Cellular and Molecular Life Sciences

, Volume 71, Issue 15, pp 2787–2814 | Cite as

Neuronal calcium signaling: function and dysfunction



Calcium (Ca2+) is an universal second messenger that regulates the most important activities of all eukaryotic cells. It is of critical importance to neurons as it participates in the transmission of the depolarizing signal and contributes to synaptic activity. Neurons have thus developed extensive and intricate Ca2+ signaling pathways to couple the Ca2+ signal to their biochemical machinery. Ca2+ influx into neurons occurs through plasma membrane receptors and voltage-dependent ion channels. The release of Ca2+ from the intracellular stores, such as the endoplasmic reticulum, by intracellular channels also contributes to the elevation of cytosolic Ca2+. Inside the cell, Ca2+ is controlled by the buffering action of cytosolic Ca2+-binding proteins and by its uptake and release by mitochondria. The uptake of Ca2+ in the mitochondrial matrix stimulates the citric acid cycle, thus enhancing ATP production and the removal of Ca2+ from the cytosol by the ATP-driven pumps in the endoplasmic reticulum and the plasma membrane. A Na+/Ca2+ exchanger in the plasma membrane also participates in the control of neuronal Ca2+. The impaired ability of neurons to maintain an adequate energy level may impact Ca2+ signaling: this occurs during aging and in neurodegenerative disease processes. The focus of this review is on neuronal Ca2+ signaling and its involvement in synaptic signaling processes, neuronal energy metabolism, and neurotransmission. The contribution of altered Ca2+ signaling in the most important neurological disorders will then be considered.


Calcium signaling Calcium channels Calcium pumps Neurons Neurodegenerative disorders Migraine 



The original work by the authors has been supported over the years by grants from the Italian Ministry of University and Research (FIRB2001 to E.C., PRIN 2003, 2005 and 2008 to M.B), the Telethon Foundation (Project GGP04169 to M.B.), the FP6 program of the European Union (FP6 Network of Excellence NeuroNe, LSH-2003-2.1.3-3 to E.C. and Integrated Project Eurohear to E.C.), the Human Frontier Science Program Organization to E.C., the ERANet-Neuron (nEUROsyn), and CARIPARO Foundation to E.C, the Italian National Research Council (Agenzia 2000, CNR) and by grant from the University of Padova (Progetto di Ateneo 2008 CPDA082825) to M.B. Tito Calì is supported by the University of Padova (Progetto Giovani GRIC128SP0, Bando 2012). We apologize to many authors who have published substantial scientific contributions in the field of this specific Ca2+ research whose work could not or not sufficiently be cited here. This is due to space restrictions. Figures 1, 3 and 5 were produced using ServierMedical Art (http://www.servier.com/serviermedical-art/powerpoint-image-bank).


  1. 1.
    Carafoli E, Malmstrom K, Sigel E, Crompton M (1976) The regulation of intracellular calcium. Clin Endocrinol (Oxf) 5[Suppl]:49S–59SGoogle Scholar
  2. 2.
    Brini M, Cali T, Ottolini D, Carafoli E (2013) Intracellular calcium homeostasis and signaling. Met Ions Life Sci 12:119–168. doi: 10.1007/978-94-007-5561-1_5 PubMedGoogle Scholar
  3. 3.
    Mellstrom B, Savignac M, Gomez-Villafuertes R, Naranjo JR (2008) Ca2+-operated transcriptional networks: molecular mechanisms and in vivo models. Physiol Rev 88(2):421–449. doi: 10.1152/physrev.00041.2005 PubMedGoogle Scholar
  4. 4.
    Carafoli E (2007) The unusual history and unique properties of the calcium signal. In: Krebs J, Michalak M (eds) Calcium: a matter of life and death, vol 41. Elsevier, Amsterdam, pp 3–22Google Scholar
  5. 5.
    Prakriya M, Feske S, Gwack Y, Srikanth S, Rao A, Hogan PG (2006) Orai1 is an essential pore subunit of the CRAC channel. Nature 443(7108):230–233. doi: 10.1038/nature05122 PubMedGoogle Scholar
  6. 6.
    Hofmann F, Lacinova L, Klugbauer N (1999) Voltage-dependent calcium channels: from structure to function. Rev Physiol Biochem Pharmacol 139:33–87PubMedGoogle Scholar
  7. 7.
    Catterall WA (2000) Structure and regulation of voltage-gated Ca2+ channels. Annu Rev Cell Dev Biol 16:521–555. doi: 10.1146/annurev.cellbio.16.1.521 PubMedGoogle Scholar
  8. 8.
    Davies A, Hendrich J, Van Minh AT, Wratten J, Douglas L, Dolphin AC (2007) Functional biology of the alpha(2)delta subunits of voltage-gated calcium channels. Trends Pharmacol Sci 28(5):220–228. doi: 10.1016/j.tips.2007.03.005 PubMedGoogle Scholar
  9. 9.
    Hoppa MB, Lana B, Margas W, Dolphin AC, Ryan TA (2012) Alpha2delta expression sets presynaptic calcium channel abundance and release probability. Nature 486(7401):122–125. doi: 10.1038/nature11033 PubMedCentralPubMedGoogle Scholar
  10. 10.
    Catterall WA (2011) Voltage-gated calcium channels. Cold Spring Harb Perspect Biol 3(8):a003947. doi: 10.1101/cshperspect.a003947 PubMedCentralPubMedGoogle Scholar
  11. 11.
    Miyashita T, Oda Y, Horiuchi J, Yin JC, Morimoto T, Saitoe M (2012) Mg(2+) block of Drosophila NMDA receptors is required for long-term memory formation and CREB-dependent gene expression. Neuron 74(5):887–898. doi: 10.1016/j.neuron.2012.03.039 PubMedGoogle Scholar
  12. 12.
    Rosenmund C, Stern-Bach Y, Stevens CF (1998) The tetrameric structure of a glutamate receptor channel. Science 280(5369):1596–1599PubMedGoogle Scholar
  13. 13.
    Greger IH, Khatri L, Kong X, Ziff EB (2003) AMPA receptor tetramerization is mediated by Q/R editing. Neuron 40(4):763–774PubMedGoogle Scholar
  14. 14.
    Higuchi M, Maas S, Single FN, Hartner J, Rozov A, Burnashev N, Feldmeyer D, Sprengel R, Seeburg PH (2000) Point mutation in an AMPA receptor gene rescues lethality in mice deficient in the RNA-editing enzyme ADAR2. Nature 406(6791):78–81. doi: 10.1038/35017558 PubMedGoogle Scholar
  15. 15.
    Bowie D, Mayer ML (1995) Inward rectification of both AMPA and kainate subtype glutamate receptors generated by polyamine-mediated ion channel block. Neuron 15(2):453–462PubMedGoogle Scholar
  16. 16.
    Paoletti P, Bellone C, Zhou Q (2013) NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease. Nat Rev Neurosci 14(6):383–400. doi: 10.1038/nrn3504 PubMedGoogle Scholar
  17. 17.
    Hardingham GE, Chawla S, Cruzalegui FH, Bading H (1999) Control of recruitment and transcription-activating function of CBP determines gene regulation by NMDA receptors and L-type calcium channels. Neuron 22(4):789–798PubMedGoogle Scholar
  18. 18.
    Hardingham GE, Arnold FJ, Bading H (2001) Nuclear calcium signaling controls CREB-mediated gene expression triggered by synaptic activity. Nat Neurosci 4(3):261–267. doi: 10.1038/85109 PubMedGoogle Scholar
  19. 19.
    Hardingham GE, Arnold FJ, Bading H (2001) A calcium microdomain near NMDA receptors: on switch for ERK-dependent synapse-to-nucleus communication. Nat Neurosci 4(6):565–566. doi: 10.1038/88380 PubMedGoogle Scholar
  20. 20.
    Impey S, Goodman RH (2001) CREB signaling—timing is everything. Sci STKE 2001(82):pe1. doi: 10.1126/stke.2001.82.pe1
  21. 21.
    Wu GY, Deisseroth K, Tsien RW (2001) Activity-dependent CREB phosphorylation: convergence of a fast, sensitive calmodulin kinase pathway and a slow, less sensitive mitogen-activated protein kinase pathway. Proc Natl Acad Sci USA 98(5):2808–2813. doi: 10.1073/pnas.051634198 PubMedCentralPubMedGoogle Scholar
  22. 22.
    Barco A, Alarcon JM, Kandel ER (2002) Expression of constitutively active CREB protein facilitates the late phase of long-term potentiation by enhancing synaptic capture. Cell 108(5):689–703PubMedGoogle Scholar
  23. 23.
    Corlew R, Brasier DJ, Feldman DE, Philpot BD (2008) Presynaptic NMDA receptors: newly appreciated roles in cortical synaptic function and plasticity. Neuroscientist 14(6):609–625. doi: 10.1177/1073858408322675 PubMedCentralPubMedGoogle Scholar
  24. 24.
    Burnstock G, Di Virgilio F (2013) Purinergic signalling and cancer. Purinergic Signal. doi: 10.1007/s11302-013-9372-5 Google Scholar
  25. 25.
    Di Virgilio F, Ceruti S, Bramanti P, Abbracchio MP (2009) Purinergic signalling in inflammation of the central nervous system. Trends Neurosci 32(2):79–87. doi: 10.1016/j.tins.2008.11.003 PubMedGoogle Scholar
  26. 26.
    Franke H, Verkhratsky A, Burnstock G, Illes P (2012) Pathophysiology of astroglial purinergic signalling. Purinergic Signal 8(3):629–657. doi: 10.1007/s11302-012-9300-0 PubMedCentralPubMedGoogle Scholar
  27. 27.
    Levano-Garcia J, Dluzewski AR, Markus RP, Garcia CR (2010) Purinergic signalling is involved in the malaria parasite Plasmodium falciparum invasion to red blood cells. Purinergic Signal 6(4):365–372. doi: 10.1007/s11302-010-9202-y PubMedCentralPubMedGoogle Scholar
  28. 28.
    Pankratov Y, Lalo U, Krishtal OA, Verkhratsky A (2009) P2X receptors and synaptic plasticity. Neuroscience 158(1):137–148. doi: 10.1016/j.neuroscience.2008.03.076 PubMedGoogle Scholar
  29. 29.
    Hamilton NB, Attwell D (2010) Do astrocytes really exocytose neurotransmitters? Nat Rev Neurosci 11(4):227–238. doi: 10.1038/nrn2803 PubMedGoogle Scholar
  30. 30.
