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Trafficking and stability of voltage-gated calcium channels

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Abstract

Voltage-gated calcium channels are important mediators of calcium influx into electrically excitable cells. The amount of calcium entering through this family of channel proteins is not only determined by the functional properties of channels embedded in the plasma membrane but also by the numbers of channels that are expressed at the cell surface. The trafficking of channels is controlled by numerous processes, including co-assembly with ancillary calcium channel subunits, ubiquitin ligases, and interactions with other membrane proteins such as G protein coupled receptors. Here we provide an overview about the current state of knowledge of calcium channel trafficking to the cell membrane, and of the mechanisms regulating the stability and internalization of this important ion channel family.

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References

  1. Wheeler DB, Randall A, Tsien RW (1994) Roles of N-type and Q-type Ca2+ channels in supporting hippocampal synaptic transmission. Science 264(5155):107–111

    PubMed  CAS  Google Scholar 

  2. Dolmetsch RE et al (2001) Signalling to the nucleus by an L-type calcium channel-calmodulin complex through the MAP kinase pathway. Science 294(5541):333–339

    PubMed  CAS  Google Scholar 

  3. Tully K, Treistman SN (2004) Distinct intracellular calcium profiles following influx through N- versus L-type calcium channels: role of Ca2+-induced Ca2+ release. J Neurophysiol 92(1):135–143

    PubMed  CAS  Google Scholar 

  4. Goonasekera SA, Chen SR, Dirksen RT (2005) Reconstitution of local Ca2+ signalling between cardiac L-type Ca2+ channels and ryanodine receptors: insights into regulation by FKBP12.6. Am J Physiol Cell Physiol 289(6):C1476–C1484

    PubMed  CAS  Google Scholar 

  5. Seisenberger C et al (2000) Functional embryonic cardiomyocytes after disruption of the L-type alpha1C (Cav1.2) calcium channel gene in the mouse. J Biol Chem 275(50):39193–39199

    PubMed  CAS  Google Scholar 

  6. Cooper PJ, Soeller C, Cannell MB (2010) Excitation-contraction coupling in human heart failure examined by action potential clamp in rat cardiac myocytes. J Mol Cell Cardiol 49(6):911–917

    PubMed  CAS  Google Scholar 

  7. Wheeler DG et al (2008) CaMKII locally encodes L-type channel activity to signal to nuclear CREB in excitation-transcription coupling. J Cell Biol 183(5):849–863

    PubMed  CAS  Google Scholar 

  8. Comunanza V et al (2010) CaV1.3 as pacemaker channels in adrenal chromaffin cells: specific role on exo- and endocytosis? Channels (Austin) 4(6):440–446

    CAS  Google Scholar 

  9. Catterall WA (2011) Voltage-gated calcium channels. Cold Spring Harb Perspect Biol 3(8)

  10. Szydlowska K, Tymianski M (2010) Calcium, ischemia and excitotoxicity. Cell Calcium 47(2):122–129

    PubMed  CAS  Google Scholar 

  11. Bean BP (1989) Classes of calcium channels in vertebrate cells. Annu Rev Physiol 51:367–384

    PubMed  CAS  Google Scholar 

  12. Tsien RW et al (1988) Multiple types of neuronal calcium channels and their selective modulation. Trends Neurosci 11(10):431–438

    PubMed  CAS  Google Scholar 

  13. Catterall WA et al (2005) International Union of Pharmacology. XLVIII. Nomenclature and structure-function relationships of voltage-gated calcium channels. Pharmacol Rev 57(4):411–425

    PubMed  CAS  Google Scholar 

  14. Takahashi M et al (1987) Subunit structure of dihydropyridine-sensitive calcium channels from skeletal muscle. Proc Natl Acad Sci U S A 84(15):5478–5482

    PubMed  CAS  Google Scholar 

  15. Ahlijanian MK, Westenbroek RE, Catterall WA (1990) Subunit structure and localization of dihydropyridine-sensitive calcium channels in mammalian brain, spinal cord, and retina. Neuron 4(6):819–832

    PubMed  CAS  Google Scholar 

  16. Witcher DR et al (1993) Subunit identification and reconstitution of the N-type Ca2+ channel complex purified from brain. Science 261(5120):486–489

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  18. Minor DL Jr, Findeisen F (2010) Progress in the structural understanding of voltage-gated calcium channel (CaV) function and modulation. Channels (Austin) 4(6):459–474

    Google Scholar 

  19. Catterall WA (2010) Ion channel voltage sensors: structure, function, and pathophysiology. Neuron 67(6):915–928

    PubMed  CAS  Google Scholar 

  20. Stotz SC, Jarvis SE, Zamponi GW (2004) Functional roles of cytoplasmic loops and pore lining transmembrane helices in the voltage-dependent inactivation of HVA calcium channels. J Physiol 554(Pt 2):263–273

    PubMed  CAS  Google Scholar 

  21. Yang J et al (1993) Molecular determinants of Ca2+ selectivity and ion permeation in L-type Ca2+ channels. Nature 366(6451):158–161

    PubMed  CAS  Google Scholar 

  22. Stea A et al (1993) A beta-subunit normalizes the electrophysiological properties of a cloned N-type Ca2+ channel alpha 1-subunit. Neuropharmacology 32(11):1103–1116

    PubMed  CAS  Google Scholar 

  23. Qin N et al (1998) Unique regulatory properties of the type 2a Ca2+ channel beta subunit caused by palmitoylation. Proc Natl Acad Sci U S A 95(8):4690–4695

