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Cav1.2 channelopathies causing autism: new hallmarks on Timothy syndrome

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Abstract

Cav1.2 L-type calcium channels play key roles in long-term synaptic plasticity, sensory transduction, muscle contraction, and hormone release. De novo mutations in the gene encoding Cav1.2 (CACNA1C) causes two forms of Timothy syndrome (TS1, TS2), characterized by a multisystem disorder inclusive of cardiac arrhythmias, long QT, autism, and adrenal gland dysfunction. In both TS1 and TS2, the missense mutation G406R is on the alternatively spliced exon 8 and 8A coding for the IS6-helix of Cav1.2 and is responsible for the penetrant form of autism in most TS individuals. The mutation causes specific gain-of-function changes to Cav1.2 channel gating: a “leftward shift” of voltage-dependent activation, reduced voltage-dependent inactivation, and a “leftward shift” of steady-state inactivation. How this occurs and how Cav1.2 gating changes alter neuronal firing and synaptic plasticity is still largely unexplained. Trying to better understanding the molecular basis of Cav1.2 gating dysfunctions leading to autism, here, we will present and discuss the properties of recently reported typical and atypical TS phenotypes and the effective gating changes exhibited by missense mutations associated with long QTs without extracardiac symptoms, unrelated to TS. We will also discuss new emerging views achieved from using iPSCs-derived neurons and the newly available autistic TS2-neo mouse model, both appearing promising for understanding neuronal mistuning in autistic TS patients. We will also analyze and describe recent proposals of molecular pathways that might explain mistuned Ca2+-mediated and Ca2+-independent excitation–transcription signals to the nucleus. Briefly, we will also discuss possible pharmacological approaches to treat autism associated with L-type channelopathies.

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References

  1. Almagor L, Chomsky-Hecht O, Ben-Mocha A, Hendin-Barak D, Dascal N, Hirsch JA (2012) Ca(V)1.2 I-II linker structure and Timothy syndrome. Channels (Austin) 6:468–472

    CAS  Google Scholar 

  2. Antzelevitch C, Pollevick GD, Cordeiro JM, Casis O, Sanguinetti MC, Aizawa Y, Guerchicoff A, Pfeiffer R, Oliva A, Wollnik B, Gelber P, Bonaros EP Jr, Burashnikov E, Wu Y, Sargent JD, Schickel S, Oberheiden R, Bhatia A, Hsu LF, Haïssaguerre M, Schimpf R, Borggrefe M, Wolpert C (2007) Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death. Circulation 115:442–449

    PubMed  PubMed Central  Google Scholar 

  3. Atlas D (2013) The voltage-gated calcium channel functions as the molecular switch of synaptic transmission. Annu Rev Biochem 82:607–635

    CAS  PubMed  Google Scholar 

  4. Bader PL, Faizi M, Kim LH, Owen SF, Tadross MR, Alfa RW, Bett GC, Tsien RW, Rasmusson RL, Shamloo M (2011) Mouse model of Timothy syndrome recapitulates triad of autistic traits. Proc Natl Acad Sci U S A 108:15432–15437

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Baldelli P, Forni PE, Carbone E (2000) BDNF, NT-3 and NGF induce distinct new Ca2+ channel synthesis in developing hippocampal neurons. Eur J Neurosci 12:4017–4032

    CAS  PubMed  Google Scholar 

  6. Baldelli P, Hernandez-Guijo JM, Carabelli V, Carbone E (2005) Brain-derived neurotrophic factor enhances GABA release probability and nonuniform distribution of N- and P/Q-type channels on release sites of hippocampal inhibitory synapses. J Neurosci 25:3358–3368

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Barnabei VM, Rasmusson RL, Bett GC (2014) Autism and induced labor: is calcium a potential mechanistic link? Am J Obstet Gynecol 210:494–495

    PubMed  Google Scholar 

  8. Barrett CF, Tsien RW (2008) The Timothy syndrome mutation differentially affects voltage- and calcium-dependent inactivation of CaV1.2 L-type calcium channels. Proc Natl Acad Sci U S A 105:2157–2162

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Berger SM, Bartsch D (2014) The role of L-type voltage-gated calcium channels Cav1.2 and Cav1.3 in normal and pathological brain function. Cell Tissue Res 357:463–476

    CAS  PubMed  Google Scholar 

  10. Bett GC, Kaplan AD, Lis A, Cimato TR, Tzanakakis ES, Zhou Q, Morales MJ, Rasmusson RL (2013) Electronic “expression” of the inward rectifier in cardiocytes derived from human-induced pluripotent stem cells. Heart Rhythm 10:1903–1910

