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CaV2.1 channelopathies

  • Invited Review
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Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

Mutations in the CACNA1A gene that encodes the pore-forming α1 subunit of human voltage-gated CaV2.1 (P/Q-type) Ca2+ channels cause several autosomal-dominant neurologic disorders, including familial hemiplegic migraine type 1 (FHM1), episodic ataxia type 2, and spinocerebellar ataxia type 6 (SCA6). For each channelopathy, the review describes the disease phenotype as well as the functional consequences of the disease-causing mutations on recombinant human CaV2.1 channels and, in the case of FHM1 and SCA6, on neuronal CaV2.1 channels expressed at the endogenous physiological level in knockin mouse models. The effects of FHM1 mutations on cortical spreading depression, the phenomenon underlying migraine aura, and on cortical excitatory and inhibitory synaptic transmission in FHM1 knockin mice are also described, and their implications for the disease mechanism discussed. Moreover, the review describes different ataxic spontaneous cacna1a mouse mutants and the important insights into the cerebellar mechanisms underlying motor dysfunction caused by mutant CaV2.1 channels that were obtained from their functional characterization.

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References

  1. Abbott LC, Bump M, Brandl A, De Laune S (2000) Investigation of the role of the cerebellum in the myoclonic-like movement disorder exhibited by tottering mice. Mov Disord 15(Suppl 1):53–59

    PubMed  Google Scholar 

  2. Adams PJ, Garcia E, David LS, Mulatz KJ, Spacey SD, Snutch TP (2009) Ca(V)2.1 P/Q-type calcium channel alternative splicing affects the functional impact of familial hemiplegic migraine mutations: implications for calcium channelopathies. Channels (Austin) 3:110–121

    CAS  Google Scholar 

  3. Akerman S, Williamson DJ, Goadsby PJ (2003) Voltage-dependent calcium channels are involved in neurogenic dural vasodilatation via a presynaptic transmitter release mechanism. Br J Pharmacol 140:558–566

    Article  PubMed  CAS  Google Scholar 

  4. Ali AB, Nelson C (2006) Distinct Ca2+ channels mediate transmitter release at excitatory synapses displaying different dynamic properties in rat neocortex. Cereb Cortex 16:386–393

    Article  PubMed  Google Scholar 

  5. Alonso I, Marques JM, Sousa N, Sequeiros J, Olsson IA, Silveira I (2008) Motor and cognitive deficits in the heterozygous leaner mouse, a Cav2.1 voltage-gated Ca2+ channel mutant. Neurobiol Aging 29:1733–1743

    Article  PubMed  CAS  Google Scholar 

  6. Ayata C (2009) Spreading depression: from serendipity to targeted therapy in migraine prophylaxis. Cephalalgia 29:1095–1114

    Article  PubMed  CAS  Google Scholar 

  7. Ayata C, Shimizu-Sasamata M, Lo EH, Noebels JL, Moskowitz MA (2000) Impaired neurotransmitter release and elevated threshold for cortical spreading depression in mice with mutations in the α1A subunit of P/Q type calcium channels. Neuroscience 95:639–645

    Article  PubMed  CAS  Google Scholar 

  8. Barclay J, Balaguero N, Mione M, Ackerman SL, Letts VA, Brodbeck J, Canti C, Meir A, Page KM, Kusumi K, Perez-Reyes E, Lander ES, Frankel WN, Gardiner RM, Dolphin AC, Rees M (2001) 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 21:6095–6104

    PubMed  CAS  Google Scholar 

  9. Barrett CF, Cao YQ, Tsien RW (2005) Gating deficiency in a familial hemiplegic migraine type 1 mutant P/Q-type calcium channel. J Biol Chem 280:24064–24071

    Article  PubMed  CAS  Google Scholar 

  10. Bourinet E, Soong TW, Sutton K, Slaymaker S, Mathews E, Monteil A, Zamponi GW, Nargeot J, Snutch TP (1999) Splicing of alpha 1A subunit gene generates phenotypic variants of P- and Q-type calcium channels. Nat Neurosci 2:407–415

    Article  PubMed  CAS  Google Scholar 

  11. Campbell DB, Hess EJ (1999) L-type calcium channels contribute to the tottering mouse dystonic episodes. Mol Pharmacol 55:23–31

    PubMed  CAS  Google Scholar 

  12. Cao YQ, Piedras-Renteria ES, Smith GB, Chen G, Harata NC, Tsien RW (2004) Presynaptic Ca2+ channels compete for channel type-preferring slots in altered neurotransmission arising from Ca2+ channelopathy. Neuron 43:387–400

    Article  PubMed  CAS  Google Scholar 

  13. Cao YQ, Tsien RW (2005) Effects of familial hemiplegic migraine type 1 mutations on neuronal P/Q-type Ca2+ channel activity and inhibitory synaptic transmission. Proc Natl Acad Sci USA 102:2590–2595

    Article  PubMed  CAS  Google Scholar 

  14. Catterall WA (2000) Structure and regulation of voltage-gated Ca2+ channels. Annu Rev Cell Dev Biol 16:521–555

    Article  PubMed  CAS  Google Scholar 

  15. Catterall WA, Few AP (2008) Calcium channel regulation and presynaptic plasticity. Neuron 59:882–901

    Article  PubMed  CAS  Google Scholar 

  16. Chang SY, Yong TF, Yu CY, Liang MC, Pletnikova O, Troncoso J, Burgunder JM, Soong TW (2007) Age and gender-dependent alternative splicing of P/Q-type calcium channel EF-hand. Neuroscience 145:1026–1036

    Article  PubMed  CAS  Google Scholar 

  17. Charles A (2009) Advances in the basic and clinical science of migraine. Ann Neurol 65:491–498

    Article  PubMed  Google Scholar 

  18. Charles A, Brennan K (2009) Cortical spreading depression-new insights and persistent questions. Cephalalgia 29:1115–1124

    Article  PubMed  CAS  Google Scholar 

  19. Chaudhuri D, Alseikhan BA, Chang SY, Soong TW, Yue DT (2005) Developmental activation of calmodulin-dependent facilitation of cerebellar P-type Ca2+ current. J Neurosci 25:8282–8294