    Burnstock G, Verkhratsky A (2010) Long-term (trophic) purinergic signalling: purinoceptors control cell proliferation, differentiation and death. Cell Death Dis 1:e9. doi: 10.1038/cddis.2009.11 PubMedCentralPubMedGoogle Scholar
  31. 31.
    Zimmermann H (2011) Purinergic signaling in neural development. Semin Cell Dev Biol 22(2):194–204. doi: 10.1016/j.semcdb.2011.02.007 PubMedGoogle Scholar
  32. 32.
    Browne LE, Jiang LH, North RA (2010) New structure enlivens interest in P2X receptors. Trends Pharmacol Sci 31(5):229–237. doi: 10.1016/j.tips.2010.02.004 PubMedCentralPubMedGoogle Scholar
  33. 33.
    Burnstock G, Knight GE (2004) Cellular distribution and functions of P2 receptor subtypes in different systems. Int Rev Cytol 240:31–304. doi: 10.1016/S0074-7696(04)40002-3 PubMedGoogle Scholar
  34. 34.
    Pankratov Y, Lalo U, Krishtal O, Verkhratsky A (2003) P2X receptor-mediated excitatory synaptic currents in somatosensory cortex. Mol Cell Neurosci 24(3):842–849PubMedGoogle Scholar
  35. 35.
    Duan S, Neary JT (2006) P2X(7) receptors: properties and relevance to CNS function. Glia 54(7):738–746. doi: 10.1002/glia.20397 PubMedGoogle Scholar
  36. 36.
    Putney JW Jr (1986) A model for receptor-regulated calcium entry. Cell Calcium 7(1):1–12PubMedGoogle Scholar
  37. 37.
    Feske S (2011) Immunodeficiency due to defects in store-operated calcium entry. Ann N Y Acad Sci 1238:74–90. doi: 10.1111/j.1749-6632.2011.06240.x PubMedCentralPubMedGoogle Scholar
  38. 38.
    Putney JW (2012) Calcium signaling: deciphering the calcium-NFAT pathway. Curr Biol 22(3):R87–R89. doi: 10.1016/j.cub.2011.12.030 PubMedGoogle Scholar
  39. 39.
    Gwack Y, Srikanth S, Feske S, Cruz-Guilloty F, Oh-hora M, Neems DS, Hogan PG, Rao A (2007) Biochemical and functional characterization of Orai proteins. J Biol Chem 282(22):16232–16243. doi: 10.1074/jbc.M609630200 PubMedGoogle Scholar
  40. 40.
    Venkiteswaran G, Hasan G (2009) Intracellular Ca2+ signaling and store-operated Ca2+ entry are required in Drosophila neurons for flight. Proc Natl Acad Sci USA 106(25):10326–10331. doi: 10.1073/pnas.0902982106 PubMedCentralPubMedGoogle Scholar
  41. 41.
    Berna-Erro A, Braun A, Kraft R, Kleinschnitz C, Schuhmann MK, Stegner D, Wultsch T, Eilers J, Meuth SG, Stoll G, Nieswandt B (2009) STIM2 regulates capacitive Ca2+ entry in neurons and plays a key role in hypoxic neuronal cell death. Sci Signal 2(93):ra67. doi: 10.1126/scisignal.2000522 PubMedGoogle Scholar
  42. 42.
    Thompson JL, Mignen O, Shuttleworth TJ (2013) The ARC channel—an endogenous store-independent Orai channel. Curr Top Membr 71:125–148. doi: 10.1016/B978-0-12-407870-3.00006-8 PubMedGoogle Scholar
  43. 43.
    Rohacs T (2007) Regulation of TRP channels by PIP(2). Pflugers Arch 453(6):753–762. doi: 10.1007/s00424-006-0153-7 PubMedGoogle Scholar
  44. 44.
    Ambudkar IS, Ong HL, Liu X, Bandyopadhyay BC, Cheng KT (2007) TRPC1: the link between functionally distinct store-operated calcium channels. Cell Calcium 42(2):213–223. doi: 10.1016/j.ceca.2007.01.013 PubMedGoogle Scholar
  45. 45.
    Lu M, Branstrom R, Berglund E, Hoog A, Bjorklund P, Westin G, Larsson C, Farnebo LO, Forsberg L (2010) Expression and association of TRPC subtypes with Orai1 and STIM1 in human parathyroid. J Mol Endocrinol 44(5):285–294. doi: 10.1677/JME-09-0138 PubMedGoogle Scholar
  46. 46.
    Liao Y, Erxleben C, Yildirim E, Abramowitz J, Armstrong DL, Birnbaumer L (2007) Orai proteins interact with TRPC channels and confer responsiveness to store depletion. Proc Natl Acad Sci USA 104(11):4682–4687. doi: 10.1073/pnas.0611692104 PubMedCentralPubMedGoogle Scholar
  47. 47.
    Galione A, Evans AM, Ma J, Parrington J, Arredouani A, Cheng X, Zhu MX (2009) The acid test: the discovery of two-pore channels (TPCs) as NAADP-gated endolysosomal Ca(2+) release channels. Pflugers Arch 458(5):869–876. doi: 10.1007/s00424-009-0682-y PubMedCentralPubMedGoogle Scholar
  48. 48.
    Wang X, Zhang X, Dong XP, Samie M, Li X, Cheng X, Goschka A, Shen D, Zhou Y, Harlow J, Zhu MX, Clapham DE, Ren D, Xu H (2012) TPC proteins are phosphoinositide-activated sodium-selective ion channels in endosomes and lysosomes. Cell 151(2):372–383. doi: 10.1016/j.cell.2012.08.036 PubMedCentralPubMedGoogle Scholar
  49. 49.
    Brini M, Carafoli E (2011) The plasma membrane Ca(2)+ ATPase and the plasma membrane sodium calcium exchanger cooperate in the regulation of cell calcium. Cold Spring Harb Perspect Biol 3(2). doi: 10.1101/cshperspect.a004168
  50. 50.
    Blaustein MP, Juhaszova M, Golovina VA, Church PJ, Stanley EF (2002) Na/Ca exchanger and PMCA localization in neurons and astrocytes: functional implications. Ann N Y Acad Sci 976:356–366PubMedGoogle Scholar
  51. 51.
    Blaustein MP, Golovina VA (2001) Structural complexity and functional diversity of endoplasmic reticulum Ca(2+) stores. Trends Neurosci 24(10):602–608PubMedGoogle Scholar
  52. 52.
    Bano D, Young KW, Guerin CJ, Lefeuvre R, Rothwell NJ, Naldini L, Rizzuto R, Carafoli E, Nicotera P (2005) Cleavage of the plasma membrane Na+/Ca2+ exchanger in excitotoxicity. Cell 120(2):275–285. doi: 10.1016/j.cell.2004.11.049 PubMedGoogle Scholar
  53. 53.
    Annunziato L, Pignataro G, Boscia F, Sirabella R, Formisano L, Saggese M, Cuomo O, Gala R, Secondo A, Viggiano D, Molinaro P, Valsecchi V, Tortiglione A, Adornetto A, Scorziello A, Cataldi M, Di Renzo GF (2007) ncx1, ncx2, and ncx3 gene product expression and function in neuronal anoxia and brain ischemia. Ann N Y Acad Sci 1099:413–426. doi: 10.1196/annals.1387.050 PubMedGoogle Scholar
  54. 54.
    James P, Maeda M, Fischer R, Verma AK, Krebs J, Penniston JT, Carafoli E (1988) Identification and primary structure of a calmodulin binding domain of the Ca2+ pump of human erythrocytes. J Biol Chem 263(6):2905–2910PubMedGoogle Scholar
  55. 55.
    Enyedi A, Verma AK, Heim R, Adamo HP, Filoteo AG, Strehler EE, Penniston JT (1994) The Ca2+ affinity of the plasma membrane Ca2+ pump is controlled by alternative splicing. J Biol Chem 269(1):41–43PubMedGoogle Scholar
  56. 56.
    Falchetto R, Vorherr T, Brunner J, Carafoli E (1991) The plasma membrane Ca2+ pump contains a site that interacts with its calmodulin-binding domain. J Biol Chem 266(5):2930–2936PubMedGoogle Scholar
  57. 57.
    Falchetto R, Vorherr T, Carafoli E (1992) The calmodulin-binding site of the plasma membrane Ca2+ pump interacts with the transduction domain of the enzyme. Protein Sci 1(12):1613–1621. doi: 10.1002/pro.5560011209 PubMedCentralPubMedGoogle Scholar
  58. 58.
    Enyedi A, Vorherr T, James P, McCormick DJ, Filoteo AG, Carafoli E, Penniston JT (1989) The calmodulin binding domain of the plasma membrane Ca2+ pump interacts both with calmodulin and with another part of the pump. J Biol Chem 264(21):12313–12321PubMedGoogle Scholar
  59. 59.
    Zvaritch E, James P, Vorherr T, Falchetto R, Modyanov N, Carafoli E (1990) Mapping of functional domains in the plasma membrane Ca2+ pump using trypsin proteolysis. Biochemistry 29(35):8070–8076PubMedGoogle Scholar
  60. 60.
    Brodin P, Falchetto R, Vorherr T, Carafoli E (1992) Identification of two domains which mediate the binding of activating phospholipids to the plasma-membrane Ca2+ pump. Eur J Biochem 204(2):939–946PubMedGoogle Scholar
  61. 61.
    Oceandy D, Cartwright EJ, Emerson M, Prehar S, Baudoin FM, Zi M, Alatwi N, Venetucci L, Schuh K, Williams JC, Armesilla AL, Neyses L (2007) Neuronal nitric oxide synthase signaling in the heart is regulated by the sarcolemmal calcium pump 4b. Circulation 115(4):483–492. doi: 10.1161/CIRCULATIONAHA.106.643791 PubMedGoogle Scholar
  62. 62.
    Mohamed TM, Oceandy D, Zi M, Prehar S, Alatwi N, Wang Y, Shaheen MA, Abou-Leisa R, Schelcher C, Hegab Z, Baudoin F, Emerson M, Mamas M, Di Benedetto G, Zaccolo M, Lei M, Cartwright EJ, Neyses L (2011) Plasma membrane calcium pump (PMCA4)-neuronal nitric-oxide synthase complex regulates cardiac contractility through modulation of a compartmentalized cyclic nucleotide microdomain. J Biol Chem 286(48):41520–41529. doi: 10.1074/jbc.M111.290411 PubMedCentralPubMedGoogle Scholar
  63. 63.