    PubMed  CAS  Google Scholar 

  24. Feng ZP et al (2001) Calcium channel beta subunits differentially regulate the inhibition of N-type channels by individual Gbeta isoforms. J Biol Chem 276(48):45051–45058

    PubMed  CAS  Google Scholar 

  25. Zhang Y et al (2008) Origin of the voltage dependence of G-protein regulation of P/Q-type Ca2+ channels. J Neurosci 28(52):14176–14188

    PubMed  CAS  Google Scholar 

  26. Buraei Z, Yang J (2010) The Beta subunit of voltage-gated Ca2+ channels. Physiol Rev 90(4):1461–1506

    PubMed  CAS  Google Scholar 

  27. Richards MW, Butcher AJ, Dolphin AC (2004) Ca2+ channel beta-subunits: structural insights AID our understanding. Trends Pharmacol Sci 25(12):626–632

    PubMed  CAS  Google Scholar 

  28. Pragnell M et al (1994) Calcium channel beta-subunit binds to a conserved motif in the I–II cytoplasmic linker of the alpha 1-subunit. Nature 368(6466):67–70

    PubMed  CAS  Google Scholar 

  29. De Waard M et al (1995) Properties of the alpha 1-beta anchoring site in voltage-dependent Ca2+ channels. J Biol Chem 270(20):12056–12064

    PubMed  Google Scholar 

  30. Opatowsky Y et al (2004) Structural analysis of the voltage-dependent calcium channel beta subunit functional core and its complex with the alpha 1 interaction domain. Neuron 42(3):387–399

    PubMed  CAS  Google Scholar 

  31. Van Petegem F et al (2004) Structure of a complex between a voltage-gated calcium channel beta-subunit and an alpha-subunit domain. Nature 429(6992):671–675

    PubMed  Google Scholar 

  32. Maltez JM et al (2005) Essential Ca(V)beta modulatory properties are AID-independent. Nat Struct Mol Biol 12(4):372–377

    PubMed  CAS  Google Scholar 

  33. McGee AW et al (2004) Calcium channel function regulated by the SH3-GK module in beta subunits. Neuron 42(1):89–99

    PubMed  CAS  Google Scholar 

  34. Takahashi SX, Miriyala J, Colecraft HM (2004) Membrane-associated guanylate kinase-like properties of beta-subunits required for modulation of voltage-dependent Ca2+ channels. Proc Natl Acad Sci USA 101(18):7193–7198

    PubMed  CAS  Google Scholar 

  35. Chien AJ et al (1996) Identification of palmitoylation sites within the L-type calcium channel beta2a subunit and effects on channel function. J Biol Chem 271(43):26465–26468

    PubMed  CAS  Google Scholar 

  36. Klugbauer N, Marais E, Hofmann F (2003) Calcium channel alpha2delta subunits: differential expression, function, and drug binding. J Bioenerg Biomembr 35(6):639–647

    PubMed  CAS  Google Scholar 

  37. Davies A et al (2010) The alpha2delta subunits of voltage-gated calcium channels form GPI-anchored proteins, a posttranslational modification essential for function. Proc Natl Acad Sci USA 107(4):1654–1659

    PubMed  CAS  Google Scholar 

  38. Bauer CS et al (2010) A new look at calcium channel alpha2delta subunits. Curr Opin Neurobiol 20(5):563–571

    PubMed  CAS  Google Scholar 

  39. Robinson P et al (2011) Targeting of voltage-gated calcium channel alpha2delta-1 subunit to lipid rafts is independent from a GPI-anchoring motif. PLoS One 6(6):e19802

    PubMed  CAS  Google Scholar 

  40. Bourinet E et al (1999) Splicing of alpha 1A subunit gene generates phenotypic variants of P- and Q-type calcium channels. Nat Neurosci 2(5):407–415

    PubMed  CAS  Google Scholar 

  41. Chemin J et al (2001) Alternatively spliced alpha(1G) (Ca(V)3.1) intracellular loops promote specific T-type Ca(2+) channel gating properties. Biophys J 80(3):1238–1250

    PubMed  CAS  Google Scholar 

  42. Tang ZZ et al (2004) Transcript scanning reveals novel and extensive splice variations in human l-type voltage-gated calcium channel, Cav1.2 alpha1 subunit. J Biol Chem 279(43):44335–44343

    PubMed  CAS  Google Scholar 

  43. Takahashi SX, Mittman S, Colecraft HM (2003) Distinctive modulatory effects of five human auxiliary beta2 subunit splice variants on L-type calcium channel gating. Biophys J 84(5):3007–3021

    PubMed  CAS  Google Scholar 

  44. Gray AC, Raingo J, Lipscombe D (2007) Neuronal calcium channels: splicing for optimal performance. Cell Calcium 42(4–5):409–417

    PubMed  CAS  Google Scholar 

  45. Allen SE, Darnell RB, Lipscombe D (2010) The neuronal splicing factor Nova controls alternative splicing in N-type and P-type CaV2 calcium channels. Channels (Austin) 4(6):483–489

    CAS  Google Scholar 

  46. Liao P, Zhang HY, Soong TW (2009) Alternative splicing of voltage-gated calcium channels: from molecular biology to disease. Pflugers Arch 458(3):481–487

    PubMed  CAS  Google Scholar 

  47. Perez-Reyes E (2003) Molecular physiology of low-voltage-activated t-type calcium channels. Physiol Rev 83(1):117–161

    PubMed  CAS  Google Scholar 

  48. Perez-Reyes E et al (1998) Molecular characterization of a neuronal low-voltage-activated T-type calcium channel. Nature 391(6670):896–900