    Article  PubMed  CAS  Google Scholar 

  20. Chen H, Piedras-Renteria ES (2007) Altered frequency-dependent inactivation and steady-state inactivation of polyglutamine-expanded alpha1A in SCA6. Am J Physiol Cell Physiol 292:C1078–C1086

    Article  PubMed  CAS  Google Scholar 

  21. Cricchi F, Di Lorenzo C, Grieco GS, Rengo C, Cardinale A, Racaniello M, Santorelli FM, Nappi G, Pierelli F, Casali C (2007) Early-onset progressive ataxia associated with the first CACNA1A mutation identified within the I-II loop. J Neurol Sci 254:69–71

    Article  PubMed  CAS  Google Scholar 

  22. Cuenca-Leon E, Banchs I, Serra SA, Latorre P, Fernandez-Castillo N, Corominas R, Valverde MA, Volpini V, Fernandez-Fernandez JM, Macaya A, Cormand B (2009) Late-onset episodic ataxia type 2 associated with a novel loss-of-function mutation in the CACNA1A gene. J Neurol Sci 280:10–14

    Article  PubMed  CAS  Google Scholar 

  23. Cuenca-Leon E, Corominas R, Fernandez-Castillo N, Volpini V, Del Toro M, Roig M, Macaya A, Cormand B (2008) Genetic analysis of 27 Spanish patients with hemiplegic migraine, basilar-type migraine and childhood periodic syndromes. Cephalalgia 28:1039–1047

    Article  PubMed  CAS  Google Scholar 

  24. Denier C, Ducros A, Vahedi K, Joutel A, Thierry P, Ritz A, Castelnovo G, Deonna T, Gerard P, Devoize JL, Gayou A, Perrouty B, Soisson T, Autret A, Warter JM, Vighetto A, Van Bogaert P, Alamowitch S, Roullet E, Tournier-Lasserve E (1999) High prevalence of CACNA1A truncations and broader clinical spectrum in episodic ataxia type 2. Neurology 52:1816–1821

    PubMed  CAS  Google Scholar 

  25. Donato R, Page KM, Koch D, Nieto-Rostro M, Foucault I, Davies A, Wilkinson T, Rees M, Edwards FA, Dolphin AC (2006) The ducky(2J) mutation in Cacna2d2 results in reduced spontaneous Purkinje cell activity and altered gene expression. J Neurosci 26:12576–12586

    Article  PubMed  CAS  Google Scholar 

  26. Ducros A, Denier C, Joutel A, Cecillon M, Lescoat C, Vahedi K, Darcel F, Vicaut E, Bousser MG, Tournier-Lasserve E (2001) The clinical spectrum of familial hemiplegic migraine associated with mutations in a neuronal calcium channel. N Engl J Med 345:17–24

    Article  PubMed  CAS  Google Scholar 

  27. Ebersberger A, Portz S, Meissner W, Schaible HG, Richter F (2004) Effects of N-, P/Q- and L-type calcium channel blockers on nociceptive neurones of the trigeminal nucleus with input from the dura. Cephalalgia 24:250–261

    Article  PubMed  CAS  Google Scholar 

  28. Eikermann-Haerter K, Baum MJ, Ferrari MD, van den Maagdenberg AM, Moskowitz MA, Ayata C (2009) Androgenic suppression of spreading depression in familial hemiplegic migraine type 1 mutant mice. Ann Neurol 66:564–568

    Article  PubMed  CAS  Google Scholar 

  29. Eikermann-Haerter K, Dilekoz E, Kudo C, Savitz SI, Waeber C, Baum MJ, Ferrari MD, van den Maagdenberg AMJM, Moskowitz MA, Ayata C (2009) Genetic and hormonal factors modulate spreading depression and transient hemiparesis in mouse models of familial hemiplegic migraine type 1. J Clin Invest 119:99–109

    PubMed  CAS  Google Scholar 

  30. Eilers J, Plant T, Konnerth A (1996) Localized calcium signalling and neuronal integration in cerebellar Purkinje neurones. Cell Calcium 20:215–226

    Article  PubMed  CAS  Google Scholar 

  31. Fletcher CF, Tottene A, Lennon VA, Wilson SM, Dubel SJ, Paylor R, Hosford DA, Tessarollo L, McEnery MW, Pietrobon D, Copeland NG, Jenkins NA (2001) Dystonia and cerebellar atrophy in Cacna1a null mice lacking P/Q calcium channel activity. Faseb J 15:1288–1290

    PubMed  CAS  Google Scholar 

  32. Forti L, Pouzat C, Llano I (2000) Action potential-evoked Ca2+ signals and calcium channels in axons of developing rat cerebellar interneurons. J Physiol 527:33–48

    Article  PubMed  CAS  Google Scholar 

  33. Gatchel JR, Zoghbi HY (2005) Diseases of unstable repeat expansion: mechanisms and common principles. Nat Rev Genet 6:743–755

    Article  PubMed  CAS  Google Scholar 

  34. Goadsby PJ, Charbit AR, Andreou AP, Akerman S, Holland PR (2009) Neurobiology of migraine. Neuroscience 161:327–341

    Article  PubMed  CAS  Google Scholar 

  35. Graves TD, Imbrici P, Kors EE, Terwindt GM, Eunson LH, Frants RR, Haan J, Ferrari MD, Goadsby PJ, Hanna MG, van den Maagdenberg AM, Kullmann DM (2008) Premature stop codons in a facilitating EF-hand splice variant of CaV2.1 cause episodic ataxia type 2. Neurobiol Dis 32:10–15

    Article  PubMed  CAS  Google Scholar 

  36. Guida S, Trettel F, Pagnutti S, Mantuano E, Tottene A, Veneziano L, Fellin T, Spadaro M, Stauderman KA, Williams ME, Volsen S, Ophoff RA, Frants RR, Jodice C, Frontali M, Pietrobon D (2001) Complete loss of P/Q calcium channel activity caused by a CACNA1A missense mutation carried by patients with episodic ataxia type 2. Am J Hum Genet 68:759–764

    Article  PubMed  CAS  Google Scholar 

  37. Haan J, Kors EE, Vanmolkot KR, van den Maagdenberg AM, Frants RR, Ferrari MD (2005) Migraine genetics: an update. Curr Pain Headache Rep 9:213–220

