title: Proteolytic maturation of α2δ represents a checkpoint for activation and neuronal trafficking of latent calcium channels.
abstract: The auxiliary α2δ subunits of voltage-gated calcium channels are extracellular membrane-associated proteins, which are post-translationally cleaved into disulfide-linked polypeptides α2and δ. We now show, using α2δ constructs containing artificial cleavage sites, that this processing is an essential step permitting voltage-dependent activation of plasma membrane N-type (CaV2.2) calcium channels. Indeed, uncleaved α2δ inhibits native calcium currents in mammalian neurons. By inducing acute cell-surface proteolytic cleavage of α2δ, voltage-dependent activation of channels is promoted, independent from the trafficking role of α2δ. Uncleaved α2δ does not support trafficking of CaV2.2 channel complexes into neuronal processes, and inhibits Ca2+entry into synaptic boutons, and we can reverse this by controlled intracellular proteolytic cleavage. We propose a model whereby uncleaved α2δ subunits maintain immature calcium channels in an inhibited state. Proteolytic processing of α2δ then permits voltage-dependent activation of the channels, acting as a checkpoint allowing trafficking only of mature calcium channel complexes into neuronal processes.
authors: Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom.
authors: Ivan
authors: I
authors: Kadurin
authors: Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom.
authors: Laurent
authors: L
authors: Ferron
authors: Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom.
authors: Simon W
authors: SW
authors: Rothwell
authors: Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom.
authors: James O
authors: JO
authors: Meyer
authors: Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom.
authors: Leon R
authors: LR
authors: Douglas
authors: Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom.
authors: Claudia S
authors: CS
authors: Bauer
authors: Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom.
authors: Beatrice
authors: B
authors: Lana
authors: Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom.
authors: Wojciech
authors: W
authors: Margas
authors: Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom.
authors: Orpheas
authors: O
authors: Alexopoulos
authors: Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom.
authors: Manuela
authors: M
authors: Nieto-Rostro
authors: Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom.
authors: Wendy S
authors: WS
authors: Pratt
authors: Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom.
authors: Annette C
authors: 0000-0003-4626-4856
authors: AC
authors: Dolphin
mesh_terms: D000818:Animals; D020864:Calcium Channels, N-Type / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D009474:Neurons / Q000201:enzymology*; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D059748:Proteolysis; D011817:Rabbits; D051381:Rats
chemical_list: C503279:Cacna1b protein, rat; D020864:Calcium Channels, N-Type
keywords: Ca2+ channels; biochemistry; electrophysiology; mouse; neuron; neuroscience; rat