    PubMed  CAS  Google Scholar 

  49. Berrow NS et al (1995) Antisense depletion of beta-subunits modulates the biophysical and pharmacological properties of neuronal calcium channels. J Physiol 482(Pt 3):481–491

    PubMed  CAS  Google Scholar 

  50. De Waard M, Pragnell M, Campbell KP (1994) Ca2+ channel regulation by a conserved beta subunit domain. Neuron 13(2):495–503

    PubMed  Google Scholar 

  51. Bichet D et al (2000) The I–II loop of the Ca2+ channel alpha1 subunit contains an endoplasmic reticulum retention signal antagonized by the beta subunit. Neuron 25(1):177–190

    PubMed  CAS  Google Scholar 

  52. Obermair GJ et al (2010) Reciprocal interactions regulate targeting of calcium channel beta subunits and membrane expression of alpha1 subunits in cultured hippocampal neurons. J Biol Chem 285(8):5776–5791

    PubMed  CAS  Google Scholar 

  53. Leroy J et al (2005) Interaction via a key tryptophan in the I-II linker of N-type calcium channels is required for beta1 but not for palmitoylated beta2, implicating an additional binding site in the regulation of channel voltage-dependent properties. J Neurosci 25(30):6984–6996

    PubMed  CAS  Google Scholar 

  54. Altier C et al (2011) The Cavbeta subunit prevents RFP2-mediated ubiquitination and proteasomal degradation of L-type channels. Nat Neurosci 14(2):173–180

    PubMed  CAS  Google Scholar 

  55. Fang K, Colecraft HM (2011) Mechanism of auxiliary β-subunit-mediated membrane targeting of L-type (Cav1.2) channels. J Physiol

  56. Ye Y et al (2004) A membrane protein complex mediates retro-translocation from the ER lumen into the cytosol. Nature 429(6994):841–847

    PubMed  CAS  Google Scholar 

  57. Romisch K (2005) Endoplasmic reticulum-associated degradation. Annu Rev Cell Dev Biol 21:435–456

    PubMed  CAS  Google Scholar 

  58. Waithe D et al (2011) Beta-subunits promote the expression of Ca(V)2.2 channels by reducing their proteasomal degradation. J Biol Chem 286(11):9598–9611

    PubMed  CAS  Google Scholar 

  59. Yasuda T et al (2004) Auxiliary subunit regulation of high-voltage activated calcium channels expressed in mammalian cells. Eur J Neurosci 20(1):1–13

    PubMed  Google Scholar 

  60. Gee NS et al (1996) The novel anticonvulsant drug, gabapentin (Neurontin), binds to the alpha2delta subunit of a calcium channel. J Biol Chem 271(10):5768–5776

    PubMed  CAS  Google Scholar 

  61. Taylor CP, Angelotti T, Fauman E (2007) Pharmacology and mechanism of action of pregabalin: the calcium channel alpha2-delta (alpha2-delta) subunit as a target for antiepileptic drug discovery. Epilepsy Res 73(2):137–150

    PubMed  CAS  Google Scholar 

  62. Field MJ, Li Z, Schwarz JB (2007) Ca2+ channel alpha2-delta ligands for the treatment of neuropathic pain. J Med Chem 50(11):2569–2575

    PubMed  CAS  Google Scholar 

  63. Moore RA et al (2011) Gabapentin for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev 16(3):CD007938

    Google Scholar 

  64. Mould J et al (2004) The alpha2delta auxiliary subunit reduces affinity of omega-conotoxins for recombinant N-type (Cav2.2) calcium channels. J Biol Chem 279(33):34705–34714

    PubMed  CAS  Google Scholar 

  65. Canti C et al (2005) The metal-ion-dependent adhesion site in the Von Willebrand factor-A domain of alpha2delta subunits is key to trafficking voltage-gated Ca2 + channels. Proc Natl Acad Sci USA 102(32):11230–11235

    PubMed  CAS  Google Scholar 

  66. Barclay J et al (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(16):6095–6104

    PubMed  CAS  Google Scholar 

  67. Fuller-Bicer GA et al (2009) Targeted disruption of the voltage-dependent calcium channel alpha2/delta-1-subunit. Am J Physiol Heart Circ Physiol 297(1):H117–H124

    PubMed  CAS  Google Scholar 

  68. Neely GG et al (2010) A genome-wide Drosophila screen for heat nociception identifies alpha2delta3 as an evolutionarily conserved pain gene. Cell 143(4):628–638

    PubMed  CAS  Google Scholar 

  69. Field MJ et al (2006) Identification of the alpha2-delta-1 subunit of voltage-dependent calcium channels as a molecular target for pain mediating the analgesic actions of pregabalin. Proc Natl Acad Sci USA 103(46):17537–17542

    PubMed  CAS  Google Scholar 

  70. Uchitel OD et al (2010) Acute modulation of calcium currents and synaptic transmission by gabapentinoids. Channels (Austin) 4(6):490–496

    CAS  Google Scholar 

  71. Hendrich J et al (2008) Pharmacological disruption of calcium channel trafficking by the alpha2delta ligand gabapentin. Proc Natl Acad Sci USA 105(9):3628–3633

    PubMed  CAS  Google Scholar 

  72. Bauer CS et al (2009) The increased trafficking of the calcium channel subunit alpha2delta-1 to presynaptic terminals in neuropathic pain is inhibited by the alpha2delta ligand pregabalin. J Neurosci 29(13):4076–4088

    PubMed  CAS  Google Scholar 

  73. Tran-Van-Minh A, Dolphin AC (2010) The alpha2delta ligand gabapentin inhibits the Rab11-dependent recycling of the calcium channel subunit alpha2delta-2. J Neurosci 30(38):12856–12867