    Article  PubMed  CAS  Google Scholar 

  38. Hans M, Luvisetto S, Williams ME, Spagnolo M, Urrutia A, Tottene A, Brust PF, Johnson EC, Harpold MM, Stauderman KA, Pietrobon D (1999) Functional consequences of mutations in the human α1A calcium channel subunit linked to familial hemiplegic migraine. J Neurosci 19:1610–1619

    PubMed  CAS  Google Scholar 

  39. Hausser M, Clark BA (1997) Tonic synaptic inhibition modulates neuronal output pattern and spatiotemporal synaptic integration. Neuron 19:665–678

    Article  PubMed  CAS  Google Scholar 

  40. Hoebeek FE, Khosrovani S, Witter L, De Zeeuw CI (2008) Purkinje cell input to cerebellar nuclei in tottering: ultrastructure and physiology. Cerebellum 7:547–558

    Article  PubMed  Google Scholar 

  41. Hoebeek FE, Stahl JS, van Alphen AM, Schonewille M, Luo C, Rutteman M, van den Maagdenberg AM, Molenaar PC, Goossens HH, Frens MA, De Zeeuw CI (2005) Increased noise level of Purkinje cell activities minimizes impact of their modulation during sensorimotor control. Neuron 45:953–965

    Article  PubMed  CAS  Google Scholar 

  42. Imbrici P, Eunson LH, Graves TD, Bhatia KP, Wadia NH, Kullmann DM, Hanna MG (2005) Late-onset episodic ataxia type 2 due to an in-frame insertion in CACNA1A. Neurology 65:944–946

    Article  PubMed  CAS  Google Scholar 

  43. Imbrici P, Jaffe SL, Eunson LH, Davies NP, Herd C, Robertson R, Kullmann DM, Hanna MG (2004) Dysfunction of the brain calcium channel CaV2.1 in absence epilepsy and episodic ataxia. Brain 127:2682–2692

    Article  PubMed  Google Scholar 

  44. Inchauspe CG, Forsythe ID, Uchitel OD (2007) Changes in synaptic transmission properties due to the expression of N-type calcium channels at the calyx of Held synapse of mice lacking P/Q-type calcium channels. J Physiol 584:835–851

    Article  PubMed  CAS  Google Scholar 

  45. Inchauspe CG, Martini FJ, Forsythe ID, Uchitel OD (2004) Functional compensation of P/Q by N-type channels blocks short-term plasticity at the calyx of held presynaptic terminal. J Neurosci 24:10379–10383

    Article  PubMed  CAS  Google Scholar 

  46. Ishikawa K, Fujigasaki H, Saegusa H, Ohwada K, Fujita T, Iwamoto H, Komatsuzaki Y, Toru S, Toriyama H, Watanabe M, Ohkoshi N, Shoji S, Kanazawa I, Tanabe T, Mizusawa H (1999) Abundant expression and cytoplasmic aggregations of α1A voltage-dependent calcium channel protein associated with neurodegeneration in spinocerebellar ataxia type 6. Hum Mol Genet 8:1185–1193

    Article  PubMed  CAS  Google Scholar 

  47. Ishikawa T, Kaneko M, Shin HS, Takahashi T (2005) Presynaptic N-type and P/Q-type Ca2+ channels mediating synaptic transmission at the calyx of Held of mice. J Physiol 568:199–209

    Article  PubMed  CAS  Google Scholar 

  48. Iwasaki S, Momiyama A, Uchitel OD, Takahashi T (2000) Developmental changes in calcium channel types mediating central synaptic transmission. J Neurosci 20:59–65

    PubMed  CAS  Google Scholar 

  49. Jen JC, Graves TD, Hess EJ, Hanna MG, Griggs RC, Baloh RW (2007) Primary episodic ataxias: diagnosis, pathogenesis and treatment. Brain 130:2484–2493

    Article  PubMed  CAS  Google Scholar 

  50. Jen J, Kim GW, Baloh RW (2004) Clinical spectrum of episodic ataxia type 2. Neurology 62:17–22

    PubMed  CAS  Google Scholar 

  51. Jen J, Wan J, Graves M, Yu H, Mock AF, Coulin CJ, Kim G, Yue Q, Papazian DM, Baloh RW (2001) Loss-of-function EA2 mutations are associated with impaired neuromuscular transmission. Neurology 57:1843–1848

    PubMed  CAS  Google Scholar 

  52. Jeng CJ, Chen YT, Chen YW, Tang CY (2006) Dominant-negative effects of human P/Q-type Ca2+ channel mutations associated with episodic ataxia type 2. Am J Physiol Cell Physiol 290:C1209–C1220

    Article  PubMed  CAS  Google Scholar 

  53. Jeng CJ, Sun MC, Chen YW, Tang CY (2008) Dominant-negative effects of episodic ataxia type 2 mutations involve disruption of membrane trafficking of human P/Q-type Ca2+ channels. J Cell Physiol 214:422–433

    Article  PubMed  CAS  Google Scholar 

  54. Jouvenceau A, Eunson LH, Spauschus A, Ramesh V, Zuberi SM, Kullmann DM, Hanna MG (2001) Human epilepsy associated with dysfunction of the brain P/Q-type calcium channel. Lancet 358:801–807

    Article  PubMed  CAS  Google Scholar 

  55. Jun K, Piedras-Renteria ES, Smith SM, Wheeler DB, Lee SB, Lee TG, Chin H, Adams ME, Scheller RH, Tsien RW, Shin H-P (1999) Ablation of P/Q-type Ca2+ channel currents, altered synaptic transmission, and progressive ataxia in mice lacking the α1A -subunit. Proc Natl Acad Sci 96:15245–15250

    Article  PubMed  CAS  Google Scholar 

  56. Kaja S, van de Ven RC, Broos LA, Frants RR, Ferrari MD, van den Maagdenberg AM, Plomp JJ (2007) Characterization of acetylcholine release and the compensatory contribution of non-Ca(v)2.1 channels at motor nerve terminals of leaner Ca(v)2.1-mutant mice. Neuroscience 144:1278–1287