    PubMed  Google Scholar 

  11. Bett GC, Lis A, Wersinger SR, Baizer JS, Duffey ME, Rasmusson RL (2012) A mouse model of Timothy syndrome: a complex autistic disorder resulting from a point mutation in Cav1.2. N Am J Med Sci 5:135–140

    Google Scholar 

  12. Betzenhauser MJ, Pitt GS, Antzelevitch C (2015) Calcium channel mutations in cardiac arrhythmia syndromes. Curr Mol Pharmacol 8:133–142

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Bhat S, Dao DT, Terrillion CE, Arad M, Smith RJ, Soldatov NM, Gould TD (2012) CACNA1C (Cav1.2) in the pathophysiology of psychiatric disease. Prog Neurobiol 99:1–14

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Bidaud I, Lory P (2011) Hallmarks of the channelopathies associated with L-type calcium channels: a focus on the Timothy mutations in Ca(v)1.2 channels. Biochimie 93:2080–2086

    CAS  PubMed  Google Scholar 

  15. Boczek NJ, Best JM, Tester DJ, Giudicessi JR, Middha S, Evans JM, Kamp TJ, Ackerman MJ (2013) Exome sequencing and systems biology converge to identify novel mutations in the L-type calcium channel, CACNA1C, linked to autosomal dominant long QT syndrome. Circ Cardiovasc Genet 6:279–289

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Boczek NJ, Miller EM, Ye D, Nesterenko VV, Tester DJ, Antzelevitch C, Czosek RJ, Ackerman MJ, Ware SM (2015) Novel Timothy syndrome mutation leading to increase in CACNA1C window current. Heart Rhythm 12:211–219

    PubMed  Google Scholar 

  17. Breitenkamp AF, Matthes J, Nass RD, Sinzig J, Lehmkuhl G, Nurnberg P, Herzig S (2014) Rare mutations of CACNB2 found in autism spectrum disease-affected families alter calcium channel function. PLoS One 9:e95579

    PubMed  PubMed Central  Google Scholar 

  18. Buraei Z, Yang J (2010) The ß subunit of voltage-gated Ca2+ channels. Physiol Rev 90:1461–1506

    CAS  PubMed  Google Scholar 

  19. Buraei Z, Yang J (2013) Structure and function of the beta subunit of voltage-gated Ca(2)(+) channels. Biochim Biophys Acta 1828:1530–1540

    CAS  PubMed  Google Scholar 

  20. Calorio C, Gavello D, Guarina L, Salio C, Sassoe-Pognetto M, Riganti C, Bianchi FT, Hofer NT, Tuluc P, Obermair GJ, Defilippi P, Balzac F, Turco E, Bett GC, Rasmusson RL, Carbone E (2019) Impaired chromaffin cell excitability and exocytosis in autistic Timothy syndrome TS2-neo mouse rescued by L-type calcium channel blockers. J Physiol Lond 597:1705–1733

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Carbone E, Borges R, Eiden LE, Garcia AG, Hernandez-Cruz A (2019) Chromaffin cells of the adrenal medulla: physiology, pharmacology, and disease. Compr Physiol 9:1443–1502

    PubMed  Google Scholar 

  22. Catterall WA (1995) Structure and function of voltage-gated ion channels. Annu Rev Biochem 64:493–531

    CAS  PubMed  Google Scholar 

  23. Catterall WA (2011) Voltage-gated calcium channels. Cold Spring Harb Perspect Biol 3:23

    Google Scholar 

  24. Cheli VT, Santiago González DA, Zamora NN, Lama TN, Spreuer V, Rasmusson RL, Bett GC, Panagiotakos G, Paez PM (2018) Enhanced oligodendrocyte maturation and myelination in a mouse model of Timothy syndrome. Glia 66:2324–2339

    PubMed  PubMed Central  Google Scholar 

  25. Coffey JM, Vadas AJ, Puleo TR, Lewis KP, Pirrone GF, Rudolph HL, Helms ED, Wood TD, Flynn-Charlebois A (2018) Synthesis and characterization of a deuterium labeled stercobilin: a potential biomarker for autism. J Label Compd Radiopharm 61:742–748

    CAS  Google Scholar 

  26. De Waard M, Pragnell M, Campbell KP (1994) Ca2+ channel regulation by a conserved beta subunit domain. Neuron 13:495–503

    PubMed  Google Scholar 

  27. Dhara M, Mohrmann R, Bruns D (2018) v-SNARE function in chromaffin cells. Pflugers Arch - Eur J Physiol 470:169–180

    CAS  Google Scholar 

  28. Dick IE, Joshi-Mukherjee R, Yang W, Yue DT (2016) Arrhythmogenesis in Timothy syndrome is associated with defects in Ca(2+)-dependent inactivation. Nat Commun 7:10370