    PubMed  CAS  Google Scholar 

  74. Obermair GJ et al (2005) The Ca2+ channel alpha2delta-1 subunit determines Ca2+ current kinetics in skeletal muscle but not targeting of alpha1S or excitation-contraction coupling. J Biol Chem 280(3):2229–2237

    PubMed  CAS  Google Scholar 

  75. Obermair GJ, Tuluc P, Flucher BE (2008) Auxiliary Ca(2+) channel subunits: lessons learned from muscle. Curr Opin Pharmacol 8(3):311–318

    PubMed  CAS  Google Scholar 

  76. Gach MP et al (2008) Alpha2delta1 dihydropyridine receptor subunit is a critical element for excitation-coupled calcium entry but not for formation of tetrads in skeletal myotubes. Biophys J 94(8):3023–3034

    PubMed  CAS  Google Scholar 

  77. Letts VA et al (1998) The mouse stargazer gene encodes a neuronal Ca2+-channel gamma subunit. Nat Genet 19(4):340–347

    PubMed  CAS  Google Scholar 

  78. Chen L et al (2000) Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms. Nature 408(6815):936–943

    PubMed  CAS  Google Scholar 

  79. Tomita S et al (2005) Stargazin modulates AMPA receptor gating and trafficking by distinct domains. Nature 435(7045):1052–1058

    PubMed  CAS  Google Scholar 

  80. Kato AS et al (2010) TARPs differentially decorate AMPA receptors to specify neuropharmacology. Trends Neurosci 33(5):241–248

    PubMed  CAS  Google Scholar 

  81. Korber C et al (2007) The transmembrane AMPA receptor regulatory protein gamma 4 is a more effective modulator of AMPA receptor function than stargazin (gamma 2). J Neurosci 27(31):8442–8447

    PubMed  Google Scholar 

  82. Waithe D, Ferron L, Dolphin AC (2011) Stargazin-related protein {gamma}7 is associated with signalling endosomes in superior cervical ganglion neurons and modulates neurite outgrowth. J Cell Sci 124(Pt 12):2049–2057

    PubMed  CAS  Google Scholar 

  83. Rousset M et al (2001) Functional roles of gamma2, gamma3 and gamma4, three new Ca2+ channel subunits, in P/Q-type Ca2+ channel expressed in Xenopus oocytes. J Physiol 532(Pt 3):583–593

    PubMed  CAS  Google Scholar 

  84. Tselnicker I et al (2010) Stargazin modulates neuronal voltage-dependent Ca(2+) channel Ca(v)2.2 by a Gbetagamma-dependent mechanism. J Biol Chem 285(27):20462–20471

    PubMed  CAS  Google Scholar 

  85. Tselnicker I, Dascal N (2010) Further characterization of regulation of Ca(V)2.2 by stargazin. Channels (Austin) 4(5):351–354

    CAS  Google Scholar 

  86. Moss FJ et al (2002) The novel product of a five-exon stargazin-related gene abolishes Ca(V)2.2 calcium channel expression. Embo J 21(7):1514–1523

    PubMed  CAS  Google Scholar 

  87. Hansen JP et al (2004) Calcium channel gamma6 subunits are unique modulators of low voltage-activated (Cav3.1) calcium current. J Mol Cell Cardiol 37(6):1147–1158

    PubMed  CAS  Google Scholar 

  88. Lin Z et al (2008) A critical GxxxA motif in the gamma6 calcium channel subunit mediates its inhibitory effect on Cav3.1 calcium current. J Physiol 586(Pt 22):5349–5366

    PubMed  CAS  Google Scholar 

  89. Chen RS, Best PM (2009) A small peptide inhibitor of the low voltage-activated calcium channel Cav3.1. Mol Pharmacol 75(5):1042–1051

    PubMed  CAS  Google Scholar 

  90. DeMaria CD et al (2001) Calmodulin bifurcates the local Ca2+ signal that modulates P/Q-type Ca2+ channels. Nature 411(6836):484–489

    PubMed  CAS  Google Scholar 

  91. Liang H et al (2003) Unified mechanisms of Ca2+ regulation across the Ca2+ channel family. Neuron 39(6):951–960

    PubMed  CAS  Google Scholar 

  92. Halling DB, Aracena-Parks P, Hamilton SL (2005) Regulation of voltage-gated Ca2+ channels by calmodulin. Sci STKE 2005(315):re15

    PubMed  Google Scholar 

  93. Black DJ et al (2005) Calmodulin interactions with IQ peptides from voltage-dependent calcium channels. Am J Physiol Cell Physiol 288(3):C669–C676

    PubMed  CAS  Google Scholar 

  94. Kim EY et al (2008) Structures of CaV2 Ca2+/CaM-IQ domain complexes reveal binding modes that underlie calcium-dependent inactivation and facilitation. Structure 16(10):1455–1467

    PubMed  CAS  Google Scholar 

  95. Tang W et al (2003) Apocalmodulin and Ca2+ calmodulin-binding sites on the CaV1.2 channel. Biophys J 85(3):1538–1547

    PubMed  CAS  Google Scholar 

  96. Erickson MG et al (2001) Preassociation of calmodulin with voltage-gated Ca(2+) channels revealed by FRET in single living cells. Neuron 31(6):973–985

    PubMed  CAS  Google Scholar 

  97. Stroffekova K (2008) Ca2+/CaM-dependent inactivation of the skeletal muscle L-type Ca2+ channel (Cav1.1). Pflugers Arch 455(5):873–884