    Article  PubMed  CAS  Google Scholar 

  57. Kaja S, van de Ven RC, Broos LA, Veldman H, van Dijk JG, Verschuuren JJ, Frants RR, Ferrari MD, van den Maagdenberg AM, Plomp JJ (2005) Gene dosage-dependent transmitter release changes at neuromuscular synapses of CACNA1A R192Q knock in mice are non-progressive and do not lead to morphological changes or muscle weakness. Neuroscience 135:81–95

    Article  PubMed  CAS  Google Scholar 

  58. Kaja S, Van de Ven RC, Ferrari MD, Frants RR, Van den Maagdenberg AM, Plomp JJ (2006) Compensatory contribution of Cav2.3 channels to acetylcholine release at the neuromuscular junction of tottering mice. J Neurophysiol 95:2698–2704

    Article  PubMed  CAS  Google Scholar 

  59. Kaja S, Van De Ven RC, Frants RR, Ferrari MD, Van Den Maagdenberg AM, Plomp JJ (2008) Reduced ACh release at neuromuscular synapses of heterozygous leaner Ca(v)2.1-mutant mice. Synapse 62:337–344

    Article  PubMed  CAS  Google Scholar 

  60. Kaja S, van de Ven RC, van Dijk JG, Verschuuren JJ, Arahata K, Frants RR, Ferrari MD, van den Maagdenberg AM, Plomp JJ (2007) Severely impaired neuromuscular synaptic transmission causes muscle weakness in the Cacna1a-mutant mouse rolling Nagoya. Eur J NeuroSci 25:2009–2020

    Article  PubMed  Google Scholar 

  61. Kanumilli S, Tringham EW, Payne CE, Dupere JR, Venkateswarlu K, Usowicz MM (2006) Alternative splicing generates a smaller assortment of CaV2.1 transcripts in cerebellar Purkinje cells than in the cerebellum. Physiol Genomics 24:86–96

    PubMed  CAS  Google Scholar 

  62. Katoh A, Jindal JA, Raymond JL (2007) Motor deficits in homozygous and heterozygous p/q-type calcium channel mutants. J Neurophysiol 97:1280–1287

    Article  PubMed  CAS  Google Scholar 

  63. Knight YE, Bartsch T, Kaube H, Goadsby PJ (2002) P/Q-type calcium-channel blockade in the periaqueductal gray facilitates trigeminal nociception: a functional genetic link for migraine? J Neurosci 22:RC213

    PubMed  Google Scholar 

  64. Kodama T, Itsukaichi-Nishida Y, Fukazawa Y, Wakamori M, Miyata M, Molnar E, Mori Y, Shigemoto R, Imoto K (2006) A CaV2.1 calcium channel mutation rocker reduces the number of postsynaptic AMPA receptors in parallel fiber-Purkinje cell synapses. Eur J NeuroSci 24:2993–3007

    Article  PubMed  Google Scholar 

  65. Koester HJ, Sakmann B (2000) Calcium dynamics associated with action potentials in single nerve terminals of pyramidal cells in layer 2/3 of the young rat neocortex. J Physiol 529(Pt 3):625–646

    Article  PubMed  CAS  Google Scholar 

  66. Kordasiewicz HB, Thompson RM, Clark HB, Gomez CM (2006) C-termini of P/Q-type Ca2+ channel alpha1A subunits translocate to nuclei and promote polyglutamine-mediated toxicity. Hum Mol Genet 15:1587–1599

    Article  PubMed  CAS  Google Scholar 

  67. Kors EE, Terwindt GM, Vermeulen FL, Fitzsimons RB, Jardine PE, Heywood P, Love S, van den Maagdenberg AM, Haan J, Frants RR, Ferrari MD (2001) Delayed cerebral edema and fatal coma after minor head trauma: role of the CACNA1A calcium channel subunit gene and relationship with familial hemiplegic migraine. Ann Neurol 49:753–760

    Article  PubMed  CAS  Google Scholar 

  68. Kraus RL, Sinnegger MJ, Glossmann H, Hering S, Striessnig J (1998) Familial hemiplegic migraine mutations change α1A Ca2+ channel kinetics. J Biol Chem 273:5586–5590

    Article  PubMed  CAS  Google Scholar 

  69. Kraus RL, Sinnegger M, Koschak A, Glossmann H, Stenirri S, Carrera P, Striessnig J (2000) Three new familial hemiplegic migraine mutants affect P/Q-type Ca2+channel kinetics. J Biol Chem 275:9239–9243

    Article  PubMed  CAS  Google Scholar 

  70. Kruglikov I, Rudy B (2008) Perisomatic GABA release and thalamocortical integration onto neocortical excitatory cells are regulated by neuromodulators. Neuron 58:911–924

    Article  PubMed  CAS  Google Scholar 

  71. Labrum RW, Rajakulendran S, Graves TD, Eunson LH, Bevan R, Sweeney MG, Hammans SR, Tubridy N, Britton T, Carr LJ, Ostergaard JR, Kennedy CR, Al-Memar A, Kullmann DM, Schorge S, Temple K, Davis MB, Hanna MG (2009) Large scale calcium channel gene rearrangements in episodic ataxia and hemiplegic migraine: implications for diagnostic testing. J Med Genet 46:786–791

    Article  PubMed  CAS  Google Scholar 

  72. Levy D, Strassman AM, Burstein R (2009) A critical view on the role of migraine triggers in the genesis of migraine pain. Headache 49:953–957

    Article  PubMed  Google Scholar 

  73. Li L, Bischofberger J, Jonas P (2007) Differential gating and recruitment of P/Q-, N-, and R-type Ca2+ channels in hippocampal mossy fiber boutons. J Neurosci 27:13420–13429

    Article  PubMed  CAS  Google Scholar 

  74. Liu S, Friel DD (2008) Impact of the leaner P/Q-type Ca2+ channel mutation on excitatory synaptic transmission in cerebellar Purkinje cells. J Physiol 586:4501–4515

    PubMed  CAS  Google Scholar 

  75. Llinas RR, Choi S, Urbano FJ, Shin HS (2007) Gamma-band deficiency and abnormal thalamocortical activity in P/Q-type channel mutant mice. Proc Natl Acad Sci USA 104:17819–17824