    Ficarella R, Di Leva F, Bortolozzi M, Ortolano S, Donaudy F, Petrillo M, Melchionda S, Lelli A, Domi T, Fedrizzi L, Lim D, Shull GE, Gasparini P, Brini M, Mammano F, Carafoli E (2007) A functional study of plasma-membrane calcium-pump isoform 2 mutants causing digenic deafness. Proc Natl Acad Sci USA 104(5):1516–1521. doi: 10.1073/pnas.0609775104 PubMedCentralPubMedGoogle Scholar
  64. 64.
    Spiden SL, Bortolozzi M, Di Leva F, de Angelis MH, Fuchs H, Lim D, Ortolano S, Ingham NJ, Brini M, Carafoli E, Mammano F, Steel KP (2008) The novel mouse mutation Oblivion inactivates the PMCA2 pump and causes progressive hearing loss. PLoS Genet 4(10):e1000238. doi: 10.1371/journal.pgen.1000238 PubMedCentralPubMedGoogle Scholar
  65. 65.
    Street VA, McKee-Johnson JW, Fonseca RC, Tempel BL, Noben-Trauth K (1998) Mutations in a plasma membrane Ca2+-ATPase gene cause deafness in deafwaddler mice. Nat Genet 19(4):390–394PubMedGoogle Scholar
  66. 66.
    Bortolozzi M, Brini M, Parkinson N, Crispino G, Scimemi P, De Siati RD, Di Leva F, Parker A, Ortolano S, Arslan E, Brown SD, Carafoli E, Mammano F (2010) The novel PMCA2 pump mutation Tommy impairs cytosolic calcium clearance in hair cells and links to deafness in mice. J Biol Chem 285(48):37693–37703. doi: 10.1074/jbc.M110.170092 PubMedCentralPubMedGoogle Scholar
  67. 67.
    Takahashi K, Kitamura K (1999) A point mutation in a plasma membrane Ca(2+)-ATPase gene causes deafness in Wriggle Mouse Sagami. Biochem Biophys Res Commun 261(3):773–778PubMedGoogle Scholar
  68. 68.
    Schultz JM, Yang Y, Caride AJ, Filoteo AG, Penheiter AR, Lagziel A, Morell RJ, Mohiddin SA, Fananapazir L, Madeo AC, Penniston JT, Griffith AJ (2005) Modification of human hearing loss by plasma-membrane calcium pump PMCA2. N Engl J Med 352(15):1557–1564PubMedGoogle Scholar
  69. 69.
    Zanni G, Cali T, Kalscheuer VM, Ottolini D, Barresi S, Lebrun N, Montecchi-Palazzi L, Hu H, Chelly J, Bertini E, Brini M, Carafoli E (2012) Mutation of plasma membrane Ca2+ ATPase isoform 3 in a family with X-linked congenital cerebellar ataxia impairs Ca2+ homeostasis. Proc Natl Acad Sci USA 109(36):14514–14519. doi: 10.1073/pnas.1207488109 PubMedCentralPubMedGoogle Scholar
  70. 70.
    Taylor CW, Tovey SC (2010) IP(3) receptors: toward understanding their activation. Cold Spring Harb Perspect Biol 2(12):a004010. doi: 10.1101/cshperspect.a004010 PubMedCentralPubMedGoogle Scholar
  71. 71.
    Taylor CW, Laude AJ (2002) IP3 receptors and their regulation by calmodulin and cytosolic Ca2+. Cell Calcium 32(5–6):321–334PubMedGoogle Scholar
  72. 72.
    Lanner JT, Georgiou DK, Joshi AD, Hamilton SL (2010) Ryanodine receptors: structure, expression, molecular details, and function in calcium release. Cold Spring Harb Perspect Biol 2(11):a003996. doi: 10.1101/cshperspect.a003996 PubMedCentralPubMedGoogle Scholar
  73. 73.
    De Flora A, Franco L, Guida L, Bruzzone S, Zocchi E (1998) Ectocellular CD38-catalyzed synthesis and intracellular Ca(2+)-mobilizing activity of cyclic ADP-ribose. Cell Biochem Biophys 28(1):45–62. doi: 10.1007/BF02738309 PubMedGoogle Scholar
  74. 74.
    Brini M, Carafoli E (2009) Calcium pumps in health and disease. Physiol Rev 89(4):1341–1378. doi: 10.1152/physrev.00032.2008 PubMedGoogle Scholar
  75. 75.
    Jouaville LS, Pinton P, Bastianutto C, Rutter GA, Rizzuto R (1999) Regulation of mitochondrial ATP synthesis by calcium: evidence for a long-term metabolic priming. Proc Natl Acad Sci USA 96(24):13807–13812PubMedCentralPubMedGoogle Scholar
  76. 76.
    Denton RM (2009) Regulation of mitochondrial dehydrogenases by calcium ions. Biochim Biophys Acta 1787(11):1309–1316. doi: 10.1016/j.bbabio.2009.01.005 PubMedGoogle Scholar
  77. 77.
    Hajnoczky G, Robb-Gaspers LD, Seitz MB, Thomas AP (1995) Decoding of cytosolic calcium oscillations in the mitochondria. Cell 82(3):415–424PubMedGoogle Scholar
  78. 78.
    Hajnoczky G, Hager R, Thomas AP (1999) Mitochondria suppress local feedback activation of inositol 1,4, 5-trisphosphate receptors by Ca2+. J Biol Chem 274(20):14157–14162PubMedGoogle Scholar
  79. 79.
    Hoth M, Fanger CM, Lewis RS (1997) Mitochondrial regulation of store-operated calcium signaling in T lymphocytes. J Cell Biol 137(3):633–648PubMedCentralPubMedGoogle Scholar
  80. 80.
    Baughman JM, Perocchi F, Girgis HS, Plovanich M, Belcher-Timme CA, Sancak Y, Bao XR, Strittmatter L, Goldberger O, Bogorad RL, Koteliansky V, Mootha VK (2011) Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter. Nature 476(7360):341–345. doi: 10.1038/nature10234 PubMedCentralPubMedGoogle Scholar
  81. 81.
    De Stefani D, Raffaello A, Teardo E, Szabo I, Rizzuto R (2011) A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter. Nature 476(7360):336–340. doi: 10.1038/nature10230 PubMedGoogle Scholar
  82. 82.
    Raffaello A, De Stefani D, Sabbadin D, Teardo E, Merli G, Picard A, Checchetto V, Moro S, Szabo I, Rizzuto R (2013) The mitochondrial calcium uniporter is a multimer that can include a dominant-negative pore-forming subunit. EMBO J 32(17):2362–2376. doi: 10.1038/emboj.2013.157 PubMedGoogle Scholar
  83. 83.
    Csordas G, Golenar T, Seifert EL, Kamer KJ, Sancak Y, Perocchi F, Moffat C, Weaver D, de la Fuente Perez S, Bogorad R, Koteliansky V, Adijanto J, Mootha VK, Hajnoczky G (2013) MICU1 controls both the threshold and cooperative activation of the mitochondrial Ca(2)(+) uniporter. Cell Metab 17(6):976–987. doi: 10.1016/j.cmet.2013.04.020 PubMedCentralPubMedGoogle Scholar
  84. 84.
    Mallilankaraman K, Doonan P, Cardenas C, Chandramoorthy HC, Muller M, Miller R, Hoffman NE, Gandhirajan RK, Molgo J, Birnbaum MJ, Rothberg BS, Mak DO, Foskett JK, Madesh M (2012) MICU1 is an essential gatekeeper for MCU-mediated mitochondrial Ca(2+) uptake that regulates cell survival. Cell 151(3):630–644. doi: 10.1016/j.cell.2012.10.011 PubMedCentralPubMedGoogle Scholar
  85. 85.
    Plovanich M, Bogorad RL, Sancak Y, Kamer KJ, Strittmatter L, Li AA, Girgis HS, Kuchimanchi S, De Groot J, Speciner L, Taneja N, Oshea J, Koteliansky V, Mootha VK (2013) MICU2, a paralog of MICU1, resides within the mitochondrial uniporter complex to regulate calcium handling. PLoS One 8(2):e55785. doi: 10.1371/journal.pone.0055785 PubMedCentralPubMedGoogle Scholar
  86. 86.
    Sancak Y, Markhard AL, Kitami T, Kovacs-Bogdan E, Kamer KJ, Udeshi ND, Carr SA, Chaudhuri D, Clapham DE, Li AA, Calvo SE, Goldberger O, Mootha VK (2013) EMRE is an essential component of the mitochondrial calcium uniporter complex. Science 342:1379–1382. doi: 10.1126/science.1242993 Google Scholar
  87. 87.
    Carafoli E, Tiozzo R, Lugli G, Crovetti F, Kratzing C (1974) The release of calcium from heart mitochondria by sodium. J Mol Cell Cardiol 6(4):361–371PubMedGoogle Scholar
  88. 88.
    Palty R, Silverman WF, Hershfinkel M, Caporale T, Sensi SL, Parnis J, Nolte C, Fishman D, Shoshan-Barmatz V, Herrmann S, Khananshvili D, Sekler I (2010) NCLX is an essential component of mitochondrial Na+/Ca2+ exchange. Proc Natl Acad Sci USA 107(1):436–441. doi: 10.1073/pnas.0908099107 PubMedCentralPubMedGoogle Scholar
  89. 89.
    Bernardi P, von Stockum S (2012) The permeability transition pore as a Ca(2+) release channel: new answers to an old question. Cell Calcium 52(1):22–27. doi: 10.1016/j.ceca.2012.03.004 PubMedCentralPubMedGoogle Scholar
  90. 90.
    Bernardi P (2013) The mitochondrial permeability transition pore: a mystery solved? Front Physiol 4:95. doi: 10.3389/fphys.2013.00095 PubMedCentralPubMedGoogle Scholar
  91. 91.
    Bonora M, Bononi A, De Marchi E, Giorgi C, Lebiedzinska M, Marchi S, Patergnani S, Rimessi A, Suski JM, Wojtala A, Wieckowski MR, Kroemer G, Galluzzi L, Pinton P (2013) Role of the c subunit of the FO ATP synthase in mitochondrial permeability transition. Cell Cycle 12(4):674–683. doi: 10.4161/cc.23599 PubMedCentralPubMedGoogle Scholar
  92. 92.
    Giorgio V, von Stockum S, Antoniel M, Fabbro A, Fogolari F, Forte M, Glick GD, Petronilli V, Zoratti M, Szabo I, Lippe G, Bernardi P (2013) Dimers of mitochondrial ATP synthase form the permeability transition pore. Proc Natl Acad Sci USA 110(15):5887–5892. doi: 10.1073/pnas.1217823110 PubMedCentralPubMedGoogle Scholar
  93. 93.
