Therefore an understanding of their basic mechanism(s) of action is of paramount importance. ![]() The α 2δ subunits of voltage-gated calcium channels (Ca V) have been identified to be key proteins in synaptic function and synaptogenesis ( Dickman et al., 2008 Kurshan et al., 2009 Hoppa et al., 2012 Eroglu et al., 2009 Saheki and Bargmann, 2009). Proteolytic processing of α 2δ then permits voltage-dependent activation of the channels, acting as a checkpoint allowing trafficking only of mature calcium channel complexes into neuronal processes. ![]() We propose a model whereby uncleaved α 2δ subunits maintain immature calcium channels in an inhibited state. ![]() Uncleaved α 2δ does not support trafficking of Ca V2.2 channel complexes into neuronal processes, and inhibits Ca 2+ entry into synaptic boutons, and we can reverse this by controlled intracellular proteolytic cleavage. By inducing acute cell-surface proteolytic cleavage of α 2δ, voltage-dependent activation of channels is promoted, independent from the trafficking role of α 2δ. Indeed, uncleaved α2δ inhibits native calcium currents in mammalian neurons. We now show, using α 2δ constructs containing artificial cleavage sites, that this processing is an essential step permitting voltage-dependent activation of plasma membrane N-type (Ca V2.2) calcium channels. ![]() The auxiliary α 2δ subunits of voltage-gated calcium channels are extracellular membrane-associated proteins, which are post-translationally cleaved into disulfide-linked polypeptides α 2 and δ.
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June 2023
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