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Ehlinger DG, Commons KG (2017) Altered Cav1.2 function in the Timothy syndrome mouse model produces ascending serotonergic abnormalities. Eur J Neurosci 46:2416–2425

    PubMed  PubMed Central  Google Scholar 

  30. Ertel EA, Campbell KP, Harpold MM, Hofmann F, Mori Y, Perez-Reyes E, Schwartz A, Snutch TP, Tanabe T, Birnbaumer L, Tsien RW, Catterall WA (2000) Nomenclature of voltage-gated calcium channels. Neuron 25:533–535

    CAS  PubMed  Google Scholar 

  31. Erxleben C, Liao Y, Gentile S, Chin D, Gomez-Alegria C, Mori Y, Birnbaumer L, Armstrong DL (2006) Cyclosporin and Timothy syndrome increase mode 2 gating of CaV1.2 calcium channels through aberrant phosphorylation of S6 helices. Proc Natl Acad Sci U S A 103:3932–3937

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Etemad S, Obermair GJ, Bindreither D, Benedetti A, Stanika R, Di Biase V, Burtscher V, Koschak A, Kofler R, Geley S, Wille A, Lusser A, Flockerzi V, Flucher BE (2014) Differential neuronal targeting of a new and two known calcium channel β4 subunit splice variants correlates with their regulation of gene expression. J Neurosci 34:1446–1461

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Etheridge SP, Bowles NE, Arrington CB, Pilcher T, Rope A, Wilde AA, Alders M, Saarel EV, Tavernier R, Timothy KW, Tristani-Firouzi M (2011) Somatic mosaicism contributes to phenotypic variation in Timothy syndrome. Am J Med Genet A 155a:2578–2583

    PubMed  Google Scholar 

  34. Ferreira MAR, O’Donovan MC, Meng YA, Jones IR, Ruderfer DM, Jones L, Fan J, Kirov G, Perlis RH, Green EK, Smoller JW, Grozeva D, Stone J, Nikolov I, Chambert K, Hamshere ML, Nimgaonkar VL, Moskvina V, Thase ME, Caesar S, Sachs GS, Franklin J, Gordon-Smith K, Ardlie KG, Gabriel SB, Fraser C, Blumenstiel B, Defelice M, Breen G, Gill M, Morris DW, Elkin A, Muir WJ, McGhee KA, Williamson R, MacIntyre DJ, MacLean AW, Clair DS, Robinson M, Van Beck M, Pereira ACP, Kandaswamy R, McQuillin A, Collier DA, Bass NJ, Young AH, Lawrence J, Ferrier IN, Anjorin A, Farmer A, Curtis D, Scolnick EM, Mcguffin P, Daly MJ, Corvin AP, Holmans PA, Blackwood DH, Gurling HM, Owen MJ, Purcell SM, Sklar P, Craddock N, Wellcome Trust Case Control C (2008) Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nat Genet 40:1056–1058

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Frohler S, Kieslich M, Langnick C, Feldkamp M, Opgen-Rhein B, Berger F, Will JC, Chen W (2014) Exome sequencing helped the fine diagnosis of two siblings afflicted with atypical Timothy syndrome (TS2). BMC Med Genet 15:48

    PubMed  PubMed Central  Google Scholar 

  36. Fukuyama M, Wang Q, Kato K, Ohno S, Ding W-G, Toyoda F, Itoh H, Kimura H, Makiyama T, Ito M, Matsuura H, Horie M (2014) Long QT syndrome type 8: novel CACNA1C mutations causing QT prolongation and variant phenotypes. Europace 16:1828–1837

    PubMed  Google Scholar 

  37. Gavello D, Calorio C, Franchino C, Cesano F, Carabelli V, Carbone E, Marcantoni A (2018) Early alterations of hippocampal neuronal firing induced by Abeta42. Cereb Cortex 28:433–446

    PubMed  Google Scholar 

  38. Gavello D, Rojo-Ruiz J, Marcantoni A, Franchino C, Carbone E, Carabelli V (2012) Leptin counteracts the hypoxia-induced inhibition of spontaneously firing hippocampal neurons: a microelectrode array study. PLoS One 7:e41530

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Gillis J, Burashnikov E, Antzelevitch C, Blaser S, Gross G, Turner L, Babul-Hirji R, Chitayat D (2012) Long QT, syndactyly, joint contractures, stroke and novel CACNA1C mutation: expanding the spectrum of Timothy syndrome. Am J Med Genet A 158a:182–187