    Chin D, Means AR (2000) Calmodulin: a prototypical calcium sensor. Trends Cell Biol 10(8):322–328PubMedGoogle Scholar
  94. 94.
    Catterall WA, Few AP (2008) Calcium channel regulation and presynaptic plasticity. Neuron 59(6):882–901. doi: 10.1016/j.neuron.2008.09.005 PubMedGoogle Scholar
  95. 95.
    Schwaller B (2009) The continuing disappearance of “pure” Ca2+ buffers. Cell Mol Life Sci 66(2):275–300. doi: 10.1007/s00018-008-8564-6 PubMedGoogle Scholar
  96. 96.
    Schmidt H, Eilers J (2009) Spine neck geometry determines spino-dendritic cross-talk in the presence of mobile endogenous calcium binding proteins. J Comput Neurosci 27(2):229–243. doi: 10.1007/s10827-009-0139-5 PubMedGoogle Scholar
  97. 97.
    Schmidt H, Kunerth S, Wilms C, Strotmann R, Eilers J (2007) Spino-dendritic cross-talk in rodent Purkinje neurons mediated by endogenous Ca2+-binding proteins. J Physiol 581(Pt 2):619–629. doi: 10.1113/jphysiol.2007.127860 PubMedCentralPubMedGoogle Scholar
  98. 98.
    Fierro L, Llano I (1996) High endogenous calcium buffering in Purkinje cells from rat cerebellar slices. J Physiol 496(Pt 3):617–625PubMedCentralPubMedGoogle Scholar
  99. 99.
    Schwaller B, Tetko IV, Tandon P, Silveira DC, Vreugdenhil M, Henzi T, Potier MC, Celio MR, Villa AE (2004) Parvalbumin deficiency affects network properties resulting in increased susceptibility to epileptic seizures. Mol Cell Neurosci 25(4):650–663. doi: 10.1016/j.mcn.2003.12.006 PubMedGoogle Scholar
  100. 100.
    Gall D, Roussel C, Susa I, D’Angelo E, Rossi P, Bearzatto B, Galas MC, Blum D, Schurmans S, Schiffmann SN (2003) Altered neuronal excitability in cerebellar granule cells of mice lacking calretinin. J Neurosci 23(28):9320–9327PubMedGoogle Scholar
  101. 101.
    Moreno H, Burghardt NS, Vela-Duarte D, Masciotti J, Hua F, Fenton AA, Schwaller B, Small SA (2012) The absence of the calcium-buffering protein calbindin is associated with faster age-related decline in hippocampal metabolism. Hippocampus 22(5):1107–1120. doi: 10.1002/hipo.20957 PubMedCentralPubMedGoogle Scholar
  102. 102.
    Pongs O, Lindemeier J, Zhu XR, Theil T, Engelkamp D, Krah-Jentgens I, Lambrecht HG, Koch KW, Schwemer J, Rivosecchi R et al (1993) Frequenin—a novel calcium-binding protein that modulates synaptic efficacy in the Drosophila nervous system. Neuron 11(1):15–28PubMedGoogle Scholar
  103. 103.
    McFerran BW, Graham ME, Burgoyne RD (1998) Neuronal Ca2+ sensor 1, the mammalian homologue of frequenin, is expressed in chromaffin and PC12 cells and regulates neurosecretion from dense-core granules. J Biol Chem 273(35):22768–22772PubMedGoogle Scholar
  104. 104.
    McFerran BW, Weiss JL, Burgoyne RD (1999) Neuronal Ca(2+) sensor 1. Characterization of the myristoylated protein, its cellular effects in permeabilized adrenal chromaffin cells, Ca(2+)-independent membrane association, and interaction with binding proteins, suggesting a role in rapid Ca(2+) signal transduction. J Biol Chem 274(42):30258–30265PubMedGoogle Scholar
  105. 105.
    Weiss JL, Archer DA, Burgoyne RD (2000) Neuronal Ca2+ sensor-1/frequenin functions in an autocrine pathway regulating Ca2+ channels in bovine adrenal chromaffin cells. J Biol Chem 275(51):40082–40087. doi: 10.1074/jbc.M008603200 PubMedGoogle Scholar
  106. 106.
    Tsujimoto T, Jeromin A, Saitoh N, Roder JC, Takahashi T (2002) Neuronal calcium sensor 1 and activity-dependent facilitation of P/Q-type calcium currents at presynaptic nerve terminals. Science 295(5563):2276–2279. doi: 10.1126/science.1068278 PubMedGoogle Scholar
  107. 107.
    Sippy T, Cruz-Martin A, Jeromin A, Schweizer FE (2003) Acute changes in short-term plasticity at synapses with elevated levels of neuronal calcium sensor-1. Nat Neurosci 6(10):1031–1038. doi: 10.1038/nn1117 PubMedCentralPubMedGoogle Scholar
  108. 108.
    Jo J, Heon S, Kim MJ, Son GH, Park Y, Henley JM, Weiss JL, Sheng M, Collingridge GL, Cho K (2008) Metabotropic glutamate receptor-mediated LTD involves two interacting Ca(2+) sensors, NCS-1 and PICK1. Neuron 60(6):1095–1111. doi: 10.1016/j.neuron.2008.10.050 PubMedCentralPubMedGoogle Scholar
  109. 109.
    Dason JS, Romero-Pozuelo J, Marin L, Iyengar BG, Klose MK, Ferrus A, Atwood HL (2009) Frequenin/NCS-1 and the Ca2+-channel alpha1-subunit co-regulate synaptic transmission and nerve-terminal growth. J Cell Sci 122(Pt 22):4109–4121. doi: 10.1242/jcs.055095 PubMedGoogle Scholar
  110. 110.
    Lee A, Wong ST, Gallagher D, Li B, Storm DR, Scheuer T, Catterall WA (1999) Ca2+/calmodulin binds to and modulates P/Q-type calcium channels. Nature 399(6732):155–159. doi: 10.1038/20194 PubMedGoogle Scholar
  111. 111.
    An WF, Bowlby MR, Betty M, Cao J, Ling HP, Mendoza G, Hinson JW, Mattsson KI, Strassle BW, Trimmer JS, Rhodes KJ (2000) Modulation of A-type potassium channels by a family of calcium sensors. Nature 403(6769):553–556. doi: 10.1038/35000592 PubMedGoogle Scholar
  112. 112.
    Carrion AM, Link WA, Ledo F, Mellstrom B, Naranjo JR (1999) DREAM is a Ca2+-regulated transcriptional repressor. Nature 398(6722):80–84. doi: 10.1038/18044 PubMedGoogle Scholar
  113. 113.
    Buxbaum JD, Choi EK, Luo Y, Lilliehook C, Crowley AC, Merriam DE, Wasco W (1998) Calsenilin: a calcium-binding protein that interacts with the presenilins and regulates the levels of a presenilin fragment. Nat Med 4(10):1177–1181. doi: 10.1038/2673 PubMedGoogle Scholar
  114. 114.
    De Strooper B, Iwatsubo T, Wolfe MS (2012) Presenilins and gamma-secretase: structure, function, and role in Alzheimer disease. Cold Spring Harb Perspect Med 2(1):a006304. doi: 10.1101/cshperspect.a006304 PubMedCentralPubMedGoogle Scholar
  115. 115.
    Gomez-Villafuertes R, Torres B, Barrio J, Savignac M, Gabellini N, Rizzato F, Pintado B, Gutierrez-Adan A, Mellstrom B, Carafoli E, Naranjo JR (2005) Downstream regulatory element antagonist modulator regulates Ca2+ homeostasis and viability in cerebellar neurons. J Neurosci 25(47):10822–10830. doi: 10.1523/JNEUROSCI.3912-05.2005 PubMedGoogle Scholar
  116. 116.
    Ronkainen JJ, Hanninen SL, Korhonen T, Koivumaki JT, Skoumal R, Rautio S, Ronkainen VP, Tavi P (2011) Ca2+-calmodulin-dependent protein kinase II represses cardiac transcription of the L-type calcium channel alpha(1C)-subunit gene (Cacna1c) by DREAM translocation. J Physiol 589(Pt 11):2669–2686. doi: 10.1113/jphysiol.2010.201400 PubMedCentralPubMedGoogle Scholar
  117. 117.
    Fontan-Lozano A, Romero-Granados R, del-Pozo-Martin Y, Suarez-Pereira I, Delgado-Garcia JM, Penninger JM, Carrion AM (2009) Lack of DREAM protein enhances learning and memory and slows brain aging. Curr Biol 19(1):54–60. doi: 10.1016/j.cub.2008.11.056 PubMedGoogle Scholar
  118. 118.
    Alexander JC, McDermott CM, Tunur T, Rands V, Stelly C, Karhson D, Bowlby MR, An WF, Sweatt JD, Schrader LA (2009) The role of calsenilin/DREAM/KChIP3 in contextual fear conditioning. Learn Mem 16(3):167–177. doi: 10.1101/lm.1261709 PubMedCentralPubMedGoogle Scholar
  119. 119.
    Wu LJ, Mellstrom B, Wang H, Ren M, Domingo S, Kim SS, Li XY, Chen T, Naranjo JR, Zhuo M (2010) DREAM (downstream regulatory element antagonist modulator) contributes to synaptic depression and contextual fear memory. Mol Brain 3:3. doi: 10.1186/1756-6606-3-3 PubMedCentralPubMedGoogle Scholar
  120. 120.
    Zhang Y, Su P, Liang P, Liu T, Liu X, Liu XY, Zhang B, Han T, Zhu YB, Yin DM, Li J, Zhou Z, Wang KW, Wang Y (2010) The DREAM protein negatively regulates the NMDA receptor through interaction with the NR1 subunit. J Neurosci 30(22):7575–7586. doi: 10.1523/JNEUROSCI.1312-10.2010 PubMedGoogle Scholar
  121. 121.
    Rivera-Arconada I, Benedet T, Roza C, Torres B, Barrio J, Krzyzanowska A, Avendano C, Mellstrom B, Lopez-Garcia JA, Naranjo JR (2010) DREAM regulates BDNF-dependent spinal sensitization. Mol Pain 6:95. doi: 10.1186/1744-8069-6-95 PubMedCentralPubMedGoogle Scholar
  122. 122.
    Karp G (2002) Cell and molecular biology. Wiley, New YorkGoogle Scholar
  123. 123.
    Hudmon A, Schulman H (2002) Neuronal CA2+/calmodulin-dependent protein kinase II: the role of structure and autoregulation in cellular function. Annu Rev Biochem 71:473–510. doi: 10.1146/annurev.biochem.71.110601.135410 PubMedGoogle Scholar
  124. 124.
