1. Dolphin, A.C. Calcium Channel Auxiliary α2δ and β Subunits: Trafficking and One Step Beyond. Nat. Rev. Neurosci. 2012, 13, 542–555. [CrossRef] [PubMed]
2. Felix, R.; Gurnett, C.A.; de Waard, M.; Campbell, K.P. Dissection of Functional Domains of the Voltage-Dependent Ca2+ Channel Alpha2delta Subunit. J. Neurosci. 1997, 17, 6884–6891. [CrossRef] [PubMed]
3. Catterall, W.A. Voltage-Gated Calcium Channels. Cold Spring Harb. Perspect. Biol. 2011, 3, a003947. [CrossRef] [PubMed]
4. Calderón-Rivera, A.; Andrade, A.; Hernández-Hernández, O.; González-Ramírez, R.; Sandoval, A.; Rivera, M.; Gomora, J.C.; Felix, R. Identification of a Disulfide Bridge Essential for Structure and Function of the Voltage-Gated Ca2+ Channel α2δ-1
Auxiliary Subunit. Cell Calcium 2012, 51, 22–30. [CrossRef] [PubMed]
5. Ablinger, C.; Geisler, S.M.; Stanika, R.I.; Klein, C.T.; Obermair, G.J. Neuronal α2δ Proteins and Brain Disorders. Pflügers Arch.-Eur.
J. Physiol. 2020, 472, 845–863. [CrossRef]
6. Andrade, A.; Brennecke, A.; Mallat, S.; Brown, J.; Gomez-Rivadeneira, J.; Czepiel, N.; Londrigan, L. Genetic Associations between
Voltage-Gated Calcium Channels and Psychiatric Disorders. Int. J. Mol. Sci. 2019, 20, 3537. [CrossRef]
7. Eroglu, C.; Allen, N.J.; Susman, M.W.; O’Rourke, N.A.; Park, C.Y.; Ozkan, E.; Chakraborty, C.; Mulinyawe, S.B.; Annis, D.S.; Huberman, A.D.; et al. Gabapentin Receptor Alpha2delta-1 Is a Neuronal Thrombospondin Receptor Responsible for Excitatory
CNS Synaptogenesis. Cell 2009, 139, 380–392. [CrossRef]
8. Risher, W.C.; Kim, N.; Koh, S.; Choi, J.-E.; Mitev, P.; Spence, E.F.; Pilaz, L.-J.; Wang, D.; Feng, G.; Silver, D.L.; et al. Thrombospondin
Receptor α2δ-1 Promotes Synaptogenesis and Spinogenesis via Postsynaptic Rac1. J. Cell Biol. 2018, 217, 3747–3765. [CrossRef]
9. Beeson, K.A.; Beeson, R.; Westbrook, G.L.; Schnell, E. α2δ-2 Protein Controls Structure and Function at the Cerebellar Climbing
Fiber Synapse. J. Neurosci. 2020, 40, 2403–2415. [CrossRef]
10. Fell, B.; Eckrich, S.; Blum, K.; Eckrich, T.; Hecker, D.; Obermair, G.J.; Münkner, S.; Flockerzi, V.; Schick, B.; Engel, J. α2δ2 Controls
the Function and Trans-Synaptic Coupling of Cav1.3 Channels in Mouse Inner Hair Cells and Is Essential for Normal Hearing.
J. Neurosci. 2016, 36, 11024–11036. [CrossRef]
11. Geisler, S.; Schöpf, C.L.; Stanika, R.; Kalb, M.; Campiglio, M.; Repetto, D.; Traxler, L.; Missler, M.; Obermair, G.J. Presynaptic
α2δ-2 Calcium Channel Subunits Regulate Postsynaptic GABAA Receptor Abundance and Axonal Wiring. J. Neurosci. 2019, 39,
2581–2605. [CrossRef] [PubMed]
12. Pirone, A.; Kurt, S.; Zuccotti, A.; Rüttiger, L.; Pilz, P.; Brown, D.H.; Franz, C.; Schweizer, M.; Rust, M.B.; Rübsamen, R.; et al. α2δ3
Is Essential for Normal Structure and Function of Auditory Nerve Synapses and Is a Novel Candidate for Auditory Processing
Disorders. J. Neurosci. 2014, 34, 434–445. [CrossRef] [PubMed]
13. Caylor, R.C.; Jin, Y.; Ackley, B.D. The Caenorhabditis Elegans Voltage-Gated Calcium Channel Subunits UNC-2 and UNC-36
and the Calcium-Dependent Kinase UNC-43/CaMKII Regulate Neuromuscular Junction Morphology. Neural Dev. 2013, 8, 10.