    PubMed  Google Scholar 

  40. Green EK, Grozeva D, Jones I, Jones L, Kirov G, Caesar S, Gordon-Smith K, Fraser C, Forty L, Russell E, Hamshere ML, Moskvina V, Nikolov I, Farmer A, McGuffin P, Holmans PA, Owen MJ, O'Donovan MC, Craddock N (2010) The bipolar disorder risk allele at CACNA1C also confers risk of recurrent major depression and of schizophrenia. Mol Psychiatry 15:1016–1022

    CAS  PubMed  Google Scholar 

  41. Guarina L, Vandael DH, Carabelli V, Carbone E (2017) Low pHo boosts burst firing and catecholamine release by blocking TASK-1 and BK channels while preserving Cav1 channels in mouse chromaffin cells. J Physiol 595:2587–2609

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Han D, Xue X, Yan Y, Li G (2019) Highlight article: dysfunctional Cav1.2 channel in Timothy syndrome, from cell to bedside. Exp Biol Med (Maywood) 244:960–971

    CAS  Google Scholar 

  43. Hanlon MR, Berrow NS, Dolphin AC, Wallace BA (1999) Modelling of a voltage-dependent Ca2+ channel beta subunit as a basis for understanding its functional properties. FEBS Lett 445:366–370

    CAS  PubMed  Google Scholar 

  44. Hering S, Zangerl-Plessl EM, Beyl S, Hohaus A, Andranovits S, Timin EN (2018) Calcium channel gating. Pflugers Arch - Eur J Physiol 470:1291–1309

    CAS  Google Scholar 

  45. Hiippala A, Tallila J, Myllykangas S, Koskenvuo JW, Alastalo TP (2015) Expanding the phenotype of Timothy syndrome type 2: an adolescent with ventricular fibrillation but normal development. Am J Med Genet A 167A:629–634

    PubMed  Google Scholar 

  46. Hofer NT, Tuluc P, Ortner NJ, Nikonishyna YV, Fernándes-Quintero ML, Liedl KR, Flucher BE, Cox H, Striessnig J (2020) Biophysical classification of a CACNA1D de novo mutation as a high-risk mutation for a severe neurodevelopmental disorder. Mol Autism 11:4–4

    PubMed  PubMed Central  Google Scholar 

  47. Hofmann F, Lacinová L, Klugbauer N (1999) Voltage-dependent calcium channels: from structure to function. Rev Physiol Biochem Pharmacol 139:33–87

    CAS  PubMed  Google Scholar 

  48. Kabir ZD, Martinez-Rivera A, Rajadhyaksha AM (2017) From gene to behavior: L-type calcium channel mechanisms underlying neuropsychiatric symptoms. Neurotherapeutics 14:588–613

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Kabitzke PA, Brunner D, He D, Fazio PA, Cox K, Sutphen J, Thiede L, Sabath E, Hanania T, Alexandrov V, Rasmusson R, Spooren W, Ghosh A, Feliciano P, Biemans B, Benedetti M, Clayton AL (2017) Comprehensive analysis of two Shank3 and the Cacna1c mouse models of autism spectrum disorder. Genes Brain Behav

  50. Kawaida M, Abe T, Nakanishi T, Miyahara Y, Yamagishi H, Sakamoto M, Yamada T (2016) A case of Timothy syndrome with adrenal medullary dystrophy. Pathol Int 66:587–592

    CAS  PubMed  Google Scholar 

  51. Krey JF, Pasca SP, Shcheglovitov A, Yazawa M, Schwemberger R, Rasmusson R, Dolmetsch RE (2013) Timothy syndrome is associated with activity-dependent dendritic retraction in rodent and human neurons. Nat Neurosci 16:201–209

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Li B, Tadross MR, Tsien RW (2016) Sequential ionic and conformational signaling by calcium channels drives neuronal gene expression. Science (New York, NY) 351:863–867

    CAS  Google Scholar 

  53. Liao P, Soong TW (2010) CaV1.2 channelopathies: from arrhythmias to autism, bipolar disorder, and immunodeficiency. Pflugers Arch - Eur J Physiol 460:353–359

    CAS  Google Scholar 

  54. Lingle CJ, Martinez-Espinosa PL, Guarina L, Carbone E (2018) Roles of Na(+), Ca(2+), and K(+) channels in the generation of repetitive firing and rhythmic bursting in adrenal chromaffin cells. Pflugers Arch - Eur J Physiol 470:39–52