    PubMed  CAS  Google Scholar 

  98. Bell DC et al (2001) Biophysical properties, pharmacology, and modulation of human, neuronal L-type (alpha(1D), Ca(V)1.3) voltage-dependent calcium currents. J Neurophysiol 85(2):816–827

    PubMed  CAS  Google Scholar 

  99. Hoda JC et al (2006) Effects of congenital stationary night blindness type 2 mutations R508Q and L1364H on Cav1.4 L-type Ca2+ channel function and expression. J Neurochem 96(6):1648–1658

    PubMed  CAS  Google Scholar 

  100. Peterson BZ et al (2000) Critical determinants of Ca(2+)-dependent inactivation within an EF-hand motif of L-type Ca(2+) channels. Biophys J 78(4):1906–1920

    PubMed  CAS  Google Scholar 

  101. Zuhlke RD et al (1999) Calmodulin supports both inactivation and facilitation of L-type calcium channels. Nature 399(6732):159–162

    PubMed  CAS  Google Scholar 

  102. Singh A et al (2006) C-terminal modulator controls Ca2+-dependent gating of Ca(v)1.4 L-type Ca2+ channels. Nat Neurosci 9(9):1108–1116

    PubMed  CAS  Google Scholar 

  103. Wahl-Schott C et al (2006) Switching off calcium-dependent inactivation in L-type calcium channels by an autoinhibitory domain. Proc Natl Acad Sci USA 103(42):15657–15662

    PubMed  CAS  Google Scholar 

  104. Griessmeier K et al (2009) Calmodulin is a functional regulator of Cav1.4 L-type Ca2+ channels. J Biol Chem 284(43):29809–29816

    PubMed  CAS  Google Scholar 

  105. Bourdin B et al (2010) Molecular determinants of the CaVbeta-induced plasma membrane targeting of the CaV1.2 channel. J Biol Chem 285(30):22853–22863

    PubMed  CAS  Google Scholar 

  106. Gao T et al (2000) Role of the C terminus of the alpha 1C (CaV1.2) subunit in membrane targeting of cardiac L-type calcium channels. J Biol Chem 275(33):25436–25444

    PubMed  CAS  Google Scholar 

  107. Ravindran A et al (2009) Functional properties of the CaV1.2 calcium channel activated by calmodulin in the absence of alpha2delta subunits. Channels (Austin) 3(1):25–31

    CAS  Google Scholar 

  108. Bernatchez G, Talwar D, Parent L (1998) Mutations in the EF-hand motif impair the inactivation of barium currents of the cardiac alpha1C channel. Biophys J 75(4):1727–1739

    PubMed  CAS  Google Scholar 

  109. Brunet S, Scheuer T, Catterall WA (2009) Cooperative regulation of Ca(v)1.2 channels by intracellular Mg(2+), the proximal C-terminal EF-hand, and the distal C-terminal domain. J Gen Physiol 134(2):81–94

    PubMed  CAS  Google Scholar 

  110. Brunet S et al (2005) Modulation of CaV1.2 channels by Mg2+ acting at an EF-hand motif in the COOH-terminal domain. J Gen Physiol 126(4):311–323

    PubMed  CAS  Google Scholar 

  111. Wang HG et al (2007) Ca2+/calmodulin regulates trafficking of Ca(V)1.2 Ca2+ channels in cultured hippocampal neurons. J Neurosci 27(34):9086–9093

    PubMed  CAS  Google Scholar 

  112. Fallon JL et al (2009) Crystal structure of dimeric cardiac L-type calcium channel regulatory domains bridged by Ca2+* calmodulins. Proc Natl Acad Sci USA 106(13):5135–5140

    PubMed  CAS  Google Scholar 

  113. Kim EY et al (2010) Multiple C-terminal tail Ca(2+)/CaMs regulate Ca(V)1.2 function but do not mediate channel dimerization. Embo J 29(23):3924–3938

    PubMed  CAS  Google Scholar 

  114. Benmocha A et al (2009) Characterization of the calmodulin-binding site in the N terminus of CaV1.2. Channels (Austin) 3(5):337–342

    CAS  Google Scholar 

  115. Dick IE et al (2008) A modular switch for spatial Ca2+ selectivity in the calmodulin regulation of CaV channels. Nature 451(7180):830–834

    PubMed  CAS  Google Scholar 

  116. Kobrinsky E et al (2005) Differential role of the alpha1C subunit tails in regulation of the Cav1.2 channel by membrane potential, beta subunits, and Ca2+ ions. J Biol Chem 280(13):12474–12485

    PubMed  CAS  Google Scholar 

  117. Leuranguer V et al (1998) Antisense depletion of beta-subunits fails to affect T-type calcium channels properties in a neuroblastoma cell line. Neuropharmacology 37(6):701–708

    PubMed  CAS  Google Scholar 

  118. Dubel SJ et al (2004) Plasma membrane expression of T-type calcium channel alpha(1) subunits is modulated by high voltage-activated auxiliary subunits. J Biol Chem 279(28):29263–29269

    PubMed  CAS  Google Scholar 

  119. Dolphin AC et al (1999) The effect of alpha2-delta and other accessory subunits on expression and properties of the calcium channel alpha1G. J Physiol 519(Pt 1):35–45

    PubMed  CAS  Google Scholar 

  120. Khosravani H, Zamponi GW (2006) Voltage-gated calcium channels and idiopathic generalized epilepsies. Physiol Rev 86(3):941–966

    PubMed  CAS  Google Scholar 

  121. Khosravani H et al (2004) Gating effects of mutations in the Cav3.2 T-type calcium channel associated with childhood absence epilepsy. J Biol Chem 279(11):9681–9684