[CrossRef]
14. Kurshan, P.T.; Oztan, A.; Schwarz, T.L. Presynaptic α2δ-3 Is Required for Synaptic Morphogenesis Independent of Its Ca2+-
Channel Functions. Nat. Neurosci. 2009, 12, 1415–1423. [CrossRef] [PubMed]
15. Schlick, B.; Flucher, B.E.; Obermair, G.J. Voltage-Activated Calcium Channel Expression Profiles in Mouse Brain and Cultured
Hippocampal Neurons. Neuroscience 2010, 167, 786–798. [CrossRef]
16. Kerov, V.; Laird, J.G.; Joiner, M.-L.; Knecht, S.; Soh, D.; Hagen, J.; Gardner, S.H.; Gutierrez, W.; Yoshimatsu, T.; Bhattarai, S.; et al.
α2δ-4 Is Required for the Molecular and Structural Organization of Rod and Cone Photoreceptor Synapses. J. Neurosci. 2018, 38,
6145–6160. [CrossRef] [PubMed]
17. Knoflach, D.; Kerov, V.; Sartori, S.B.; Obermair, G.J.; Schmuckermair, C.; Liu, X.; Sothilingam, V.; Garcia Garrido, M.; Baker, S.A.;
Glösmann, M.; et al. Cav1.4 IT Mouse as Model for Vision Impairment in Human Congenital Stationary Night Blindness Type 2.
Channels 2013, 7, 503–513. [CrossRef]
18. Wang, Y.; Fehlhaber, K.E.; Sarria, I.; Cao, Y.; Ingram, N.T.; Guerrero-Given, D.; Throesch, B.; Baldwin, K.; Kamasawa, N.; Ohtsuka,
T.; et al. The Auxiliary Calcium Channel Subunit α2δ4 Is Required for Axonal Elaboration, Synaptic Transmission, and Wiring of
Rod Photoreceptors. Neuron 2017, 93, 1359–1374. [CrossRef]
19. Wycisk, K.A.; Budde, B.; Feil, S.; Skosyrski, S.; Buzzi, F.; Neidhardt, J.; Glaus, E.; Nürnberg, P.; Ruether, K.; Berger, W. Structural
and Functional Abnormalities of Retinal Ribbon Synapses Due to Cacna2d4 Mutation. Investig. Ophthalmolo. Vis. Sci. 2006, 47,
3523–3530. [CrossRef]
20. van Loo, K.M.J.; Rummel, C.K.; Pitsch, J.; Müller, J.A.; Bikbaev, A.F.; Martinez-Chavez, E.; Blaess, S.; Dietrich, D.; Heine, M.;
Becker, A.J.; et al. Calcium Channel Subunit α2δ4 Is Regulated by Early Growth Response 1 and Facilitates Epileptogenesis. J. Neurosci. 2019, 39, 3175–3187. [CrossRef]
Int. J. Mol. Sci. 2022, 23, 9885 22 of 23
21. Klomp, A.; Omichi, R.; Iwasa, Y.; Smith, R.J.; Usachev, Y.M.; Russo, A.F.; Narayanan, N.S.; Lee, A. The Voltage-Gated Ca2+ Channel Subunit α2δ-4 Regulates Locomotor Behavior and Sensorimotor Gating in Mice. PLoS ONE 2022, 17, e0263197. [CrossRef] [PubMed]
22. Cottrell, G.S.; Soubrane, C.H.; Hounshell, J.A.; Lin, H.; Owenson, V.; Rigby, M.; Cox, P.J.; Barker, B.S.; Ottolini, M.; Ince, S.; et al. CACHD1 Is an α2δ-Like Protein That Modulates CaV3 Voltage-Gated Calcium Channel Activity. J. Neurosci. 2018, 38, 9186–9201. [CrossRef] [PubMed]
23. Stephens, G.J.; Cottrell, G.S. CACHD1: A New Activity-Modifying Protein for Voltage-Gated Calcium Channels. Channels 2019, 13, 120–123. [CrossRef] [PubMed]
24. Dahimene, S.; Page, K.M.; Kadurin, I.; Ferron, L.; Ho, D.Y.; Powell, G.T.; Pratt, W.S.; Wilson, S.W.; Dolphin, A.C. The α2δ-like Protein Cachd1 Increases N-Type Calcium Currents and Cell Surface Expression and Competes with α2δ-1. Cell Rep. 2018, 25, 1610–1621. [CrossRef]
25. Schöpf, C.L.; Ablinger, C.; Geisler, S.M.; Stanika, R.I.; Campiglio, M.; Kaufmann, W.A.; Nimmervoll, B.; Schlick, B.; Brockhaus, J.; Missler, M.; et al. Presynaptic α2δ Subunits Are Key Organizers of Glutamatergic Synapses. Proc. Natl. Acad. Sci. USA 2021, 118, e1920827118. [CrossRef]