    CAS  Google Scholar 

  55. Ma H, Groth RD, Cohen SM, Emery JF, Li B, Hoedt E, Zhang G, Neubert TA, Tsien RW (2014) γCaMKII shuttles Ca2+/CaM to the nucleus to trigger CREB phosphorylation and gene expression. Cell 159:281–294

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Mahapatra S, Marcantoni A, Vandael DHF, Striessnig J, Carbone E (2011) Are Ca(v)1.3 pacemaker channels in chromaffin cells? Possible bias from resting cell conditions and DHP blockers usage. Channels 5:219–224

    PubMed  PubMed Central  Google Scholar 

  57. Marcantoni A, Baldelli P, Hernandez-Guijo JM, Comunanza V, Carabelli V, Carbone E (2007) L-type calcium channels in adrenal chromaffin cells: role in pace-making and secretion. Cell Calcium 42:397–408

    CAS  PubMed  Google Scholar 

  58. Marcantoni A, Carabelli V, Vandael DH, Comunanza V, Carbone E (2009) PDE type-4 inhibition increases L-type Ca2+ currents, action potential firing, and quantal size of exocytosis in mouse chromaffin cells. Pflugers Arch - Eur J Physiol 457:1093–1110

    CAS  Google Scholar 

  59. Marcantoni A, Cerullo MS, Buxeda P, Tomagra G, Giustetto M, Chiantia G, Carabelli V, Carbone E (2020) Abeta42 oligomers up-regulate the excitatory synapses by potentiating presynaptic release while impairing postsynaptic NMDA receptors. J Physiol 598:2183–2197

    CAS  PubMed  Google Scholar 

  60. Marcantoni A, Vandael DHF, Mahapatra S, Carabelli V, Sinnegger-Brauns MJ, Striessnig J, Carbone E (2010) Loss of Cav1.3 channels reveals the critical role of L-type and BK channel coupling in pacemaking mouse adrenal chromaffin cells. J Neurosci 30:491–504

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Minor DL Jr, Findeisen F (2010) Progress in the structural understanding of voltage-gated calcium channel (CaV) function and modulation. Channels (Austin) 4:459–474

    Google Scholar 

  62. Moon AL, Haan N, Wilkinson LS, Thomas KL, Hall J (2018) CACNA1C: association with psychiatric disorders, behavior, and neurogenesis. Schizophr Bull 44:958–965

    PubMed  PubMed Central  Google Scholar 

  63. Mullins C, Fishell G, Tsien RW (2016) Unifying views of autism spectrum disorders: a consideration of autoregulatory feedback loops. Neuron 89:1131–1156

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Murphy TH, Worley PF, Baraban JM (1991) L-type voltage-sensitive calcium channels mediate synaptic activation of immediate early genes. Neuron 7:625–635

    CAS  PubMed  Google Scholar 

  65. Nimmervoll B, Flucher BE, Obermair GJ (2013) Dominance of P/Q-type calcium channels in depolarization-induced presynaptic FM dye release in cultured hippocampal neurons. Neuroscience 253:330–340

    CAS  PubMed  Google Scholar 

  66. Obermair GJ, Schlick B, Di Biase V, Subramanyam P, Gebhart M, Baumgartner S, Flucher BE (2010) Reciprocal interactions regulate targeting of calcium channel beta subunits and membrane expression of alpha1 subunits in cultured hippocampal neurons. J Biol Chem 285:5776–5791

    CAS  PubMed  Google Scholar 

  67. Ouimet T, Foster NE, Tryfon A, Hyde KL (2012) Auditory-musical processing in autism spectrum disorders: a review of behavioral and brain imaging studies. Ann N Y Acad Sci 1252:325–331

    PubMed  Google Scholar 

  68. Ozawa J, Ohno S, Saito H, Saitoh A, Matsuura H, Horie M (2018) A novel CACNA1C mutation identified in a patient with Timothy syndrome without syndactyly exerts both marked loss- and gain-of-function effects. HeartRhythm Case Rep 4:273–277

    PubMed  PubMed Central  Google Scholar 

  69. Panagiotakos G, Haveles C, Arjun A, Petrova R, Rana A, Portmann T, Paşca SP, Palmer TD, Dolmetsch RE (2019) Aberrant calcium channel splicing drives defects in cortical differentiation in Timothy syndrome. eLife 8:e51037

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Pasca SP, Panagiotakos G, Dolmetsch RE (2014) Generating human neurons in vitro and using them to understand neuropsychiatric disease. Annu Rev Neurosci 37:479–501

    CAS  PubMed  Google Scholar 

  71. Pasca SP, Portmann T, Voineagu I, Yazawa M, Shcheglovitov A, Pasca AM, Cord B, Palmer TD, Chikahisa S, Nishino S, Bernstein JA, Hallmayer J, Geschwind DH, Dolmetsch RE (2011) Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome. Nat Med 17:1657–U1176