    Bading H (2013) Nuclear calcium signalling in the regulation of brain function. Nat Rev Neurosci 14(9):593–608. doi: 10.1038/nrn3531 PubMedGoogle Scholar
  125. 125.
    Dick O, Bading H (2010) Synaptic activity and nuclear calcium signaling protect hippocampal neurons from death signal-associated nuclear translocation of FoxO3a induced by extrasynaptic N-methyl-D-aspartate receptors. J Biol Chem 285(25):19354–19361. doi: 10.1074/jbc.M110.127654 PubMedCentralPubMedGoogle Scholar
  126. 126.
    Foskett JK (2010) Inositol trisphosphate receptor Ca2+ release channels in neurological diseases. Pflugers Arch 460(2):481–494. doi: 10.1007/s00424-010-0826-0 PubMedCentralPubMedGoogle Scholar
  127. 127.
    Camandola S, Mattson MP (2011) Aberrant subcellular neuronal calcium regulation in aging and Alzheimer’s disease. Biochim Biophys Acta 1813(5):965–973. doi: 10.1016/j.bbamcr.2010.10.005 PubMedCentralPubMedGoogle Scholar
  128. 128.
    Duchen MR (2012) Mitochondria, calcium-dependent neuronal death and neurodegenerative disease. Pflugers Arch 464(1):111–121. doi: 10.1007/s00424-012-1112-0 PubMedCentralPubMedGoogle Scholar
  129. 129.
    Cali T, Ottolini D, Brini M (2012) Mitochondrial Ca(2+) and neurodegeneration. Cell Calcium 52(1):73–85. doi: 10.1016/j.ceca.2012.04.015 PubMedCentralPubMedGoogle Scholar
  130. 130.
    Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, Donaldson D, Goto J, O’Regan JP, Deng HX et al (1993) Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362(6415):59–62. doi: 10.1038/362059a0 PubMedGoogle Scholar
  131. 131.
    Carriedo SG, Yin HZ, Weiss JH (1996) Motor neurons are selectively vulnerable to AMPA/kainate receptor-mediated injury in vitro. J Neurosci 16(13):4069–4079PubMedGoogle Scholar
  132. 132.
    Rowland LP, Shneider NA (2001) Amyotrophic lateral sclerosis. N Engl J Med 344(22):1688–1700. doi: 10.1056/NEJM200105313442207 PubMedGoogle Scholar
  133. 133.
    von Lewinski F, Keller BU (2005) Ca2+, mitochondria and selective motoneuron vulnerability: implications for ALS. Trends Neurosci 28(9):494–500. doi: 10.1016/j.tins.2005.07.001 Google Scholar
  134. 134.
    Alexianu ME, Ho BK, Mohamed AH, La Bella V, Smith RG, Appel SH (1994) The role of calcium-binding proteins in selective motoneuron vulnerability in amyotrophic lateral sclerosis. Ann Neurol 36(6):846–858. doi: 10.1002/ana.410360608 PubMedGoogle Scholar
  135. 135.
    Iacopino AM, Christakos S (1990) Corticosterone regulates calbindin-D28k mRNA and protein levels in rat hippocampus. J Biol Chem 265(18):10177–10180PubMedGoogle Scholar
  136. 136.
    Beers DR, Ho BK, Siklos L, Alexianu ME, Mosier DR, Mohamed AH, Otsuka Y, Kozovska ME, McAlhany RE, Smith RG, Appel SH (2001) Parvalbumin overexpression alters immune-mediated increases in intracellular calcium, and delays disease onset in a transgenic model of familial amyotrophic lateral sclerosis. J Neurochem 79(3):499–509PubMedGoogle Scholar
  137. 137.
    Bernard-Marissal N, Moumen A, Sunyach C, Pellegrino C, Dudley K, Henderson CE, Raoul C, Pettmann B (2012) Reduced calreticulin levels link endoplasmic reticulum stress and Fas-triggered cell death in motoneurons vulnerable to ALS. J Neurosci 32(14):4901–4912. doi: 10.1523/JNEUROSCI.5431-11.2012 PubMedGoogle Scholar
  138. 138.
    Beal MF (2000) Mitochondria and the pathogenesis of ALS. Brain 123(Pt 7):1291–1292PubMedGoogle Scholar
  139. 139.
    Damiano M, Starkov AA, Petri S, Kipiani K, Kiaei M, Mattiazzi M, Flint Beal M, Manfredi G (2006) Neural mitochondrial Ca2+ capacity impairment precedes the onset of motor symptoms in G93A Cu/Zn-superoxide dismutase mutant mice. J Neurochem 96(5):1349–1361. doi: 10.1111/j.1471-4159.2006.03619.x PubMedGoogle Scholar
  140. 140.
    Carri MT, Ferri A, Battistoni A, Famhy L, Gabbianelli R, Poccia F, Rotilio G (1997) Expression of a Cu, Zn superoxide dismutase typical of familial amyotrophic lateral sclerosis induces mitochondrial alteration and increase of cytosolic Ca2+ concentration in transfected neuroblastoma SH-SY5Y cells. FEBS Lett 414(2):365–368PubMedGoogle Scholar
  141. 141.
    Ferri A, Cozzolino M, Crosio C, Nencini M, Casciati A, Gralla EB, Rotilio G, Valentine JS, Carri MT (2006) Familial ALS-superoxide dismutases associate with mitochondria and shift their redox potentials. Proc Natl Acad Sci USA 103(37):13860–13865. doi: 10.1073/pnas.0605814103 PubMedCentralPubMedGoogle Scholar
  142. 142.
    Son M, Leary SC, Romain N, Pierrel F, Winge DR, Haller RG, Elliott JL (2008) Isolated cytochrome c oxidase deficiency in G93A SOD1 mice overexpressing CCS protein. J Biol Chem 283(18):12267–12275. doi: 10.1074/jbc.M708523200 PubMedCentralPubMedGoogle Scholar
  143. 143.
    Son M, Puttaparthi K, Kawamata H, Rajendran B, Boyer PJ, Manfredi G, Elliott JL (2007) Overexpression of CCS in G93A-SOD1 mice leads to accelerated neurological deficits with severe mitochondrial pathology. Proc Natl Acad Sci USA 104(14):6072–6077. doi: 10.1073/pnas.0610923104 PubMedCentralPubMedGoogle Scholar
  144. 144.
    Mattiazzi M, D’Aurelio M, Gajewski CD, Martushova K, Kiaei M, Beal MF, Manfredi G (2002) Mutated human SOD1 causes dysfunction of oxidative phosphorylation in mitochondria of transgenic mice. J Biol Chem 277(33):29626–29633. doi: 10.1074/jbc.M203065200 PubMedGoogle Scholar
  145. 145.
    Jung C, Higgins CM, Xu Z (2002) Mitochondrial electron transport chain complex dysfunction in a transgenic mouse model for amyotrophic lateral sclerosis. J Neurochem 83(3):535–545PubMedGoogle Scholar
  146. 146.
    Jaiswal MK, Keller BU (2009) Cu/Zn superoxide dismutase typical for familial amyotrophic lateral sclerosis increases the vulnerability of mitochondria and perturbs Ca2+ homeostasis in SOD1G93A mice. Mol Pharmacol 75(3):478–489. doi: 10.1124/mol.108.050831 PubMedGoogle Scholar
  147. 147.
    Jaiswal MK, Zech WD, Goos M, Leutbecher C, Ferri A, Zippelius A, Carri MT, Nau R, Keller BU (2009) Impairment of mitochondrial calcium handling in a mtSOD1 cell culture model of motoneuron disease. BMC Neurosci 10:64. doi: 10.1186/1471-2202-10-64 PubMedCentralPubMedGoogle Scholar
  148. 148.
    Rothstein JD, Tsai G, Kuncl RW, Clawson L, Cornblath DR, Drachman DB, Pestronk A, Stauch BL, Coyle JT (1990) Abnormal excitatory amino acid metabolism in amyotrophic lateral sclerosis. Ann Neurol 28(1):18–25. doi: 10.1002/ana.410280106 PubMedGoogle Scholar
  149. 149.
    Carriedo SG, Sensi SL, Yin HZ, Weiss JH (2000) AMPA exposures induce mitochondrial Ca(2+) overload and ROS generation in spinal motor neurons in vitro. J Neurosci 20(1):240–250PubMedGoogle Scholar
  150. 150.
    Takuma H, Kwak S, Yoshizawa T, Kanazawa I (1999) Reduction of GluR2 RNA editing, a molecular change that increases calcium influx through AMPA receptors, selective in the spinal ventral gray of patients with amyotrophic lateral sclerosis. Ann Neurol 46(6):806–815PubMedGoogle Scholar
  151. 151.
    Guatteo E, Carunchio I, Pieri M, Albo F, Canu N, Mercuri NB, Zona C (2007) Altered calcium homeostasis in motor neurons following AMPA receptor but not voltage-dependent calcium channels’ activation in a genetic model of amyotrophic lateral sclerosis. Neurobiol Dis 28(1):90–100. doi: 10.1016/j.nbd.2007.07.002 PubMedGoogle Scholar
  152. 152.
    Zuccato C, Valenza M, Cattaneo E (2010) Molecular mechanisms and potential therapeutical targets in Huntington’s disease. Physiol Rev 90(3):905–981. doi: 10.1152/physrev.00041.2009 PubMedGoogle Scholar
  153. 153.
    Graham RK, Deng Y, Slow EJ, Haigh B, Bissada N, Lu G, Pearson J, Shehadeh J, Bertram L, Murphy Z, Warby SC, Doty CN, Roy S, Wellington CL, Leavitt BR, Raymond LA, Nicholson DW, Hayden MR (2006) Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin. Cell 125(6):1179–1191. doi: 10.1016/j.cell.2006.04.026 PubMedGoogle Scholar
  154. 154.
    Olzscha H, Schermann SM, Woerner AC, Pinkert S, Hecht MH, Tartaglia GG, Vendruscolo M, Hayer-Hartl M, Hartl FU, Vabulas RM (2011) Amyloid-like aggregates sequester numerous metastable proteins with essential cellular functions. Cell 144(1):67–78. doi: 10.1016/j.cell.2010.11.050 PubMedGoogle Scholar
  155. 155.
    Bao J, Sharp AH, Wagster MV, Becher M, Schilling G, Ross CA, Dawson VL, Dawson TM (1996) Expansion of polyglutamine repeat in huntingtin leads to abnormal protein interactions involving calmodulin. Proc Natl Acad Sci USA 93(10):5037–5042PubMedCentralPubMedGoogle Scholar
  156. 156.
