Presynaptic α2δ-3 is required for synaptic morphogenesis independent of its Ca2+-channel functions

Abstract

Synaptogenesis involves the transformation of a growth cone into synaptic boutons specialized for transmitter release. In Drosophila embryos lacking the α 2 δ-3 subunit of presynaptic, voltagedependent Ca 2+ channels, we find that motor neuron terminals fail to develop synaptic boutons and cytoskeletal abnormalities arise, including the loss of ankyrin2. Nevertheless, functional presynaptic specializations are present and apposed to clusters of postsynaptic glutamate receptors. Heretofore, the α 2 δ-3 protein has been thought to function strictly as an auxiliary subunit of the Ca 2+ channel, but the phenotype of α 2 δ-3 mutations cannot be explained by a channel defect: embryos lacking the pore-forming α 1 subunit cacophony form boutons. The synaptogenic function of α 2 δ-3 requires only the α 2 peptide, whose expression suffices to rescue bouton formation. Our results indicate that α 2 δ proteins have functions independent of their roles in the biophysics and localization of Ca 2+ channels, and synaptic architecture depends on these novel functions.

Anxiolytic-Like Activity of Pregabalin in the Vogel Conflict Test in α2δ-1 (R217A) and α2δ-2 (R279A) Mouse Mutants

“…Recent work has shown that ␣ 2 ␦-1 interacts with the protein thrombospondin to increase the number of excitatory synapses, that this interaction is independent of activity at calcium channels, and that the interaction and the development of excitatory synapses is blocked by application of gabapentin (Eroglu et al, 2009). In a similar way, ␣ 2 ␦-3 is involved in the development of motor neuron terminals in Drosophila, and this activity is independent of calcium channel activity (Kurshan et al, 2009).…”

The α 2 δ subunits of voltage-gated calcium channels form GPI-anchored proteins, a posttranslational modification essential for function

“…Indeed, we have shown that a population of Ca V 2.1 is present in DRMs prepared from the cerebellum (14). Calcium-channel complexes or α 2 δ subunits playing other roles [e.g., in synapse formation (28,29)] may participate in nanodomain signaling complexes, and thrombospondin is one identified interacting partner (28). Additionally, modification of lipid-raft composition by acute cholesterol depletion has marked effects on calciumchannel currents (14).…”

Characterization of Cav1.4 Complexes (α11.4, β2, and α2δ4) in HEK293T Cells and in the Retina

“…Thus, native ␣ 2 ␦ 4 -containing Ca v 1.4 channels in photoreceptors may be more strongly modulated by CaBP4 than ␣ 2 ␦ 1 -containing Ca v 1.4 channels. ␣ 2 ␦ subunits also play roles in regulating neurotransmitter release probability (69) as well as synaptogenesis (70,71), independent of effects on Ca v function. Understanding the precise roles of ␣ 2 ␦ 4 in regulating photoreceptor signaling and how its dysregulation leads to vision impairment in humans and mice (26,54) remains an important challenge for future studies.…”