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Pinggera A, Lieb A, Benedetti B, Lampert M, Monteleone S, Liedl KR, Tuluc P, Striessnig J (2015) CACNA1D de novo mutations in autism spectrum disorders activate Cav1.3 L-type calcium channels. Biol Psychiatry 77:816–822

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Pinggera A, Mackenroth L, Rump A, Schallner J, Beleggia F, Wollnik B, Striessnig J (2017) New gain-of-function mutation shows CACNA1D as recurrently mutated gene in autism spectrum disorders and epilepsy. Hum Mol Genet 26:2923–2932

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Pragnell M, De Waard M, Mori Y, Tanabe T, Snutch TP, Campbell KP (1994) Calcium channel beta-subunit binds to a conserved motif in the I-II cytoplasmic linker of the alpha 1-subunit. Nature 368:67–70

    CAS  PubMed  Google Scholar 

  75. Ramachandran KV, Hennessey JA, Barnett AS, Yin X, Stadt HA, Foster E, Shah RA, Yazawa M, Dolmetsch RE, Kirby ML, Pitt GS (2013) Calcium influx through L-type CaV1.2 Ca2+ channels regulates mandibular development. J Clin Invest 123:1638–1646

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Raybaud A, Dodier Y, Bissonnette P, Simoes M, Bichet DG, Sauve R, Parent L (2006) The role of the GX9GX3G motif in the gating of high voltage-activated Ca2+ channels. J Biol Chem 281:39424–39436

    CAS  PubMed  Google Scholar 

  77. Rendall AR, Ford AL, Perrino PA, Holly FR (2017) Auditory processing enhancements in the TS2-neo mouse model of Timothy syndrome, a rare genetic disorder associated with autism spectrum disorders. Adv Neurodev Disord 1:176–189

    PubMed  PubMed Central  Google Scholar 

  78. Ripke S, O’Dushlaine C, Chambert K, Moran JL, Kähler AK, Akterin S, Bergen SE, Collins AL, Crowley JJ, Fromer M, Kim Y, Lee SH, Magnusson PK, Sanchez N, Stahl EA, Williams S, Wray NR, Xia K, Bettella F, Borglum AD, Bulik-Sullivan BK, Cormican P, Craddock N, de Leeuw C, Durmishi N, Gill M, Golimbet V, Hamshere ML, Holmans P, Hougaard DM, Kendler KS, Lin K, Morris DW, Mors O, Mortensen PB, Neale BM, O'Neill FA, Owen MJ, Milovancevic MP, Posthuma D, Powell J, Richards AL, Riley BP, Ruderfer D, Rujescu D, Sigurdsson E, Silagadze T, Smit AB, Stefansson H, Steinberg S, Suvisaari J, Tosato S, Verhage M, Walters JT, Levinson DF, Gejman PV, Kendler KS, Laurent C, Mowry BJ, O'Donovan MC, Owen MJ, Pulver AE, Riley BP, Schwab SG, Wildenauer DB, Dudbridge F, Holmans P, Shi J, Albus M, Alexander M, Campion D, Cohen D, Dikeos D, Duan J, Eichhammer P, Godard S, Hansen M, Lerer FB, Liang KY, Maier W, Mallet J, Nertney DA, Nestadt G, Norton N, O'Neill FA, Papadimitriou GN, Ribble R, Sanders AR, Silverman JM, Walsh D, Williams NM, Wormley B, Arranz MJ, Bakker S, Bender S, Bramon E, Collier D, Crespo-Facorro B, Hall J, Iyegbe C, Jablensky A, Kahn RS, Kalaydjieva L, Lawrie S, Lewis CM, Lin K, Linszen DH, Mata I, McIntosh A, Murray RM, Ophoff RA, Powell J, Rujescu D, Van Os J, Walshe M, Weisbrod M, Wiersma D, Donnelly P, Barroso I, Blackwell JM, Bramon E, Brown MA, Casas JP, Corvin AP, Deloukas P, Duncanson A, Jankowski J, Markus HS, Mathew CG, Palmer CN, Plomin R, Rautanen A, Sawcer SJ, Trembath RC, Viswanathan AC, Wood NW, Spencer CC, Band G, Bellenguez C, Freeman C, Hellenthal G, Giannoulatou E, Pirinen M, Pearson RD, Strange A, Su Z, Vukcevic D, Donnelly P, Langford C, Hunt SE, Edkins S, Gwilliam R, Blackburn H, Bumpstead SJ, Dronov S, Gillman M, Gray E, Hammond N, Jayakumar A, McCann OT, Liddle J, Potter SC, Ravindrarajah R, Ricketts M, Tashakkori-Ghanbaria A, Waller MJ, Weston P, Widaa S, Whittaker P, Barroso I, Deloukas P, Mathew CG, Blackwell JM, Brown MA, Corvin AP, MI MC, Spencer CC, Bramon E, Corvin AP, O'Donovan MC, Stefansson K, Scolnick E, Purcell S, McCarroll SA, Sklar P, Hultman CM, Sullivan PF (2013) Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat Genet 45:1150–1159