    Yamanaka T, Nukina N (2010) Transcription factor sequestration by polyglutamine proteins. Methods Mol Biol 648:215–229. doi: 10.1007/978-1-60761-756-3_14 PubMedGoogle Scholar
  157. 157.
    Fan MM, Raymond LA (2007) N-methyl-d-aspartate (NMDA) receptor function and excitotoxicity in Huntington’s disease. Prog Neurobiol 81(5–6):272–293. doi: 10.1016/j.pneurobio.2006.11.003 PubMedGoogle Scholar
  158. 158.
    Bezprozvanny I (2007) Inositol 1,4,5-tripshosphate receptor, calcium signalling and Huntington’s disease. Subcell Biochem 45:323–335PubMedGoogle Scholar
  159. 159.
    Lim D, Fedrizzi L, Tartari M, Zuccato C, Cattaneo E, Brini M, Carafoli E (2008) Calcium homeostasis and mitochondrial dysfunction in striatal neurons of Huntington disease. J Biol Chem 283(9):5780–5789. doi: 10.1074/jbc.M704704200 PubMedGoogle Scholar
  160. 160.
    Seto-Ohshima A, Emson PC, Lawson E, Mountjoy CQ, Carrasco LH (1988) Loss of matrix calcium-binding protein-containing neurons in Huntington’s disease. Lancet 1(8597):1252–1255PubMedGoogle Scholar
  161. 161.
    Dong G, Gross K, Qiao F, Ferguson J, Callegari EA, Rezvani K, Zhang D, Gloeckner CJ, Ueffing M, Wang H (2012) Calretinin interacts with huntingtin and reduces mutant huntingtin-caused cytotoxicity. J Neurochem 123(3):437–446. doi: 10.1111/j.1471-4159.2012.07919.x PubMedGoogle Scholar
  162. 162.
    Sun Y, Savanenin A, Reddy PH, Liu YF (2001) Polyglutamine-expanded huntingtin promotes sensitization of N-methyl-d-aspartate receptors via post-synaptic density 95. J Biol Chem 276(27):24713–24718. doi: 10.1074/jbc.M103501200 PubMedGoogle Scholar
  163. 163.
    Benchoua A, Trioulier Y, Zala D, Gaillard MC, Lefort N, Dufour N, Saudou F, Elalouf JM, Hirsch E, Hantraye P, Deglon N, Brouillet E (2006) Involvement of mitochondrial complex II defects in neuronal death produced by N-terminus fragment of mutated huntingtin. Mol Biol Cell 17(4):1652–1663. doi: 10.1091/mbc.E05-07-0607 PubMedCentralPubMedGoogle Scholar
  164. 164.
    Beal MF, Brouillet E, Jenkins BG, Ferrante RJ, Kowall NW, Miller JM, Storey E, Srivastava R, Rosen BR, Hyman BT (1993) Neurochemical and histologic characterization of striatal excitotoxic lesions produced by the mitochondrial toxin 3-nitropropionic acid. J Neurosci 13(10):4181–4192PubMedGoogle Scholar
  165. 165.
    Panov AV, Gutekunst CA, Leavitt BR, Hayden MR, Burke JR, Strittmatter WJ, Greenamyre JT (2002) Early mitochondrial calcium defects in Huntington’s disease are a direct effect of polyglutamines. Nat Neurosci 5(8):731–736. doi: 10.1038/nn884 PubMedGoogle Scholar
  166. 166.
    Panov AV, Burke JR, Strittmatter WJ, Greenamyre JT (2003) In vitro effects of polyglutamine tracts on Ca2+-dependent depolarization of rat and human mitochondria: relevance to Huntington’s disease. Arch Biochem Biophys 410(1):1–6PubMedGoogle Scholar
  167. 167.
    Choo YS, Johnson GV, MacDonald M, Detloff PJ, Lesort M (2004) Mutant huntingtin directly increases susceptibility of mitochondria to the calcium-induced permeability transition and cytochrome c release. Hum Mol Genet 13(14):1407–1420. doi: 10.1093/hmg/ddh162 PubMedGoogle Scholar
  168. 168.
    Tang TS, Tu H, Chan EY, Maximov A, Wang Z, Wellington CL, Hayden MR, Bezprozvanny I (2003) Huntingtin and huntingtin-associated protein 1 influence neuronal calcium signaling mediated by inositol-(1,4,5) triphosphate receptor type 1. Neuron 39(2):227–239PubMedCentralPubMedGoogle Scholar
  169. 169.
    Dreses-Werringloer U, Lambert JC, Vingtdeux V, Zhao H, Vais H, Siebert A, Jain A, Koppel J, Rovelet-Lecrux A, Hannequin D, Pasquier F, Galimberti D, Scarpini E, Mann D, Lendon C, Campion D, Amouyel P, Davies P, Foskett JK, Campagne F, Marambaud P (2008) A polymorphism in CALHM1 influences Ca2+ homeostasis, Abeta levels, and Alzheimer’s disease risk. Cell 133(7):1149–1161. doi: 10.1016/j.cell.2008.05.048 PubMedCentralPubMedGoogle Scholar
  170. 170.
    Bezprozvanny I, Mattson MP (2008) Neuronal calcium mishandling and the pathogenesis of Alzheimer’s disease. Trends Neurosci 31(9):454–463. doi: 10.1016/j.tins.2008.06.005 PubMedCentralPubMedGoogle Scholar
  171. 171.
    Green KN, LaFerla FM (2008) Linking calcium to Abeta and Alzheimer’s disease. Neuron 59(2):190–194. doi: 10.1016/j.neuron.2008.07.013 PubMedGoogle Scholar
  172. 172.
    Berridge MJ (2010) Calcium hypothesis of Alzheimer’s disease. Pflugers Arch 459(3):441–449. doi: 10.1007/s00424-009-0736-1 PubMedGoogle Scholar
  173. 173.
    Lopez JR, Lyckman A, Oddo S, Laferla FM, Querfurth HW, Shtifman A (2008) Increased intraneuronal resting [Ca2+] in adult Alzheimer’s disease mice. J Neurochem 105(1):262–271. doi: 10.1111/j.1471-4159.2007.05135.x PubMedGoogle Scholar
  174. 174.
    Kuchibhotla KV, Goldman ST, Lattarulo CR, Wu HY, Hyman BT, Bacskai BJ (2008) Abeta plaques lead to aberrant regulation of calcium homeostasis in vivo resulting in structural and functional disruption of neuronal networks. Neuron 59(2):214–225. doi: 10.1016/j.neuron.2008.06.008 PubMedCentralPubMedGoogle Scholar
  175. 175.
    Lauren J, Gimbel DA, Nygaard HB, Gilbert JW, Strittmatter SM (2009) Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers. Nature 457(7233):1128–1132. doi: 10.1038/nature07761 PubMedCentralPubMedGoogle Scholar
  176. 176.
    Mattson MP, Cheng B, Davis D, Bryant K, Lieberburg I, Rydel RE (1992) beta-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity. J Neurosci 12(2):376–389PubMedGoogle Scholar
  177. 177.
    Kawahara M, Kuroda Y (2000) Molecular mechanism of neurodegeneration induced by Alzheimer’s beta-amyloid protein: channel formation and disruption of calcium homeostasis. Brain Res Bull 53(4):389–397PubMedGoogle Scholar
  178. 178.
    Kagan BL, Hirakura Y, Azimov R, Azimova R, Lin MC (2002) The channel hypothesis of Alzheimer’s disease: current status. Peptides 23(7):1311–1315PubMedGoogle Scholar
  179. 179.
    Price SA, Held B, Pearson HA (1998) Amyloid beta protein increases Ca2+ currents in rat cerebellar granule neurones. NeuroReport 9(3):539–545PubMedGoogle Scholar
  180. 180.
    Tu H, Nelson O, Bezprozvanny A, Wang Z, Lee SF, Hao YH, Serneels L, De Strooper B, Yu G, Bezprozvanny I (2006) Presenilins form ER Ca2+ leak channels, a function disrupted by familial Alzheimer’s disease-linked mutations. Cell 126(5):981–993. doi: 10.1016/j.cell.2006.06.059 PubMedCentralPubMedGoogle Scholar
  181. 181.
    Stutzmann GE, Smith I, Caccamo A, Oddo S, Laferla FM, Parker I (2006) Enhanced ryanodine receptor recruitment contributes to Ca2+ disruptions in young, adult, and aged Alzheimer’s disease mice. J Neurosci 26(19):5180–5189. doi: 10.1523/JNEUROSCI.0739-06.2006 PubMedGoogle Scholar
  182. 182.
    Cheung KH, Shineman D, Muller M, Cardenas C, Mei L, Yang J, Tomita T, Iwatsubo T, Lee VM, Foskett JK (2008) Mechanism of Ca2+ disruption in Alzheimer’s disease by presenilin regulation of InsP3 receptor channel gating. Neuron 58(6):871–883. doi: 10.1016/j.neuron.2008.04.015 PubMedCentralPubMedGoogle Scholar
  183. 183.
    Brunello L, Zampese E, Florean C, Pozzan T, Pizzo P, Fasolato C (2009) Presenilin-2 dampens intracellular Ca2+ stores by increasing Ca2+ leakage and reducing Ca2+ uptake. J Cell Mol Med 13(9B):3358–3369. doi: 10.1111/j.1582-4934.2009.00755.x PubMedGoogle Scholar
  184. 184.
    Green KN, Demuro A, Akbari Y, Hitt BD, Smith IF, Parker I, LaFerla FM (2008) SERCA pump activity is physiologically regulated by presenilin and regulates amyloid beta production. J Cell Biol 181(7):1107–1116. doi: 10.1083/jcb.200706171 PubMedCentralPubMedGoogle Scholar
  185. 185.
    Zampese E, Fasolato C, Kipanyula MJ, Bortolozzi M, Pozzan T, Pizzo P (2011) Presenilin 2 modulates endoplasmic reticulum (ER)-mitochondria interactions and Ca2+ cross-talk. Proc Natl Acad Sci USA 108(7):2777–2782. doi: 10.1073/pnas.1100735108 PubMedCentralPubMedGoogle Scholar
  186. 186.
    Leissring MA, Parker I, LaFerla FM (1999) Presenilin-2 mutations modulate amplitude and kinetics of inositol 1,4,5-trisphosphate-mediated calcium signals. J Biol Chem 274(46):32535–32538PubMedGoogle Scholar
  187. 187.
