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  • Review Article
  • Published:

Targeting voltage-gated calcium channels in neurological and psychiatric diseases

Key Points

  • Voltage-gated calcium channels are of critical importance for nervous system function at the cellular and network levels.

  • Aberrant calcium channel function is associated with a wide range of neurological and psychiatric conditions.

  • Calcium channel dysfunction can occur as a result of mutations in genes encoding calcium channels, or owing to alterations in channel trafficking and regulation.

  • Calcium channel blockers may be effective in the treatment of Parkinson disease, drug addiction, pain, anxiety and epilepsy.

  • Cell-specific alternative splicing of calcium channel genes creates additional calcium channel diversity and is an important consideration in drug design.

  • The development of new calcium channel inhibitors is challenging, and may require unconventional approaches such as targeting associations with interacting proteins.

Abstract

Voltage-gated calcium channels are important regulators of brain, heart and muscle functions, and their dysfunction can give rise to pathophysiological conditions ranging from cardiovascular disorders to neurological and psychiatric conditions such as epilepsy, pain and autism. In the nervous system, calcium channel blockers have been used successfully to treat absence seizures, and are emerging as potential therapeutic avenues for pathologies such as pain, Parkinson disease, addiction and anxiety. This Review provides an overview of calcium channels as drug targets for nervous system disorders, and discusses potential challenges and opportunities for the development of new clinically effective calcium channel inhibitors.

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Figure 1: Locations of drug interaction sites on voltage-gated calcium channels.
Figure 2: Role of voltage-gated calcium channels in the primary afferent pain pathway.
Figure 3: Role of T-type calcium channels in the thalamocortical circuitry.
Figure 4: Role of L-type calcium channels in the degeneration of dopaminergic neurons during Parkinson disease.
Figure 5: Role of L-type calcium channels in drug addiction.

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References

  1. Cain, S. M. & Snutch, T. P. T-type calcium channels in burst-firing, network synchrony, and epilepsy. Biochim. Biophys. Acta 1828, 1572–1578 (2013).

    Article  CAS  PubMed  Google Scholar 

  2. Hook, S. S. & Means, A. R. Ca2+/CaM-dependent kinases: from activation to function. Annu. Rev. Pharmacol. Toxicol. 41, 471–505 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. Wheeler, D. B., Randall, A. & Tsien, R. W. Roles of N-type and Q-type Ca2+ channels in supporting hippocampal synaptic transmission. Science 264, 107–111 (1994).

    Article  CAS  PubMed  Google Scholar 

  4. Dolmetsch, R. E., Pajvani, U., Fife, K., Spotts, J. M. & Greenberg, M. E. Signaling to the nucleus by an L-type calcium channel-calmodulin complex through the MAP kinase pathway. Science 294, 333–339 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Wheeler, D. G. et al. CaV1 and CaV2 channels engage distinct modes of Ca2+ signaling to control CREB-dependent gene expression. Cell 149, 1112–1124 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Tanabe, T., Beam, K. G., Adams, B. A., Niidome, T. & Numa, S. Regions of the skeletal muscle dihydropyridine receptor critical for excitation-contraction coupling. Nature 346, 567–569 (1990).

    Article  CAS  PubMed  Google Scholar 

  7. Simms, B. A. & Zamponi, G. W. Neuronal voltage-gated calcium channels: structure, function, and dysfunction. Neuron 82, 24–45 (2014).

    Article  CAS  PubMed  Google Scholar 

  8. Catterall, W. A., Perez-Reyes, E., Snutch, T. P. & Striessnig, J. International union of pharmacology. XLVIII. Nomenclature and structure-function relationships of voltage-gated calcium channels. Pharmacol. Rev. 57, 411–425 (2005).

    Article  CAS  PubMed  Google Scholar 

  9. Lipscombe, D., Andrade, A. & Allen, S. E. Alternative splicing: functional diversity among voltage-gated calcium channels and behavioral consequences. Biochim. Biophys. Acta 1828, 1522–1529 (2013).

    Article  CAS  PubMed  Google Scholar 

  10. Dolphin, A. C. Calcium channel auxiliary α2δ and β subunits: trafficking and one step beyond. Nat. Rev. Neurosci. 13, 542–555 (2012).

    Article  CAS  PubMed  Google Scholar 

  11. Lory, P. & Mezghrani, A. Calcium channelopathies in inherited neurological disorders: relevance to drug screening for acquired channel disorders. IDrugs 13, 467–471 (2010).

    CAS  PubMed  Google Scholar 

  12. Felix, R. Calcium channelopathies. Neuromolecular Med. 8, 307–318 (2006).

    Article  CAS  PubMed  Google Scholar 

  13. Bean, B. P. Classes of calcium channels in vertebrate cells. Annu. Rev. Physiol. 51, 367–384 (1989).

    Article  CAS  PubMed  Google Scholar 

  14. Nowycky, M. C., Fox, A. P. & Tsien, R. W. Three types of neuronal calcium channel with different calcium agonist sensitivity. Nature 316, 440–443 (1985).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  16. Bourinet, E. et al. Splicing of α1A subunit gene generates phenotypic variants of P- and Q-type calcium channels. Nat. Neurosci. 2, 407–415 (1999).

    Article  CAS  PubMed  Google Scholar 

  17. Richards, K. S., Swensen, A. M., Lipscombe, D. & Bommert, K. Novel CaV2.1 clone replicates many properties of Purkinje cell CaV2.1 current. Eur. J. Neurosci. 26, 2950–2961 (2007).

    Article  PubMed  Google Scholar 

  18. Catterall, W. A. Ion channel voltage sensors: structure, function, and pathophysiology. Neuron 67, 915–928 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Bladen, C. & Zamponi, G. W. Common mechanisms of drug interactions with sodium and T-type calcium channels. Mol. Pharmacol. 82, 481–487 (2012).