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Russo I, Gavello D, Menna E, Vandael D, Veglia C, Morello N, Corradini I, Focchi E, Alfieri A, Angelini C, Bianchi FT, Morellato A, Marcantoni A, Sassoe-Pognetto M, Ottaviani MM, Yekhlef L, Giustetto M, Taverna S, Carabelli V, Matteoli M, Carbone E, Turco E, Defilippi P (2019) p140Cap regulates GABAergic synaptogenesis and development of hippocampal inhibitory circuits. Cereb Cortex 29:91–105

    PubMed  Google Scholar 

  80. Seisenberger C, Specht V, Welling A, Platzer J, Pfeifer A, Kuhbandner S, Striessnig J, Klugbauer N, Feil R, Hofmann F (2000) Functional embryonic cardiomyocytes after disruption of the L-type alpha(1C) (Ca(v)1.2) calcium channel gene in the mouse. J Biol Chem 275:39193–39199

    CAS  PubMed  Google Scholar 

  81. Sekera ER, Rudolph HL, Carro SD, Morales MJ, Bett GCL, Rasmusson RL, Wood TD (2017) Depletion of stercobilin in fecal matter from a mouse model of autism spectrum disorders. Metabolomics 13:132

    PubMed  PubMed Central  Google Scholar 

  82. Servili E, Trus M, Atlas D (2019) Ion occupancy of the channel pore is critical for triggering excitation-transcription (ET) coupling. Cell Calcium 84:102102

    CAS  PubMed  Google Scholar 

  83. Servili E, Trus M, Maayan D, Atlas D (2018) Beta-subunit of the voltage-gated Ca(2+) channel Cav1.2 drives signaling to the nucleus via H-Ras. Proc Natl Acad Sci U S A 115:E8624–e8633

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Servili E, Trus M, Sajman J, Sherman E, Atlas D (2020) Elevated basal transcription can underlie timothy channel association with autism related disorders. Prog Neurobiol 101820

  85. Shi CZ, Soldatov NM (2002) Molecular determinants of voltage-dependent slow inactivation of the Ca2+ channel. J Biol Chem 277:6813–6821

    CAS  PubMed  Google Scholar 

  86. Splawski I, Timothy KW, Decher N, Kumar P, Sachse FB, Beggs AH, Sanguinetti MC, Keating MT (2005) Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations. Proc Natl Acad Sci U S A 102:8089–8096

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Splawski I, Timothy KW, Sharpe LM, Decher N, Kumar P, Bloise R, Napolitano C, Schwartz PJ, Joseph RM, Condouris K, Tager-Flusberg H, Priori SG, Sanguinetti MC, Keating MT (2004) Ca(v)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell 119:19–31

    CAS  PubMed  Google Scholar 

  88. Stotz SC, Hamid J, Spaetgens RL, Jarvis SE, Zamponi GW (2000) Fast inactivation of voltage-dependent calcium channels. A hinged-lid mechanism? J Biol Chem 275:24575–24582

    CAS  PubMed  Google Scholar 

  89. Stotz SC, Jarvis SE, Zamponi GW (2004) Functional roles of cytoplasmic loops and pore lining transmembrane helices in the voltage-dependent inactivation of HVA calcium channels. J Physiol 554:263–273

    CAS  PubMed  Google Scholar 

  90. Tadmouri A, Kiyonaka S, Barbado M, Rousset M, Fablet K, Sawamura S, Bahembera E, Pernet-Gallay K, Arnoult C, Miki T, Sadoul K, Gory-Faure S, Lambrecht C, Lesage F, Akiyama S, Khochbin S, Baulande S, Janssens V, Andrieux A, Dolmetsch R, Ronjat M, Mori Y, De Waard M (2012) Cacnb4 directly couples electrical activity to gene expression, a process defective in juvenile epilepsy. EMBO J 31:3730–3744

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Tadross MR, Ben Johny M, Yue DT (2010) Molecular endpoints of Ca2+/calmodulin- and voltage-dependent inactivation of Ca(v)1.3 channels. J Gen Physiol 135:197–215