26. Obermair, G.J.; Szabo, Z.; Bourinet, E.; Flucher, B.E. Differential Targeting of the L-Type Ca2+ Channel Alpha 1C (CaV1.2) to Synaptic and Extrasynaptic Compartments in Hippocampal Neurons. Eur. J. Neurosci. 2004, 19, 2109–2122. [CrossRef]
27. Stanika, R.; Campiglio, M.; Pinggera, A.; Lee, A.; Striessnig, J.; Flucher, B.E.; Obermair, G.J. Splice Variants of the CaV1.3 L-Type Calcium Channel Regulate Dendritic Spine Morphology. Sci. Rep. 2016, 6, 34528. [CrossRef]
28. Brockhaus, J.; Schreitmüller, M.; Repetto, D.; Klatt, O.; Reissner, C.; Elmslie, K.; Heine, M.; Missler, M. α-Neurexins Together with α2δ-1 Auxiliary Subunits Regulate Ca2+ Influx through Cav2.1 Channels. J. Neurosci. 2018, 38, 8277–8294. [CrossRef]
29. Scott, M.B.; Kammermeier, P.J. CaV2 Channel Subtype Expression in Rat Sympathetic Neurons Is Selectively Regulated by α2δ Subunits. Channels 2017, 11, 555–573. [CrossRef]
30. Hoppa, M.B.; Lana, B.; Margas, W.; Dolphin, A.C.; Ryan, T.A. α2δ Expression Sets Presynaptic Calcium Channel Abundance and Release Probability. Nature 2012, 486, 122–125. [CrossRef]
31. Geisler, S.M.; Benedetti, A.; Schöpf, C.L.; Schwarzer, C.; Stefanova, N.; Schwartz, A.; Obermair, G.J. Phenotypic Characterization and Brain Structure Analysis of Calcium Channel Subunit α2δ-2 Mutant (Ducky) and α2δ Double Knockout Mice. Front. Synaptic Neurosci. 2021, 13, 634412. [CrossRef] [PubMed]
32. Gao, S.; Yao, X.; Yan, N. Structure of Human Cav2.2 Channel Blocked by the Painkiller Ziconotide. Nature 2021, 596, 143–147. [CrossRef] [PubMed]
33. Held, R.G.; Liu, C.; Ma, K.; Ramsey, A.M.; Tarr, T.B.; de Nola, G.; Wang, S.S.H.; Wang, J.; van den Maagdenberg, A.M.J.M.; Schneider, T.; et al. Synapse and Active Zone Assembly in the Absence of Presynaptic Ca2+ Channels and Ca2+ Entry. Neuron 2020, 107, 667–683.e9. [CrossRef] [PubMed]
34. Smith, M.; Flodman, P.L.; Gargus, J.J.; Simon, M.T.; Verrell, K.; Haas, R.; Reiner, G.E.; Naviaux, R.; Osann, K.; Spence, M.A.; et al. Mitochondrial and Ion Channel Gene Alterations in Autism. Biochim. Biophys. Acta 2012, 1817, 1796–1802. [CrossRef] [PubMed]
35. Purcell, S.M.; Moran, J.L.; Fromer, M.; Ruderfer, D.; Solovieff, N.; Roussos, P.; O’Dushlaine, C.; Chambert, K.; Bergen, S.E.; Kähler,
A.; et al. A Polygenic Burden of Rare Disruptive Mutations in Schizophrenia. Nature 2014, 506, 185–190. [CrossRef]
36. van den Bossche, M.J.; Strazisar, M.; de Bruyne, S.; Bervoets, C.; Lenaerts, A.-S.; de Zutter, S.; Nordin, A.; Norrback, K.-F.; Goossens, D.; de Rijk, P.; et al. Identification of a CACNA2D4 Deletion in Late Onset Bipolar Disorder Patients and Implications for the Involvement of Voltage-Dependent Calcium Channels in Psychiatric Disorders. Am. J. Med. Genetics. Part B Neuropsychiatr.
Genet. 2012, 159B, 465–475. [CrossRef] [PubMed]
37. Rudan Njavro, J.; Klotz, J.; Dislich, B.; Wanngren, J.; Shmueli, M.D.; Herber, J.; Kuhn, P.-H.; Kumar, R.; Koeglsperger, T.; Conrad,
M.; et al. Mouse Brain Proteomics Establishes MDGA1 and CACHD1 as in Vivo Substrates of the Alzheimer Protease BACE1.