    Article  PubMed  Google Scholar 

  76. Lonchamp E, Dupont JL, Doussau F, Shin HS, Poulain B, Bossu JL (2009) Deletion of Cav2.1(alpha1(A)) subunit of Ca2+-channels impairs synaptic GABA and glutamate release in the mouse cerebellar cortex in cultured slices. Eur J NeuroSci 30:2293–2307

    Article  PubMed  Google Scholar 

  77. Luvisetto S, Fellin T, Spagnolo M, Hivert B, Brust PF, Harpold MM, Stauderman KA, Williams ME, Pietrobon D (2004) Modal gating of human CaV2.1 (P/Q-type) calcium channels: I. The slow and the fast gating modes and their modulation by beta subunits. J Gen Physiol 124:445–461

    Article  PubMed  CAS  Google Scholar 

  78. Luvisetto S, Marinelli S, Panasiti MS, D’Amato FR, Fletcher CF, Pavone F, Pietrobon D (2006) Pain sensitivity in mice lacking the Ca(v)2.1alpha1 subunit of P/Q-type Ca2+ channels. Neuroscience 142:823–832

    Article  PubMed  CAS  Google Scholar 

  79. Maselli RA, Wan J, Dunne V, Graves M, Baloh RW, Wollmann RL, Jen J (2003) Presynaptic failure of neuromuscular transmission and synaptic remodeling in EA2. Neurology 61:1743–1748

    PubMed  CAS  Google Scholar 

  80. Matsushita K, Wakamori M, Rhyu IJ, Arii T, Oda S, Mori Y, Imoto K (2002) Bidirectional alterations in cerebellar synaptic transmission of tottering and rolling Ca2+ channel mutant mice. J Neurosci 22:4388–4398

    PubMed  CAS  Google Scholar 

  81. Matsuyama Z, Wakamori M, Mori Y, Kawakami H, Nakamura S, Imoto K (1999) Direct alteration of the P/Q-type Ca2+ channel property by polyglutamine expansion in spinocerebellar ataxia 6. J Neurosci 19:RC14, 11–15

    PubMed  CAS  Google Scholar 

  82. Melliti K, Grabner M, Seabrook GR (2003) The familial hemiplegic migraine mutation R192Q reduces G-protein-mediated inhibition of P/Q-type (Ca(V)2.1) calcium channels expressed in human embryonic kidney cells. J Physiol 546:337–347

    Article  PubMed  CAS  Google Scholar 

  83. Mermelstein PG, Foehring RC, Tkatch T, Song WJ, Baranauskas G, Surmeier DJ (1999) Properties of Q-type calcium channels in neostriatal and cortical neurons are correlated with beta subunit expression. J Neurosci 19:7268–7277

    PubMed  CAS  Google Scholar 

  84. Mezghrani A, Monteil A, Watschinger K, Sinnegger-Brauns MJ, Barrere C, Bourinet E, Nargeot J, Striessnig J, Lory P (2008) A destructive interaction mechanism accounts for dominant-negative effects of misfolded mutants of voltage-gated calcium channels. J Neurosci 28:4501–4511

    Article  PubMed  CAS  Google Scholar 

  85. Miki T, Zwingman TA, Wakamori M, Lutz CM, Cook SA, Hosford DA, Herrup K, Fletcher CF, Mori Y, Frankel WN, Letts VA (2008) Two novel alleles of tottering with distinct Ca(v)2.1 calcium channel neuropathologies. Neuroscience 155:31–44

    Article  PubMed  CAS  Google Scholar 

  86. Mintz IM, Adams ME, Bean BP (1992) P-type calcium channels in rat central and peripheral neurons. Neuron 9:85–95

    Article  PubMed  CAS  Google Scholar 

  87. Mintz IM, Sabatini BL, Regehr WG (1995) Calcium control of transmitter release at a cerebellar synapse. Neuron 15:675–688

    Article  PubMed  CAS  Google Scholar 

  88. Mochida S, Few AP, Scheuer T, Catterall WA (2008) Regulation of presynaptic Ca(V)2.1 channels by Ca2+ sensor proteins mediates short-term synaptic plasticity. Neuron 57:210–216

    Article  PubMed  CAS  Google Scholar 

  89. Mori Y, Wakamori M, Oda S, Fletcher CF, Sekiguchi N, Mori E, Copeland NG, Jenkins NA, Matsushita K, Matsuyama Z, Imoto K (2000) Reduced voltage sensitivity of activation of P/Q-type Ca2+ channels is associated with the ataxic mouse mutation Rolling Nagoya (tgrol). J Neurosci 20:5654–5662

    PubMed  CAS  Google Scholar 

  90. Mullner C, Broos LA, van den Maagdenberg AM, Striessnig J (2004) Familial hemiplegic migraine type 1 mutations K1336E, W1684R, and V1696I Alter Cav2.1 Ca2+ channel gating: evidence for beta-subunit isoform-specific effects. J Biol Chem 279:51844–51850

    Article  PubMed  CAS  Google Scholar 

  91. Ophoff RA, Terwindt GM, Vergouwe MN, van Eijk R, Oefner PJ, Hoffman SMG, Lamerdin JE, Mohrenweiser HW, Bulman DE, Ferrari M, Haan J, Lindhout D, van Hommen G-JB, Hofker MH, Ferrari MD, Frants RR (1996) Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell 87:543–552

    Article  PubMed  CAS  Google Scholar 

  92. Ovsepian SV, Friel DD (2008) The leaner P/Q-type calcium channel mutation renders cerebellar Purkinje neurons hyper-excitable and eliminates Ca2+-Na+ spike bursts. Eur J NeuroSci 27:93–103

    Article  PubMed  Google Scholar 

  93. Page KM, Heblich F, Davies A, Butcher AJ, Leroy J, Bertaso F, Pratt WS, Dolphin AC (2004) Dominant-negative calcium channel suppression by truncated constructs involves a kinase implicated in the unfolded protein response. J Neurosci 24:5400–5409

    Article  PubMed  CAS  Google Scholar 

  94. Pardo NE, Hajela RK, Atchison WD (2006) Acetylcholine release at neuromuscular junctions of adult tottering mice is controlled by N-(cav2.2) and R-type (cav2.3) but not L-type (cav1.2) Ca2+ channels. J Pharmacol Exp Ther 319:1009–1020