    PubMed  CAS  Google Scholar 

  122. Peloquin JB et al (2006) Functional analysis of Ca3.2 T-type calcium channel mutations linked to childhood absence epilepsy. Epilepsia 47(3):655–658

    PubMed  Google Scholar 

  123. Heron SE et al (2007) Extended spectrum of idiopathic generalized epilepsies associated with CACNA1H functional variants. Ann Neurol 62(6):560–568

    PubMed  CAS  Google Scholar 

  124. Khosravani H et al (2005) Effects of Cav3.2 channel mutations linked to idiopathic generalized epilepsy. Ann Neurol 57(5):745–749

    PubMed  CAS  Google Scholar 

  125. Vitko I et al (2005) Functional characterization and neuronal modeling of the effects of childhood absence epilepsy variants of CACNA1H, a T-type calcium channel. J Neurosci 25(19):4844–4855

    PubMed  CAS  Google Scholar 

  126. Vitko I et al (2007) The I-II loop controls plasma membrane expression and gating of Ca(v)3.2 T-type Ca2 + channels: a paradigm for childhood absence epilepsy mutations. J Neurosci 27(2):322–330

    PubMed  CAS  Google Scholar 

  127. Shcheglovitov A et al (2008) Alternative splicing within the I–II loop controls surface expression of T-type Ca(v)3.1 calcium channels. FEBS Lett 582(27):3765–3770

    PubMed  CAS  Google Scholar 

  128. Baumgart JP et al (2008) I–II loop structural determinants in the gating and surface expression of low voltage-activated calcium channels. PLoS One 3(8):e2976

    PubMed  Google Scholar 

  129. Perez-Reyes E (2010) Characterization of the gating brake in the I-II loop of CaV3 T-type calcium channels. Channels (Austin) 4(6):453–458

    CAS  Google Scholar 

  130. David LS et al (2010) Splice-variant changes of the Ca(V)3.2 T-type calcium channel mediate voltage-dependent facilitation and associate with cardiac hypertrophy and development. Channels (Austin) 4(5):375–389

    CAS  Google Scholar 

  131. Powell KL et al (2009) A Cav3.2 T-type calcium channel point mutation has splice-variant-specific effects on function and segregates with seizure expression in a polygenic rat model of absence epilepsy. J Neurosci 29(2):371–380

    PubMed  CAS  Google Scholar 

  132. Cain SM, Snutch TP (2010) Contributions of T-type calcium channel isoforms to neuronal firing. Channels (Austin) 4(6):475–482

    CAS  Google Scholar 

  133. Aromolaran KA et al (2009) Kelch-like 1 protein upregulates T-type currents by an actin-F dependent increase in alpha(1H) channels via the recycling endosome. Channels (Austin) 3(6):402–412

    CAS  Google Scholar 

  134. Aromolaran KA et al (2010) T-type current modulation by the actin-binding protein Kelch-like 1. Am J Physiol Cell Physiol 298(6):C1353–C1362

    PubMed  CAS  Google Scholar 

  135. Westenbroek RE et al (1992) Biochemical properties and subcellular distribution of an N-type calcium channel alpha 1 subunit. Neuron 9(6):1099–1115

    PubMed  CAS  Google Scholar 

  136. Westenbroek RE, Hoskins L, Catterall WA (1998) Localization of Ca2+ channel subtypes on rat spinal motor neurons, interneurons, and nerve terminals. J Neurosci 18(16):6319–6330

    PubMed  CAS  Google Scholar 

  137. Westenbroek RE et al (1995) Immunochemical identification and subcellular distribution of the alpha 1A subunits of brain calcium channels. J Neurosci 15(10):6403–6418

    PubMed  CAS  Google Scholar 

  138. Hell JW et al (1993) Identification and differential subcellular localization of the neuronal class C and class D L-type calcium channel alpha 1 subunits. J Cell Biol 123(4):949–962

    PubMed  CAS  Google Scholar 

  139. Davare MA et al (2001) A beta2 adrenergic receptor signalling complex assembled with the Ca2 + channel Cav1.2. Science 293(5527):98–101

    PubMed  CAS  Google Scholar 

  140. Obermair GJ et al (2004) Differential targeting of the L-type Ca2+ channel alpha 1C (CaV1.2) to synaptic and extrasynaptic compartments in hippocampal neurons. Eur J Neurosci 19(8):2109–2122

    PubMed  Google Scholar 

  141. Tippens AL et al (2008) Ultrastructural evidence for pre- and postsynaptic localization of Cav1.2 L-type Ca2+ channels in the rat hippocampus. J Comp Neurol 506(4):569–583

    PubMed  CAS  Google Scholar 

  142. Zhang H et al (2005) Association of CaV1.3 L-type calcium channels with Shank. J Neurosci 25(5):1037–1049

    PubMed  CAS  Google Scholar 

  143. Morgans CW (2001) Localization of the alpha(1F) calcium channel subunit in the rat retina. Invest Ophthalmol Vis Sci 42(10):2414–2418

    PubMed  CAS  Google Scholar 

  144. Sheets L et al (2011) Ribeye is required for presynaptic Ca(V)1.3a channel localization and afferent innervation of sensory hair cells. Development 138(7):1309–1319

    PubMed  CAS  Google Scholar 

  145. Kisilevsky AE et al (2008) D1 receptors physically interact with N-type calcium channels to regulate channel distribution and dendritic calcium entry. Neuron 58(4):557–570