FASEB J. 2020, 34, 2465–2482. [CrossRef]
38. Moran, Y.; Zakon, H.H. The Evolution of the Four Subunits of Voltage-Gated Calcium Channels: Ancient Roots, Increasing
Complexity, and Multiple Losses. Genome Biol. Evol. 2014, 6, 2210–2217. [CrossRef]
39. Neely, G.G.; Hess, A.; Costigan, M.; Keene, A.C.; Goulas, S.; Langeslag, M.; Griffin, R.S.; Belfer, I.; Dai, F.; Smith, S.B.; et al. A
Genome-Wide Drosophila Screen for Heat Nociception Identifies α2δ3 as an Evolutionarily Conserved Pain Gene. Cell 2010, 143,
628–638. [CrossRef]
40. Brodbeck, J.; Davies, A.; Courtney, J.-M.; Meir, A.; Balaguero, N.; Canti, C.; Moss, F.J.; Page, K.M.; Pratt, W.S.; Hunt, S.P.; et al. The
Ducky Mutation in Cacna2d2 Results in Altered Purkinje Cell Morphology and Is Associated with the Expression of a Truncated
Alpha2Delta-2 Protein with Abnormal Function. J. Biol. Chem. 2002, 277, 7684–7693. [CrossRef]
41. Barclay, J.; Balaguero, N.; Mione, M.; Ackerman, S.L.; Letts, V.A.; Brodbeck, J.; Canti, C.; Meir, A.; Page, K.M.; Kusumi, K.; et al. Ducky Mouse Phenotype of Epilepsy and Ataxia Is Associated with Mutations in the Cacna2d2 Gene and Decreased Calcium
Channel Current in Cerebellar Purkinje Cells. J. Neurosci. 2001, 21, 6095–6104. [CrossRef] [PubMed]
42. Kaech, S.; Banker, G. Culturing Hippocampal Neurons. Nat. Protoc. 2006, 1, 2406–2415. [CrossRef] [PubMed]
43. Obermair, G.J.; Schlick, B.; Di Biase, V.; Subramanyam, P.; Gebhart, M.; Baumgartner, S.; Flucher, B.E. Reciprocal Interactions
Regulate Targeting of Calcium Channel Beta Subunits and Membrane Expression of Alpha1 Subunits in Cultured Hippocampal Neurons. J. Biol. Chem. 2010, 285, 5776–5791. [CrossRef]
Int. J. Mol. Sci. 2022, 23, 9885 23 of 23
44. Bacchi, N.; Messina, A.; Burtscher, V.; Dassi, E.; Provenzano, G.; Bozzi, Y.; Demontis, G.C.; Koschak, A.; Denti, M.A.; Casarosa, S. A New Splicing Isoform of Cacna2d4 Mimicking the Effects of c.2451insC Mutation in the Retina: Novel Molecular and Electrophysiological Insights. Investig. Ophthalmol. Vis. Sci. 2015, 56, 4846–4856. [CrossRef] [PubMed]
45. Petersen, T.N.; Brunak, S.; von Heijne, G.; Nielsen, H. SignalP 4.0: Discriminating Signal Peptides from Transmembrane Regions. Nat. Methods 2011, 8, 785–786. [CrossRef]
46. Folci, A.; Steinberger, A.; Lee, B.; Stanika, R.; Scheruebel, S.; Campiglio, M.; Ramprecht, C.; Pelzmann, B.; Hell, J.W.; Obermair, G.J.; et al. Molecular Mimicking of C-Terminal Phosphorylation Tunes the Surface Dynamics of CaV1.2 Calcium Channels in Hippocampal Neurons. J. Biol. Chem. 2018, 293, 1040–1053. [CrossRef]
47. Di Biase, V.; Flucher, B.E.; Obermair, G.J. Resolving Sub-Synaptic Compartments with Double Immunofluorescence Labeling In Hippocampal Neurons. J. Neurosci. Methods 2009, 176, 78–84. [CrossRef]
48. Emsley, P.; Lohkamp, B.; Scott, W.G.; Cowtan, K. Features and Development of Coot. Acta Crystallogr. Sect. D Biol. Crystallogr. 2010, 66, 486–501. [CrossRef]
49. Krissinel, E.; Henrick, K. Inference of Macromolecular Assemblies from Crystalline State. J. Mol. Biol. 2007, 372, 774–797. [CrossRef]