    Guo Q, Furukawa K, Sopher BL, Pham DG, Xie J, Robinson N, Martin GM, Mattson MP (1996) Alzheimer’s PS-1 mutation perturbs calcium homeostasis and sensitizes PC12 cells to death induced by amyloid beta-peptide. NeuroReport 8(1):379–383PubMedGoogle Scholar
  188. 188.
    Chan SL, Mayne M, Holden CP, Geiger JD, Mattson MP (2000) Presenilin-1 mutations increase levels of ryanodine receptors and calcium release in PC12 cells and cortical neurons. J Biol Chem 275(24):18195–18200. doi: 10.1074/jbc.M000040200 PubMedGoogle Scholar
  189. 189.
    Lee SY, Hwang DY, Kim YK, Lee JW, Shin IC, Oh KW, Lee MK, Lim JS, Yoon DY, Hwang SJ, Hong JT (2006) PS2 mutation increases neuronal cell vulnerability to neurotoxicants through activation of caspase-3 by enhancing of ryanodine receptor-mediated calcium release. FASEB J 20(1):151–153. doi: 10.1096/fj.05-4017fje;1 PubMedGoogle Scholar
  190. 190.
    Smith IF, Green KN, LaFerla FM (2005) Calcium dysregulation in Alzheimer’s disease: recent advances gained from genetically modified animals. Cell Calcium 38(3–4):427–437. doi: 10.1016/j.ceca.2005.06.021 PubMedGoogle Scholar
  191. 191.
    Cheung KH, Mei L, Mak DO, Hayashi I, Iwatsubo T, Kang DE, Foskett JK (2010) Gain-of-function enhancement of IP3 receptor modal gating by familial Alzheimer’s disease-linked presenilin mutants in human cells and mouse neurons. Sci Signal 3(114):ra22. doi: 10.1126/scisignal.2000818 PubMedCentralPubMedGoogle Scholar
  192. 192.
    Smith IF, Hitt B, Green KN, Oddo S, LaFerla FM (2005) Enhanced caffeine-induced Ca2+ release in the 3xTg-AD mouse model of Alzheimer’s disease. J Neurochem 94(6):1711–1718. doi: 10.1111/j.1471-4159.2005.03332.x PubMedGoogle Scholar
  193. 193.
    Supnet C, Grant J, Kong H, Westaway D, Mayne M (2006) Amyloid-beta-(1–42) increases ryanodine receptor-3 expression and function in neurons of TgCRND8 mice. J Biol Chem 281(50):38440–38447. doi: 10.1074/jbc.M606736200 PubMedGoogle Scholar
  194. 194.
    Chakroborty S, Briggs C, Miller MB, Goussakov I, Schneider C, Kim J, Wicks J, Richardson JC, Conklin V, Cameransi BG, Stutzmann GE (2012) Stabilizing ER Ca2+ channel function as an early preventative strategy for Alzheimer’s disease. PLoS One 7(12):e52056. doi: 10.1371/journal.pone.0052056 PubMedCentralPubMedGoogle Scholar
  195. 195.
    Giacomello M, Barbiero L, Zatti G, Squitti R, Binetti G, Pozzan T, Fasolato C, Ghidoni R, Pizzo P (2005) Reduction of Ca2+ stores and capacitative Ca2+ entry is associated with the familial Alzheimer’s disease presenilin-2 T122R mutation and anticipates the onset of dementia. Neurobiol Dis 18(3):638–648. doi: 10.1016/j.nbd.2004.10.016 PubMedGoogle Scholar
  196. 196.
    Zatti G, Ghidoni R, Barbiero L, Binetti G, Pozzan T, Fasolato C, Pizzo P (2004) The presenilin 2 M239I mutation associated with familial Alzheimer’s disease reduces Ca2+ release from intracellular stores. Neurobiol Dis 15(2):269–278. doi: 10.1016/j.nbd.2003.11.002 PubMedGoogle Scholar
  197. 197.
    Zatti G, Burgo A, Giacomello M, Barbiero L, Ghidoni R, Sinigaglia G, Florean C, Bagnoli S, Binetti G, Sorbi S, Pizzo P, Fasolato C (2006) Presenilin mutations linked to familial Alzheimer’s disease reduce endoplasmic reticulum and Golgi apparatus calcium levels. Cell Calcium 39(6):539–550. doi: 10.1016/j.ceca.2006.03.002 PubMedGoogle Scholar
  198. 198.
    Hedskog L, Pinho CM, Filadi R, Ronnback A, Hertwig L, Wiehager B, Larssen P, Gellhaar S, Sandebring A, Westerlund M, Graff C, Winblad B, Galter D, Behbahani H, Pizzo P, Glaser E, Ankarcrona M (2013) Modulation of the endoplasmic reticulum–mitochondria interface in Alzheimer’s disease and related models. Proc Natl Acad Sci USA 110(19):7916–7921. doi: 10.1073/pnas.1300677110 PubMedCentralPubMedGoogle Scholar
  199. 199.
    Dauer W, Przedborski S (2003) Parkinson’s disease: mechanisms and models. Neuron 39(6):889–909PubMedGoogle Scholar
  200. 200.
    de Lau LM, Breteler MM (2006) Epidemiology of Parkinson’s disease. Lancet Neurol 5(6):525–535. doi: 10.1016/S1474-4422(06)70471-9 PubMedGoogle Scholar
  201. 201.
    Trinh J, Farrer M (2013) Advances in the genetics of Parkinson disease. Nat Rev Neurol 9(8):445–454. doi: 10.1038/nrneurol.2013.132 PubMedGoogle Scholar
  202. 202.
    Beal MF (2005) Mitochondria take center stage in aging and neurodegeneration. Ann Neurol 58(4):495–505. doi: 10.1002/ana.20624 PubMedGoogle Scholar
  203. 203.
    Vives-Bauza C, Przedborski S (2011) Mitophagy: the latest problem for Parkinson’s disease. Trends Mol Med 17(3):158–165. doi: 10.1016/j.molmed.2010.11.002 PubMedGoogle Scholar
  204. 204.
    Corti O, Brice A (2013) Mitochondrial quality control turns out to be the principal suspect in parkin and PINK1-related autosomal recessive Parkinson’s disease. Curr Opin Neurobiol 23(1):100–108. doi: 10.1016/j.conb.2012.11.002 PubMedGoogle Scholar
  205. 205.
    Exner N, Lutz AK, Haass C, Winklhofer KF (2012) Mitochondrial dysfunction in Parkinson’s disease: molecular mechanisms and pathophysiological consequences. EMBO J 31(14):3038–3062. doi: 10.1038/emboj.2012.170 PubMedCentralPubMedGoogle Scholar
  206. 206.
    McCoy MK, Cookson MR (2012) Mitochondrial quality control and dynamics in Parkinson’s disease. Antioxid Redox Signal 16(9):869–882. doi: 10.1089/ars.2011.4074;  10.1089/ars.2011.4019
  207. 207.
    Damier P, Hirsch EC, Agid Y, Graybiel AM (1999) The substantia nigra of the human brain. I. Nigrosomes and the nigral matrix, a compartmental organization based on calbindin D(28K) immunohistochemistry. Brain 122(Pt 8):1421–1436PubMedGoogle Scholar
  208. 208.
    German DC, Manaye KF, Sonsalla PK, Brooks BA (1992) Midbrain dopaminergic cell loss in Parkinson’s disease and MPTP-induced parkinsonism: sparing of calbindin-D28k-containing cells. Ann N Y Acad Sci 648:42–62PubMedGoogle Scholar
  209. 209.
    Nedergaard S, Flatman JA, Engberg I (1993) Nifedipine- and omega-conotoxin-sensitive Ca2+ conductances in guinea-pig substantia nigra pars compacta neurones. J Physiol 466:727–747PubMedCentralPubMedGoogle Scholar
  210. 210.
    Mosharov EV, Larsen KE, Kanter E, Phillips KA, Wilson K, Schmitz Y, Krantz DE, Kobayashi K, Edwards RH, Sulzer D (2009) Interplay between cytosolic dopamine, calcium, and alpha-synuclein causes selective death of substantia nigra neurons. Neuron 62(2):218–229. doi: 10.1016/j.neuron.2009.01.033 PubMedCentralPubMedGoogle Scholar
  211. 211.
    Guzman JN, Sanchez-Padilla J, Wokosin D, Kondapalli J, Ilijic E, Schumacker PT, Surmeier DJ (2010) Oxidant stress evoked by pacemaking in dopaminergic neurons is attenuated by DJ-1. Nature 468(7324):696–700. doi: 10.1038/nature09536 PubMedGoogle Scholar
  212. 212.
    Surmeier DJ, Schumacker PT (2013) Calcium, bioenergetics, and neuronal vulnerability in Parkinson’s disease. J Biol Chem 288(15):10736–10741. doi: 10.1074/jbc.R112.410530 PubMedCentralPubMedGoogle Scholar
  213. 213.
    Ottolini D, Cali T, Negro A, Brini M (2013) The Parkinson disease-related protein DJ-1 counteracts mitochondrial impairment induced by the tumour suppressor protein p53 by enhancing endoplasmic reticulum–mitochondria tethering. Hum Mol Genet 22(11):2152–2168. doi: 10.1093/hmg/ddt068 PubMedGoogle Scholar
  214. 214.
    Cali T, Ottolini D, Negro A, Brini M (2013) Enhanced parkin levels favor ER-mitochondria crosstalk and guarantee Ca(2+) transfer to sustain cell bioenergetics. Biochim Biophys Acta 1832(4):495–508. doi: 10.1016/j.bbadis.2013.01.004 PubMedGoogle Scholar
  215. 215.
    Cali T, Ottolini D, Negro A, Brini M (2012) alpha-Synuclein controls mitochondrial calcium homeostasis by enhancing endoplasmic reticulum-mitochondria interactions. J Biol Chem 287(22):17914–17929. doi: 10.1074/jbc.M111.302794 PubMedCentralPubMedGoogle Scholar
  216. 216.
    Melachroinou K, Xilouri M, Emmanouilidou E, Masgrau R, Papazafiri P, Stefanis L, Vekrellis K (2013) Deregulation of calcium homeostasis mediates secreted alpha-synuclein-induced neurotoxicity. Neurobiol Aging. doi: 10.1016/j.neurobiolaging.2013.06.006 PubMedGoogle Scholar
  217. 217.
    Hettiarachchi NT, Parker A, Dallas ML, Pennington K, Hung CC, Pearson HA, Boyle JP, Robinson P, Peers C (2009) alpha-Synuclein modulation of Ca2+ signaling in human neuroblastoma (SH-SY5Y) cells. J Neurochem 111(5):1192–1201. doi: 10.1111/j.1471-4159.2009.06411.x PubMedGoogle Scholar
  218. 218.