    Article  PubMed  CAS  Google Scholar 

  95. Piedras-Renteria ES, Pyle JL, Diehn M, Glickfeld LL, Harata NC, Cao Y, Kavalali ET, Brown PO, Tsien RW (2004) Presynaptic homeostasis at CNS nerve terminals compensates for lack of a key Ca2+ entry pathway. Proc Natl Acad Sci USA 101:3609–3614

    Article  PubMed  CAS  Google Scholar 

  96. Piedras-Renteria ES, Watase K, Harata N, Zhuchenko O, Zoghbi HY, Lee CC, Tsien RW (2001) Increased expression of alpha 1A Ca2+ channel currents arising from expanded trinucleotide repeats in spinocerebellar ataxia type 6. J Neurosci 21:9185–9193

    PubMed  CAS  Google Scholar 

  97. Pietrobon D (2002) Calcium channels and channelopathies of the central nervous system. Mol Neurobiol 25:31–50

    Article  PubMed  CAS  Google Scholar 

  98. Pietrobon D (2005) Function and dysfunction of synaptic calcium channels: insights from mouse models. Curr Opin Neurobiol 15:257–265

    Article  PubMed  CAS  Google Scholar 

  99. Pietrobon D (2005) Migraine: new molecular mechanisms. Neuroscientist 11:373–386

    Article  PubMed  CAS  Google Scholar 

  100. Pietrobon D (2007) Familial hemiplegic migraine. Neurotherapeutics 4:274–284

    Article  PubMed  CAS  Google Scholar 

  101. Pietrobon D, Striessnig J (2003) Neurobiology of migraine. Nat Rev Neurosci 4:386–398

    Article  PubMed  CAS  Google Scholar 

  102. Pineda JC, Waters RS, Foehring RC (1998) Specificity in the interaction of HVA Ca2+ channel types with Ca2+-dependent AHPs and firing behavior in neocortical pyramidal neurons. J Neurophysiol 79:2522–2534

    PubMed  CAS  Google Scholar 

  103. Plomp JJ, van den Maagdenberg AM, Kaja S (2009) The ataxic Cacna1a-mutant mouse rolling Nagoya: an overview of neuromorphological and electrophysiological findings. Cerebellum 8:222–230

    Article  PubMed  Google Scholar 

  104. Qian J, Noebels JL (2001) Presynaptic Ca2+ channels and neurotransmitter release at the terminal of a mouse cortical neuron. J Neurosci 21:3721–3728

    PubMed  CAS  Google Scholar 

  105. Raike RS, Kordasiewicz HB, Thompson RM, Gomez CM (2007) Dominant-negative suppression of Cav2.1 currents by alpha(1)2.1 truncations requires the conserved interaction domain for beta subunits. Mol Cell Neurosci 34:168–177

    Article  PubMed  CAS  Google Scholar 

  106. Randall A, Tsien RW (1995) Pharmacological dissection of multiple types of Ca2+ channel currents in rat cerebellar granule neurons. J Neurosci 15:2995–3012

    PubMed  CAS  Google Scholar 

  107. Restituito S, Thompson RM, Eliet J, Raike RS, Riedl M, Charnet P, Gomez CM (2000) The polyglutamine expansion in spinocerebellar ataxia type 6 causes a β subunit-specific enhanced activation of P/Q-type calcium channels in Xenopus oocytes. J Neurosci 20:6394–6403

    PubMed  CAS  Google Scholar 

  108. Riant F, Lescoat C, Vahedi K, Kaphan E, Toutain A, Soisson T, Wiener-Vacher SR, Tournier-Lasserve E (2009) Identification of CACNA1A large deletions in four patients with episodic ataxia. Neurogenetics 11:101–106

    Article  PubMed  CAS  Google Scholar 

  109. Rozov A, Burnashev N, Sakmann B, Neher E (2001) Transmitter release modulation by intracellular Ca2+ buffers in facilitating and depressing nerve terminals of pyramidal cells in layer 2/3 of the rat neocortex indicates a target cell-specific difference in presynaptic calcium dynamics. J Physiol 531:807–826

    Article  PubMed  CAS  Google Scholar 

  110. Saegusa H, Wakamori M, Matsuda Y, Wang J, Mori Y, Zong S, Tanabe T (2007) Properties of human Cav2.1 channel with a spinocerebellar ataxia type 6 mutation expressed in Purkinje cells. Mol Cell Neurosci 34:261–270

    Article  PubMed  CAS  Google Scholar 

  111. Saito H, Okada M, Miki T, Wakamori M, Futatsugi A, Mori Y, Mikoshiba K, Suzuki N (2009) Knockdown of Cav2.1 calcium channels is sufficient to induce neurological disorders observed in natural occurring Cacna1a mutants in mice. Biochem Biophys Res Commun 390:1029–1033

    Article  PubMed  CAS  Google Scholar 

  112. Sasaki S, Huda K, Inoue T, Miyata M, Imoto K (2006) Impaired feedforward inhibition of the thalamocortical projection in epileptic Ca2+ channel mutant mice, tottering. J Neurosci 26:3056–3065

    Article  PubMed  CAS  Google Scholar 

  113. Sawada K, Kalam Azad A, Sakata-Haga H, Lee NS, Jeong YG, Fukui Y (2009) Striking pattern of Purkinje cell loss in cerebellum of an ataxic mutant mouse, tottering. Acta Neurobiol Exp (Wars) 69:138–145

    Google Scholar 

  114. Serra SA, Fernandez-Castillo N, Macaya A, Cormand B, Valverde MA, Fernandez-Fernandez JM (2009) The hemiplegic migraine-associated Y1245C mutation in CACNA1A results in a gain of channel function due to its effect on the voltage sensor and G-protein-mediated inhibition. Pflugers Arch 458:489–502

    Article  PubMed  CAS  Google Scholar 

  115. Shakkottai VG, Chou CH, Oddo S, Sailer CA, Knaus HG, Gutman GA, Barish ME, LaFerla FM, Chandy KG (2004) Enhanced neuronal excitability in the absence of neurodegeneration induces cerebellar ataxia. J Clin Invest 113:582–590

    PubMed  CAS  Google Scholar 

  116. Shu Y, Hasenstaub A, McCormick DA (2003) Turning on and off recurrent balanced cortical activity. Nature 423:288–293

