conversely, we found α2δ4 to be essential for increasing the number of functional Ca V 1.4 channels at ribbons. The role of α2δ4 in setting the number of functional Ca V 1.4 in the presynaptic active zones of photoreceptors is consistent with the described roles of α2δ1-3 in trafficking other members of Ca V family in neurons (Cassidy et al, 2014; D’Arco et al, 2015; Fell et al, 2016; Hoppa et al, 2012) and their reported chaperone-like function in promoting surface localization of Ca V channels in reconstituted systems (Dolphin, 2013). …”

“…These observations may suggest a general mechanism by which α2δ proteins exert synaptogenenic effects. For instance, loss of α2δ3 function has been shown to result in deficits in synapse formation and a decrease of synaptic transmission (Hoppa et al, 2012; Pirone et al, 2014), whereas overexpression of α2δ1 was reported to increase assembly of functional synapses working in concert with extracellular matrix protein thrombospondin 1 (Eroglu et al, 2009) and α2δ3 in hair cells was shown to control trans -synaptically AMPA receptor recruitment (Fell et al, 2016). Despite these advances, the molecular mechanisms that mediate the effects of α2δ proteins on synapse formation were not elucidated.…”

“…These proteins are thought to act mainly by promoting Ca V surface expression (Cassidy et al, 2014; D’Arco et al, 2015; Hoppa et al, 2012; Lee et al, 2015). However, their effects on the biophysical properties of the Ca V channels are controversial and were reported mostly in heterologous overexpression systems (Bangalore et al, 1996; Felix et al, 1997; Fell et al, 2016; Singer et al, 1991). In addition, α2δ proteins have been implicated in synapse formation, acting independently from but possibly in cooperation with Ca V channels (Eroglu et al, 2009; Kurshan et al, 2009).…”

Transcellular Nanoalignment of Synaptic Function

“…Potential trans-synaptic links are suggested by interactions of α2δ with the LRR domain of ELFN1 in the cleft of rod photoreceptor synapses (Wang et al, 2017). A recent study also observed loss of both Ca 2+ channels and AMPARs/PSD-95 co-localization upon α2δ loss in auditory ribbon synapses, implicating a role in organizing this synapse (Fell et al, 2016). Intriguingly, the C. elegans α2δ protein participates in retrograde signaling via neurexin-neuroligin interactions (Tong et al, 2017).…”

Clarin-1 gene transfer rescues auditory synaptopathy in model of Usher syndrome

“…Defects of the presynaptic scaffold protein Syd1 (synaptic-defective-1) at the neuromuscular junction result in abnormal presynaptic neurexin targeting, impairing the postsynaptic density cluster organization of neuroligin-1 and glutamatergic receptors (40). A role for the auxiliary Ca 2+ channel subunit Ca V α 2 δ 2 in the trans-synaptic coupling of IHC Ca V 1.3 channels with the postsynaptic AMPA receptor complex has also been recently proposed (41). Based on our findings in clarin-1-deficient mice, we suggest that clarin-1 is a member of the transsynaptic membrane interaction adhesion complex at the IHC ribbon synapse, a complex essential for the focal alignment of the presynaptic Ca V 1.3 channels and release sites with the postsynaptic AMPA receptors ( Figure 13B).…”