    PubMed  CAS  Google Scholar 

  146. McKay BE et al (2006) Ca(V)3 T-type calcium channel isoforms differentially distribute to somatic and dendritic compartments in rat central neurons. Eur J Neurosci 24(9):2581–2594

    PubMed  Google Scholar 

  147. Maximov A, Bezprozvanny I (2002) Synaptic targeting of N-type calcium channels in hippocampal neurons. J Neurosci 22(16):6939–6952

    PubMed  CAS  Google Scholar 

  148. Gardezi SR, Taylor P, Stanley EF (2010) Long C terminal splice variant CaV2.2 identified in presynaptic membrane by mass spectrometric analysis. Channels (Austin) 4(1):58–62

    CAS  Google Scholar 

  149. Khanna R et al (2006) Long splice variant N type calcium channels are clustered at presynaptic transmitter release sites without modular adaptor proteins. Neuroscience 138(4):1115–1125

    PubMed  CAS  Google Scholar 

  150. Spafford JD et al (2003) Calcium channel structural determinants of synaptic transmission between identified invertebrate neurons. J Biol Chem 278(6):4258–4267

    PubMed  CAS  Google Scholar 

  151. Rettig J et al (1996) Isoform-specific interaction of the alpha1A subunits of brain Ca2+ channels with the presynaptic proteins syntaxin and SNAP-25. Proc Natl Acad Sci USA 93(14):7363–7368

    PubMed  CAS  Google Scholar 

  152. Sheng ZH, Yokoyama CT, Catterall WA (1997) Interaction of the synprint site of N-type Ca2+ channels with the C2B domain of synaptotagmin I. Proc Natl Acad Sci USA 94(10):5405–5410

    PubMed  CAS  Google Scholar 

  153. Mochida S et al (1998) Evidence for a voltage-dependent enhancement of neurotransmitter release mediated via the synaptic protein interaction site of N-type Ca2+ channels. Proc Natl Acad Sci USA 95(24):14523–14528

    PubMed  CAS  Google Scholar 

  154. Zhong H et al (1999) Reciprocal regulation of P/Q-type Ca2+ channels by SNAP-25, syntaxin and synaptotagmin. Nat Neurosci 2(11):939–941

    PubMed  CAS  Google Scholar 

  155. Bezprozvanny I, Scheller RH, Tsien RW (1995) Functional impact of syntaxin on gating of N-type and Q-type calcium channels. Nature 378(6557):623–626

    PubMed  CAS  Google Scholar 

  156. Jarvis SE, Zamponi GW (2001) Distinct molecular determinants govern syntaxin 1A-mediated inactivation and G-protein inhibition of N-type calcium channels. J Neurosci 21(9):2939–2948

    PubMed  CAS  Google Scholar 

  157. Jarvis SE et al (2002) Molecular determinants of syntaxin 1 modulation of N-type calcium channels. J Biol Chem 277(46):44399–44407

    PubMed  CAS  Google Scholar 

  158. Stanley EF (2003) Syntaxin I modulation of presynaptic calcium channel inactivation revealed by botulinum toxin C1. Eur J Neurosci 17(6):1303–1305

    PubMed  Google Scholar 

  159. Mochida S et al (2003) Requirement for the synaptic protein interaction site for reconstitution of synaptic transmission by P/Q-type calcium channels. Proc Natl Acad Sci USA 100(5):2819–2824

    PubMed  CAS  Google Scholar 

  160. Szabo Z et al (2006) Role of the synprint site in presynaptic targeting of the calcium channel CaV2.2 in hippocampal neurons. Eur J Neurosci 24(3):709–718

    PubMed  Google Scholar 

  161. Kaneko S et al (2002) Identification and characterization of novel human Ca(v)2.2 (alpha 1B) calcium channel variants lacking the synaptic protein interaction site. J Neurosci 22(1):82–92

    PubMed  CAS  Google Scholar 

  162. Xie M et al (2007) Facilitation versus depression in cultured hippocampal neurons determined by targeting of Ca2+ channel Cavbeta4 versus Cavbeta2 subunits to synaptic terminals. J Cell Biol 178(3):489–502

    PubMed  CAS  Google Scholar 

  163. Cao YQ et al (2004) Presynaptic Ca2+ channels compete for channel type-preferring slots in altered neurotransmission arising from Ca2+ channelopathy. Neuron 43(3):387–400

    PubMed  CAS  Google Scholar 

  164. Cao YQ, Tsien RW (2010) Different relationship of N- and P/Q-type Ca2+ channels to channel-interacting slots in controlling neurotransmission at cultured hippocampal synapses. J Neurosci 30(13):4536–4546

    PubMed  CAS  Google Scholar 

  165. Bourinet E et al (2005) Silencing of the Cav3.2 T-type calcium channel gene in sensory neurons demonstrates its major role in nociception. Embo J 24(2):315–324

    PubMed  CAS  Google Scholar 

  166. Altier C et al (2007) Differential role of N-type calcium channel splice isoforms in pain. J Neurosci 27(24):6363–6373

    PubMed  CAS  Google Scholar 

  167. Bernstein GM, Jones OT (2007) Kinetics of internalization and degradation of N-type voltage-gated calcium channels: role of the alpha2/delta subunit. Cell Calcium 41(1):27–40

    PubMed  CAS  Google Scholar 

  168. Gonzalez-Gutierrez G et al (2007) The Src homology 3 domain of the beta-subunit of voltage-gated calcium channels promotes endocytosis via dynamin interaction. J Biol Chem 282(4):2156–2162

    PubMed  CAS  Google Scholar 

  169. Miranda-Laferte E et al (2011) Homodimerization of the Src homology 3 domain of the calcium channel {beta}-subunit drives dynamin-dependent endocytosis. J Biol Chem 286(25):22203–22210