    Article  PubMed  CAS  Google Scholar 

  117. Somjen GG (2001) Mechanisms of spreading depression and hypoxic spreading depression-like depolarization. Physiol Rev 81:1065–1096

    PubMed  CAS  Google Scholar 

  118. Soong TW, DeMaria CD, Alvania RS, Zweifel LS, Liang MC, Mittman S, Agnew WS, Yue DT (2002) Systematic identification of splice variants in human P/Q-type channel alpha1(2.1) subunits: implications for current density and Ca2+-dependent inactivation. J Neurosci 22:10142–10152

    PubMed  CAS  Google Scholar 

  119. Spacey SD, Hildebrand ME, Materek LA, Bird TD, Snutch TP (2004) Functional implications of a novel EA2 mutation in the P/Q-type calcium channel. Ann Neurol 56:213–220

    Article  PubMed  CAS  Google Scholar 

  120. Stephens GJ, Morris NP, Fyffe RE, Robertson B (2001) The Cav2.1/alpha1A (P/Q-type) voltage-dependent calcium channel mediates inhibitory neurotransmission onto mouse cerebellar Purkinje cells. Eur J NeuroSci 13:1902–1912

    Article  PubMed  CAS  Google Scholar 

  121. Stewart WF, Wood C, Reed ML, Roy J, Lipton RB (2008) Cumulative lifetime migraine incidence in women and men. Cephalalgia 28:1170–1178

    Article  PubMed  CAS  Google Scholar 

  122. Sutton KG, McRory JE, Guthrie H, Murphy TH, Snutch TP (1999) P/Q-type calcium channels mediate the activity-dependent feedback of syntaxin-1A. Nature 401:800–804

    Article  PubMed  CAS  Google Scholar 

  123. Takahashi E, Niimi K, Itakura C (2009) Motor coordination impairment in aged heterozygous rolling Nagoya, Cav2.1 mutant mice. Brain Res 1279:50–57

    Article  PubMed  CAS  Google Scholar 

  124. Thomsen LL, Kirchmann M, Bjornsson A, Stefansson H, Jensen RM, Fasquel AC, Petursson H, Stefansson M, Frigge ML, Kong A, Gulcher J, Stefansson K, Olesen J (2007) The genetic spectrum of a population-based sample of familial hemiplegic migraine. Brain 130:346–356

    Article  PubMed  CAS  Google Scholar 

  125. Toru S, Murakoshi T, Ishikawa K, Saegusa H, Fujigasaki H, Uchihara T, Nagayama S, Osanai M, Mizusawa H, Tanabe T (2000) Spinocerebellar ataxia type 6 mutation alters P-type calcium channel function. J Biol Chem 275:10893–10898

    Article  PubMed  CAS  Google Scholar 

  126. Tottene A, Conti R, Fabbro A, Vecchia D, Shapovalova M, Santello M, van den Maagdenberg AMJM, Ferrari MD, Pietrobon D (2009) Enhanced excitatory transmission at cortical synapses as the basis for facilitated spreading depression in Ca(v)2.1 knock in migraine mice. Neuron 61:762–773

    Article  PubMed  CAS  Google Scholar 

  127. Tottene A, Fellin T, Pagnutti S, Luvisetto S, Striessnig J, Fletcher C, Pietrobon D (2002) Familial hemiplegic migraine mutations increase Ca2+ influx through single human CaV2.1 channels and decrease maximal CaV2.1 current density in neurons. PNAS 99:13284–13289

    Article  PubMed  CAS  Google Scholar 

  128. Tottene A, Moretti A, Pietrobon D (1996) Functional diversity of P-type and R-type calcium channels in rat cerebellar neurons. J Neurosci 16:6353–6363

    PubMed  CAS  Google Scholar 

  129. Tottene A, Pivotto F, Fellin T, Cesetti T, van den Maagdenberg AM, Pietrobon D (2005) Specific kinetic alterations of human CaV2.1 calcium channels produced by mutation S218L causing familial hemiplegic migraine and delayed cerebral edema and coma after minor head trauma. J Biol Chem 280:17678–17686

    Article  PubMed  CAS  Google Scholar 

  130. Tringham EW, Payne CE, Dupere JR, Usowicz MM (2007) Maturation of rat cerebellar Purkinje cells reveals an atypical Ca2+ channel current that is inhibited by omega-agatoxin IVA and the dihydropyridine (-)-(S)-Bay K8644. J Physiol 578:693–714

    Article  PubMed  CAS  Google Scholar 

  131. Urban MO, Ren K, Sablad M, Park KT (2005) Medullary N-type and P/Q-type calcium channels contribute to neuropathy-induced allodynia. NeuroReport 16:563–566

    Article  PubMed  Google Scholar 

  132. Urbano FJ, Piedras-Renteria ES, Jun K, Shin HS, Uchitel OD, Tsien RW (2003) Altered properties of quantal neurotransmitter release at endplates of mice lacking P/Q-type Ca2+ channels. Proc Natl Acad Sci USA 100:3491–3496

    Article  PubMed  CAS  Google Scholar 

  133. Usowicz MM, Sugimori M, Cherskey B, Llinas R (1992) P-type calcium channels in the somata and dendrites of adult cerebellar Purkinje cells. Neuron 9:1185–1199

    Article  PubMed  CAS  Google Scholar 

  134. van den Maagdenberg AM, Pietrobon D, Pizzorusso T, Kaja S, Broos LA, Cesetti T, van de Ven RC, Tottene A, van der Kaa J, Plomp JJ, Frants RR, Ferrari MD (2004) A Cacna1a knock in migraine mouse model with increased susceptibility to cortical spreading depression. Neuron 41:701–710

    Article  PubMed  Google Scholar 

  135. van den Maagdenberg AM, Pizzorusso T, Kaja S, Terpolilli N, Shapovalova M, Hoebeek FE, Barrett CF, Gherardini L, van de Ven RC, Todorov B, Broos LA, Tottene A, Gao Z, Fodor M, De Zeeuw CI, Frants RR, Plesnila N, Plomp JJ, Pietrobon D, Ferrari MD (2010) High CSD susceptibility and migraine-associated symptoms in CaV2.1 S218L mice. Ann. Neurol. doi:10.1002/ana.21815