    Furukawa K, Matsuzaki-Kobayashi M, Hasegawa T, Kikuchi A, Sugeno N, Itoyama Y, Wang Y, Yao PJ, Bushlin I, Takeda A (2006) Plasma membrane ion permeability induced by mutant alpha-synuclein contributes to the degeneration of neural cells. J Neurochem 97(4):1071–1077. doi: 10.1111/j.1471-4159.2006.03803.x PubMedGoogle Scholar
  219. 219.
    Marongiu R, Spencer B, Crews L, Adame A, Patrick C, Trejo M, Dallapiccola B, Valente EM, Masliah E (2009) Mutant Pink1 induces mitochondrial dysfunction in a neuronal cell model of Parkinson’s disease by disturbing calcium flux. J Neurochem 108(6):1561–1574. doi: 10.1111/j.1471-4159.2009.05932.x PubMedCentralPubMedGoogle Scholar
  220. 220.
    Gandhi S, Wood-Kaczmar A, Yao Z, Plun-Favreau H, Deas E, Klupsch K, Downward J, Latchman DS, Tabrizi SJ, Wood NW, Duchen MR, Abramov AY (2009) PINK1-associated Parkinson’s disease is caused by neuronal vulnerability to calcium-induced cell death. Mol Cell 33(5):627–638. doi: 10.1016/j.molcel.2009.02.013 PubMedCentralPubMedGoogle Scholar
  221. 221.
    Gautier CA, Giaime E, Caballero E, Nunez L, Song Z, Chan D, Villalobos C, Shen J (2012) Regulation of mitochondrial permeability transition pore by PINK1. Mol Neurodegener 7:22. doi: 10.1186/1750-1326-7-22 PubMedGoogle Scholar
  222. 222.
    Heeman B, Van den Haute C, Aelvoet SA, Valsecchi F, Rodenburg RJ, Reumers V, Debyser Z, Callewaert G, Koopman WJ, Willems PH, Baekelandt V (2011) Depletion of PINK1 affects mitochondrial metabolism, calcium homeostasis and energy maintenance. J Cell Sci 124(Pt 7):1115–1125. doi: 10.1242/jcs.078303 PubMedGoogle Scholar
  223. 223.
    Airaksinen MS, Eilers J, Garaschuk O, Thoenen H, Konnerth A, Meyer M (1997) Ataxia and altered dendritic calcium signaling in mice carrying a targeted null mutation of the calbindin D28k gene. Proc Natl Acad Sci USA 94(4):1488–1493PubMedCentralPubMedGoogle Scholar
  224. 224.
    Lledo PM, Somasundaram B, Morton AJ, Emson PC, Mason WT (1992) Stable transfection of calbindin-D28k into the GH3 cell line alters calcium currents and intracellular calcium homeostasis. Neuron 9(5):943–954PubMedGoogle Scholar
  225. 225.
    Chard PS, Bleakman D, Christakos S, Fullmer CS, Miller RJ (1993) Calcium buffering properties of calbindin D28k and parvalbumin in rat sensory neurones. J Physiol 472:341–357PubMedCentralPubMedGoogle Scholar
  226. 226.
    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 knockin mice develop a progressive neuronal dysfunction with age-dependent accumulation of mutant CaV2.1 channels. Proc Natl Acad Sci USA 105(33):11987–11992. doi: 10.1073/pnas.0804350105 PubMedCentralPubMedGoogle Scholar
  227. 227.
    Chen X, Tang TS, Tu H, Nelson O, Pook M, Hammer R, Nukina N, Bezprozvanny I (2008) Deranged calcium signaling and neurodegeneration in spinocerebellar ataxia type 3. J Neurosci 28(48):12713–12724. doi: 10.1523/JNEUROSCI.3909-08.2008 PubMedCentralPubMedGoogle Scholar
  228. 228.
    Liu J, Tang TS, Tu H, Nelson O, Herndon E, Huynh DP, Pulst SM, Bezprozvanny I (2009) Deranged calcium signaling and neurodegeneration in spinocerebellar ataxia type 2. J Neurosci 29(29):9148–9162. doi: 10.1523/JNEUROSCI.0660-09.2009 PubMedCentralPubMedGoogle Scholar
  229. 229.
    Giacomello M, De Mario A, Primerano S, Brini M, Carafoli E (2012) Hair cells, plasma membrane Ca(2)(+) ATPase and deafness. Int J Biochem Cell Biol 44(5):679–683. doi: 10.1016/j.biocel.2012.02.006 PubMedGoogle Scholar
  230. 230.
    Empson RM, Turner PR, Nagaraja RY, Beesley PW, Knopfel T (2010) Reduced expression of the Ca(2+) transporter protein PMCA2 slows Ca(2+) dynamics in mouse cerebellar Purkinje neurones and alters the precision of motor coordination. J Physiol 588(Pt 6):907–922. doi: 10.1113/jphysiol.2009.182196 PubMedCentralPubMedGoogle Scholar
  231. 231.
    Empson RM, Akemann W, Knopfel T (2010) The role of the calcium transporter protein plasma membrane calcium ATPase PMCA2 in cerebellar Purkinje neuron function. Funct Neurol 25(3):153–158PubMedGoogle Scholar
  232. 232.
    Fierro L, DiPolo R, Llano I (1998) Intracellular calcium clearance in Purkinje cell somata from rat cerebellar slices. J Physiol 510(Pt 2):499–512PubMedCentralPubMedGoogle Scholar
  233. 233.
    Hartmann J, Konnerth A (2005) Determinants of postsynaptic Ca2+ signaling in Purkinje neurons. Cell Calcium 37(5):459–466. doi: 10.1016/j.ceca.2005.01.014 PubMedGoogle Scholar
  234. 234.
    Zhao S, Chen N, Yang Z, Huang L, Zhu Y, Guan S, Chen Q, Wang JH (2008) Ischemia deteriorates the spike encoding of rat cerebellar Purkinje cells by raising intracellular Ca2+. Biochem Biophys Res Commun 366(2):401–407. doi: 10.1016/j.bbrc.2007.11.173 PubMedGoogle Scholar
  235. 235.
    Filoteo AG, Elwess NL, Enyedi A, Caride A, Aung HH, Penniston JT (1997) Plasma membrane Ca2+ pump in rat brain. Patterns of alternative splices seen by isoform-specific antibodies. J Biol Chem 272(38):23741–23747PubMedGoogle Scholar
  236. 236.
    Pietrobon D, Moskowitz MA (2013) Pathophysiology of migraine. Annu Rev Physiol 75:365–391. doi: 10.1146/annurev-physiol-030212-183717 PubMedGoogle Scholar
  237. 237.
    de Vries B, Frants RR, Ferrari MD, van den Maagdenberg AM (2009) Molecular genetics of migraine. Hum Genet 126(1):115–132. doi: 10.1007/s00439-009-0684-z PubMedGoogle Scholar
  238. 238.
    Ophoff RA, Terwindt GM, Vergouwe MN, van Eijk R, Oefner PJ, Hoffman SM, Lamerdin JE, Mohrenweiser HW, Bulman DE, Ferrari M, Haan J, Lindhout D, van Ommen GJ, 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(3):543–552PubMedGoogle Scholar
  239. 239.
    Pietrobon D (2013) Calcium channels and migraine. Biochim Biophys Acta 1828(7):1655–1665. doi: 10.1016/j.bbamem.2012.11.012 PubMedGoogle Scholar
  240. 240.
    De Fusco M, Marconi R, Silvestri L, Atorino L, Rampoldi L, Morgante L, Ballabio A, Aridon P, Casari G (2003) Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump alpha2 subunit associated with familial hemiplegic migraine type 2. Nat Genet 33(2):192–196. doi: 10.1038/ng1081 PubMedGoogle Scholar
  241. 241.
    Rose EM, Koo JC, Antflick JE, Ahmed SM, Angers S, Hampson DR (2009) Glutamate transporter coupling to Na, K-ATPase. J Neurosci 29(25):8143–8155. doi: 10.1523/JNEUROSCI.1081-09.2009 PubMedGoogle Scholar
  242. 242.
    Tavraz NN, Friedrich T, Durr KL, Koenderink JB, Bamberg E, Freilinger T, Dichgans M (2008) Diverse functional consequences of mutations in the Na+/K+-ATPase alpha2-subunit causing familial hemiplegic migraine type 2. J Biol Chem 283(45):31097–31106. doi: 10.1074/jbc.M802771200 PubMedCentralPubMedGoogle Scholar
  243. 243.
    Tavraz NN, Durr KL, Koenderink JB, Freilinger T, Bamberg E, Dichgans M, Friedrich T (2009) Impaired plasma membrane targeting or protein stability by certain ATP1A2 mutations identified in sporadic or familial hemiplegic migraine. Channels (Austin) 3(2):82–87Google Scholar
  244. 244.
    Dichgans M, Freilinger T, Eckstein G, Babini E, Lorenz-Depiereux B, Biskup S, Ferrari MD, Herzog J, van den Maagdenberg AM, Pusch M, Strom TM (2005) Mutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine. Lancet 366(9483):371–377. doi: 10.1016/S0140-6736(05)66786-4 PubMedGoogle Scholar
  245. 245.
    Catterall WA, Kalume F, Oakley JC (2010) NaV1.1 channels and epilepsy. J Physiol 588(Pt 11):1849–1859. doi: 10.1113/jphysiol.2010.187484 PubMedCentralPubMedGoogle Scholar
  246. 246.
    Cestele S, Scalmani P, Rusconi R, Terragni B, Franceschetti S, Mantegazza M (2008) Self-limited hyperexcitability: functional effect of a familial hemiplegic migraine mutation of the Nav1.1 (SCN1A) Na+ channel. J Neurosci 28(29):7273–7283. doi: 10.1523/JNEUROSCI.4453-07.2008 PubMedCentralPubMedGoogle Scholar
  247. 247.
    Kahlig KM, Rhodes TH, Pusch M, Freilinger T, Pereira-Monteiro JM, Ferrari MD, van den Maagdenberg AM, Dichgans M, George AL Jr (2008) Divergent sodium channel defects in familial hemiplegic migraine. Proc Natl Acad Sci USA 105(28):9799–9804. doi: 10.1073/pnas.0711717105 PubMedCentralPubMedGoogle Scholar

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© Springer Basel 2014

Authors and Affiliations

  1. 1.Department of BiologyUniversity of PadovaPaduaItaly
  2. 2.Venetian Institute for Molecular Medicine (VIMM)PaduaItaly

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