    PubMed  CAS  Google Scholar 

  170. Raingo J, Castiglioni AJ, Lipscombe D (2007) Alternative splicing controls G protein-dependent inhibition of N-type calcium channels in nociceptors. Nat Neurosci 10(3):285–292

    PubMed  CAS  Google Scholar 

  171. Brittain JM et al (2009) An atypical role for collapsin response mediator protein 2 (CRMP-2) in neurotransmitter release via interaction with presynaptic voltage-gated calcium channels. J Biol Chem 284(45):31375–31390

    PubMed  CAS  Google Scholar 

  172. Brittain JM et al (2011) Suppression of inflammatory and neuropathic pain by uncoupling CRMP-2 from the presynaptic Ca(2+) channel complex. Nat Med 17(7):822–829

    PubMed  CAS  Google Scholar 

  173. Rahajeng J et al (2010) Collapsin response mediator protein-2 (Crmp2) regulates trafficking by linking endocytic regulatory proteins to dynein motors. J Biol Chem 285(42):31918–31922

    PubMed  CAS  Google Scholar 

  174. Beedle AM et al (2004) Agonist-independent modulation of N-type calcium channels by ORL1 receptors. Nat Neurosci 7(2):118–125

    PubMed  CAS  Google Scholar 

  175. Kisilevsky AE, Zamponi GW (2008) D2 dopamine receptors interact directly with N-type calcium channels and regulate channel surface expression levels. Channels (Austin) 2(4):269–277

    Google Scholar 

  176. Altier C et al (2006) ORL1 receptor-mediated internalization of N-type calcium channels. Nat Neurosci 9(1):31–40

    PubMed  CAS  Google Scholar 

  177. Green EM et al (2007) The tumor suppressor eIF3e mediates calcium-dependent internalization of the L-type calcium channel CaV1.2. Neuron 55(4):615–632

    PubMed  CAS  Google Scholar 

  178. Gomez-Ospina N et al (2006) The C terminus of the L-type voltage-gated calcium channel Ca(V)1.2 encodes a transcription factor. Cell 127(3):591–606

    PubMed  CAS  Google Scholar 

  179. Varela D, Zamponi GW (2007) Use ‘em and lose’ em-activity-induced removal of calcium channels from the plasma membrane. Neuron 55(4):539–541

    PubMed  CAS  Google Scholar 

  180. Di Biase V et al (2008) Stable membrane expression of postsynaptic CaV1.2 calcium channel clusters is independent of interactions with AKAP79/150 and PDZ proteins. J Neurosci 28(51):13845–13855

    PubMed  CAS  Google Scholar 

  181. Tsuruta F et al (2009) PIKfyve regulates CaV1.2 degradation and prevents excitotoxic cell death. J Cell Biol 187(2):279–294

    PubMed  CAS  Google Scholar 

  182. Rougier JS et al (2011) Neuronal precursor cell-expressed developmentally down-regulated 4–1 (NEDD4–1) controls the sorting of newly synthesized Ca(V)1.2 calcium channels. J Biol Chem 286(11):8829–8838

    PubMed  CAS  Google Scholar 

  183. Staub O et al (2000) Regulation of the epithelial Na+ channel by Nedd4 and ubiquitination. Kidney Int 57(3):809–815

    PubMed  CAS  Google Scholar 

  184. Albesa M et al (2011) Nedd4–2-dependent ubiquitylation and regulation of the cardiac potassium channel hERG1. J Mol Cell Cardiol 51(1):90–98

    PubMed  CAS  Google Scholar 

  185. Pirozzi G et al (1997) Identification of novel human WW domain-containing proteins by cloning of ligand targets. J Biol Chem 272(23):14611–14616

    PubMed  CAS  Google Scholar 

  186. Subramanyam P et al (2009) Activity and calcium regulate nuclear targeting of the calcium channel beta4b subunit in nerve and muscle cells. Channels (Austin) 3(5):343–355

    CAS  Google Scholar 

  187. Altier C et al (2002) Trafficking of L-type calcium channels mediated by the postsynaptic scaffolding protein AKAP79. J Biol Chem 277(37):33598–33603

    PubMed  CAS  Google Scholar 

  188. Beguin P et al (2001) Regulation of Ca2+ channel expression at the cell surface by the small G-protein kir/Gem. Nature 411(6838):701–706

    PubMed  CAS  Google Scholar 

  189. Flynn R, Zamponi GW (2010) Regulation of calcium channels by RGK proteins. Channels (Austin) 4(6):434–439

    CAS  Google Scholar 

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Acknowledgments

Work from our laboratory that we discussed here was supported by the Canadian Institutes of Health Research, the Natural Sciences and Engineering Research Council, and the Heart of Stroke Foundation of Alberta and the Northwest Territories. BAS is supported by a studentship from Alberta Innovates-Health Solutions (AI-HS). GWZ is an AI-HS Scientist and a Canada Research Chair.

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  1. Department of Physiology and Pharmacology, University of Calgary, 3330 Hospital Dr. NW, Calgary, T2N 4N1, Canada

    Brett A. Simms & Gerald W. Zamponi

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  1. Brett A. Simms
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  2. Gerald W. Zamponi
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Correspondence to Gerald W. Zamponi.

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Simms, B.A., Zamponi, G.W. Trafficking and stability of voltage-gated calcium channels. Cell. Mol. Life Sci. 69, 843–856 (2012). https://doi.org/10.1007/s00018-011-0843-y

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  • DOI: https://doi.org/10.1007/s00018-011-0843-y

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