  136. Vanegas H, Schaible H (2000) Effects of antagonists to high-threshold calcium channels upon spinal mechanisms of pain, hyperalgesia and allodynia. Pain 85:9–18

    Article  PubMed  CAS  Google Scholar 

  137. Wakamori M, Yamazaki K, Matsunodaira H, Teramoto T, Tanaka I, Niidome T, Sawada K, Nishizawa Y, Sekiguchi N, Mori E, Mori Y, Imoto K (1998) Single tottering mutations responsible for the neuropathic phenotype of the P-type calcium channel. J Biol Chem 273:34857–34867

    Article  PubMed  CAS  Google Scholar 

  138. Walter JT, Alvina K, Womack MD, Chevez C, Khodakhah K (2006) Decreases in the precision of Purkinje cell pacemaking cause cerebellar dysfunction and ataxia. Nat Neurosci 9:389–397

    Article  PubMed  CAS  Google Scholar 

  139. Wan J, Khanna R, Sandusky M, Papazian DM, Jen JC, Baloh RW (2005) CACNA1A mutations causing episodic and progressive ataxia alter channel trafficking and kinetics. Neurology 64:2090–2097

    Article  PubMed  CAS  Google Scholar 

  140. Wappl E, Koschak A, Poteser M, Sinnegger MJ, Walter D, Eberhart A, Groschner K, Glossmann H, Kraus RL, Grabner M, Striessnig J (2002) Functional consequences of P/Q-type Ca2+ channel Cav2.1 missense mutations associated with episodic ataxia type 2 and progressive ataxia. J Biol Chem 277:6960–6966

    Article  PubMed  CAS  Google Scholar 

  141. Watase K, Barrett CF, Miyazaki T, Ishiguro T, Ishikawa K, Hu Y, Unno T, Sun Y, Kasai S, Watanabe M, Gomez CM, Mizusawa H, Tsien RW, Zoghbi HY (2008) Spinocerebellar ataxia type 6 knock in mice develop a progressive neuronal dysfunction with age-dependent accumulation of mutant CaV2.1 channels. Proc Natl Acad Sci USA 105:11987–11992

    Article  PubMed  Google Scholar 

  142. Weiss N, Sandoval A, Felix R, Van den Maagdenberg A, De Waard M (2008) The S218L familial hemiplegic migraine mutation promotes deinhibition of Ca(v)2.1 calcium channels during direct G-protein regulation. Pflugers Arch 457:315–326

    Article  PubMed  CAS  Google Scholar 

  143. Westenbroek RE, Sakurai T, Elliott EM, Hell JW, Starr TVB, Snutch TP, Catterall WA (1995) Immunochemical identification and subcellular distribution of the α1A subunits of brain calcium channels. J Neurosci 15:6403–6418

    PubMed  CAS  Google Scholar 

  144. Womack MD, Chevez C, Khodakhah K (2004) Calcium-activated potassium channels are selectively coupled to P/Q-type calcium channels in cerebellar Purkinje neurons. J Neurosci 24:8818–8822

    Article  PubMed  CAS  Google Scholar 

  145. Womack M, Khodakhah K (2002) Active contribution of dendrites to the tonic and trimodal patterns of activity in cerebellar Purkinje neurons. J Neurosci 22:10603–10612

    PubMed  CAS  Google Scholar 

  146. Wu LG, Westenbroek RE, Borst JGG, Catterall WA, Sakmann B (1999) Calcium channel types with distinct presynaptic localization couple differentially to transmitter release in single calyx-type synapses. J Neurosci 19:726–736

    PubMed  CAS  Google Scholar 

  147. Xiao Y, Richter JA, Hurley JH (2008) Release of glutamate and CGRP from trigeminal ganglion neurons: Role of calcium channels and 5-HT1 receptor signaling. Mol Pain 4:12

    Article  PubMed  CAS  Google Scholar 

  148. Xie G, Clapcote SJ, Nieman BJ, Tallerico T, Huang Y, Vukobradovic I, Cordes SP, Osborne LR, Rossant J, Sled JG, Henderson JT, Roder JC (2007) Forward genetic screen of mouse reveals dominant missense mutation in the P/Q-type voltage-dependent calcium channel, CACNA1A. Genes Brain Behav 6:717–727

    Article  PubMed  CAS  Google Scholar 

  149. Zafeiriou DI, Lehmann-Horn F, Vargiami E, Teflioudi E, Ververi A, Jurkat-Rott K (2009) Episodic ataxia type 2 showing ictal hyperhidrosis with hypothermia and interictal chronic diarrhea due to a novel CACNA1A mutation. Eur J Paediatr Neurol 13:191–193

    Article  PubMed  CAS  Google Scholar 

  150. Zaitsev AV, Povysheva NV, Lewis DA, Krimer LS (2007) P/Q-type, but not N-type, calcium channels mediate GABA release from fast-spiking interneurons to pyramidal cells in rat prefrontal cortex. J Neurophysiol 97:3567–3573

    Article  PubMed  CAS  Google Scholar 

  151. Zhou YD, Turner TJ, Dunlap K (2003) Enhanced G protein-dependent modulation of excitatory synaptic transmission in the cerebellum of the Ca2+ channel-mutant mouse, tottering. J Physiol 547:497–507

    Article  PubMed  CAS  Google Scholar 

  152. Zhuchenko O, Bailey J, Bonnen P, Ashizawa T, Stockton DW, Amos C, Dobyns WB, Subramony SH, Zoghbi HY, Lee C (1997) Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the α1A-voltage-dependent calcium channel. Nature Genet 15:62–69

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

I acknowledge the support from Telethon-Italy (GGP06234), the Italian Ministry of University and Research (Prin 2007), the Fondazione CARIPARO (Calcium signaling in health and disease) and the University of Padova (Strategic Project: Physiopathology of signaling in neuronal tissue).

I gratefully thank Dr. Angelita Tottene for making the figures.

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    Daniela Pietrobon

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Pietrobon, D. CaV2.1 channelopathies. Pflugers Arch - Eur J Physiol 460, 375–393 (2010). https://doi.org/10.1007/s00424-010-0802-8

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