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Tadross MR, Yue DT (2010) Systematic mapping of the state dependence of voltage- and Ca2+-dependent inactivation using simple open-channel measurements. J Gen Physiol 135:217–227

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Tuluc P, Yarov-Yarovoy V, Benedetti B, Flucher BE (2016) Molecular interactions in the voltage sensor controlling gating properties of CaV calcium channels. Structure 24:261–271

    CAS  PubMed  Google Scholar 

  94. Vandael DH, Marcantoni A, Mahapatra S, Caro A, Ruth P, Zuccotti A, Knipper M, Carbone E (2010) Ca(v)1.3 and BK channels for timing and regulating cell firing. Mol Neurobiol 42:185–198

    CAS  PubMed  Google Scholar 

  95. Vandael DH, Ottaviani MM, Legros C, Lefort C, Guerineau NC, Allio A, Carabelli V, Carbone E (2015) Reduced availability of voltage-gated sodium channels by depolarization or blockade by tetrodotoxin boosts burst firing and catecholamine release in mouse chromaffin cellslabilit. J Physiol 593:905–927

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Vandael DHF, Zuccotti A, Striessnig J, Carbone E (2012) Ca(V)1.3-driven SK channel activation regulates pacemaking and spike frequency adaptation in mouse chromaffin cells. J Neurosci 32:16345–16359

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Voronina S, Collier D, Chvanov M, Middlehurst B, Beckett AJ, Prior IA, Criddle DN, Begg M, Mikoshiba K, Sutton R, Tepikin AV (2015) The role of Ca2+ influx in endocytic vacuole formation in pancreatic acinar cells. Biochem J 465:405–412

    CAS  PubMed  Google Scholar 

  98. Wemhöner K, Friedrich C, Stallmeyer B, Coffey AJ, Grace A, Zumhagen S, Seebohm G, Ortiz-Bonnin B, Rinné S, Sachse FB, Schulze-Bahr E, Decher N (2015) Gain-of-function mutations in the calcium channel CACNA1C (Cav1.2) cause non-syndromic long-QT but not Timothy syndrome. J Mol Cell Cardiol 80:186–195

    PubMed  Google Scholar 

  99. Wheeler DG, Barrett CF, Groth RD, Safa P, Tsien RW (2008) CaMKII locally encodes L-type channel activity to signal to nuclear CREB in excitation-transcription coupling. J Cell Biol 183:849–863

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Yang SN, Berggren PO (2005) Beta-cell CaV channel regulation in physiology and pathophysiology. Am J Phys Endocrinol Metab 288:E16–E28

    CAS  Google Scholar 

  101. Yarotskyy V, Gao G, Peterson BZ, Elmslie KS (2008) The Timothy syndrome mutation of cardiac CaV1.2 (L-type) channels: multiple altered gating mechanisms and pharmacological restoration of inactivation. J Physiol 587:551–565

    PubMed  PubMed Central  Google Scholar 

  102. Yazawa M, Dolmetsch RE (2013) Modeling Timothy syndrome with iPS cells. J Cardiovasc Transl Res 6:1–9

    PubMed  PubMed Central  Google Scholar 

  103. Zamponi GW, Striessnig J, Koschak A, Dolphin AC (2015) The physiology, pathology, and pharmacology of voltage-gated calcium channels and their future therapeutic potential. Pharmacol Rev 67:821–870

    CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This work was supported by the Telethon Foundation (grant no.GGP15110) to E.C.

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Author notes

  1. Andrea Marcantoni and Chiara Calorio contributed equally to this work.

Authors and Affiliations

  1. Department of Drug Science, Laboratory of Cellular and Molecular Neuroscience, N.I.S. Centre, Corso Raffaello 30, 10125, Torino, Italy

    Andrea Marcantoni, Chiara Calorio, Giuseppe Chiantia & Emilio Carbone

  2. Department of Biophysics, Faculty of Medicine, Akdeniz University, Antalya, Turkey

    Enis Hidisoglu

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  1. Andrea Marcantoni
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  2. Chiara Calorio
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  3. Enis Hidisoglu
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Correspondence to Emilio Carbone.

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This article is part of the special issue on Channelopathies: from mutation to diseases in Pflügers Archiv—European Journal of Physiology

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Marcantoni, A., Calorio, C., Hidisoglu, E. et al. Cav1.2 channelopathies causing autism: new hallmarks on Timothy syndrome. Pflugers Arch - Eur J Physiol 472, 775–789 (2020). https://doi.org/10.1007/s00424-020-02430-0

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