    Article  CAS  PubMed  Google Scholar 

  20. Sinnegger, M. J. et al. Nine L-type amino acid residues confer full 1,4-dihydropyridine sensitivity to the neuronal calcium channel α1A subunit. Role of L-type Met1188 J. Biol. Chem. 272, 27686–27693 (1997).

    Article  CAS  PubMed  Google Scholar 

  21. Striessnig, J. et al. Structural basis of drug binding to L Ca2+ channels. Trends Pharmacol. Sci. 19, 108–115 (1998).

    Article  CAS  PubMed  Google Scholar 

  22. Catterall, W. A. Voltage-gated calcium channels. Cold Spring Harb. Perspect. Biol. 3, a003947 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Pragnell, M. et al. Calcium channel β-subunit binds to a conserved motif in the I—II cytoplasmic linker of the α1-subunit. Nature 368, 67–70 (1994).

    Article  CAS  PubMed  Google Scholar 

  24. Dolphin, A. C. The α2δ subunits of voltage-gated calcium channels. Biochim. Biophys. Acta 1828, 1541–1549 (2012).

    Article  CAS  PubMed  Google Scholar 

  25. Altier, C. et al. The Cavβ subunit prevents RFP2-mediated ubiquitination and proteasomal degradation of L-type channels. Nat. Neurosci. 14, 173–180 (2011). This paper shows that ancillary Cavβ subunits regulate calcium channel trafficking by interfering with the ubiquitylation of the channels.

    Article  CAS  PubMed  Google Scholar 

  26. Tran- Van-Minh, A. & Dolphin, A. C. The α2δ ligand gabapentin inhibits the Rab11-dependent recycling of the calcium channel subunit α2δ-2. J. Neurosci. 30, 12856–12867 (2010).

    Article  CAS  Google Scholar 

  27. Kang, M. G. & Campbell, K. P. Gamma subunit of voltage-activated calcium channels. J. Biol. Chem. 278, 21315–21318 (2003).

    Article  CAS  PubMed  Google Scholar 

  28. Lipscombe, D., Andrade, A. & Allen, S. E. Alternative splicing: functional diversity among voltage-gated calcium channels and behavioral consequences. Biochim. Biophys. Acta 1828, 1522–1529 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Sinnegger-Brauns, M. J. et al. Expression and 1,4-dihydropyridine-binding properties of brain L-type calcium channel isoforms. Mol. Pharmacol. 75, 407–414 (2009).

    Article  CAS  PubMed  Google Scholar 

  30. Hell, J. W. et al. Identification and differential subcellular localization of the neuronal class C and class D L-type calcium channel α1 subunits. J. Cell Biol. 123, 949–962 (1993).

    Article  CAS  PubMed  Google Scholar 

  31. Hutchinson, T. E., Zhong, W., Chebolu, S., Wilson, S. M. & Darmani, N. A. L-type calcium channels contribute to 5-HT3-receptor-evoked CaMKIIα and ERK activation and induction of emesis in the least shrew (Cryptotis parva). Eur. J. Pharmacol. 755, 110–118 (2015).

    Article  CAS  PubMed  Google Scholar 

  32. Ramirez-Latorre, J. A. Functional upregulation of Ca2+-activated K+ channels in the development of substantia nigra dopamine neurons. PLoS ONE 7, e51610 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Brandt, A., Khimich, D. & Moser, T. Few CaV1.3 channels regulate the exocytosis of a synaptic vesicle at the hair cell ribbon synapse. J. Neurosci. 25, 11577–11585 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Platzer, J. et al. Congenital deafness and sinoatrial node dysfunction in mice lacking class D L-type Ca2+ channels. Cell 102, 89–97 (2000). This elegant paper implicates Cav1.3 channels in both cardiovascular function and the detection of auditory stimuli.

    Article  CAS  PubMed  Google Scholar 

  35. Baig, S. M. et al. Loss of CaV1.3 (CACNA1D) function in a human channelopathy with bradycardia and congenital deafness. Nat. Neurosci. 14, 77–84 (2011).

    Article  CAS  PubMed  Google Scholar 

  36. Lodha, N. et al. Congenital stationary night blindness in mice — a tale of two Cacna1f mutants. Adv. Exp. Med. Biol. 664, 549–558 (2010).

    Article  CAS  PubMed  Google Scholar 

  37. Lodha, N., Loucks, C. M., Beaulieu, C., Parboosingh, J. S. & Bech-Hansen, N. T. Congenital stationary night blindness: mutation update and clinical variability. Adv. Exp. Med. Biol. 723, 371–379 (2012).

    Article  CAS  PubMed  Google Scholar 

  38. Zamponi, G. W. Regulation of presynaptic calcium channels by synaptic proteins. J. Pharmacol. Sci. 92, 79–83 (2003).

    Article  CAS  PubMed  Google Scholar 

  39. Cao, Y. Q. et al. Presynaptic Ca2+ channels compete for channel type-preferring slots in altered neurotransmission arising from Ca2+ channelopathy. Neuron 43, 387–400 (2004).

    Article  CAS  PubMed  Google Scholar 

  40. Hatakeyama, S. et al. Differential nociceptive responses in mice lacking the α1B subunit of N-type Ca2+ channels. Neuroreport 12, 2423–2427 (2001).

    Article  CAS  PubMed  Google Scholar 

  41. Jun, K. et al. Ablation of P/Q-type Ca2+ channel currents, altered synaptic transmission, and progressive ataxia in mice lacking the alpha1A-subunit. Proc. Natl Acad. Sci. USA 96, 15245–15250 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Sutton, K. G., McRory, J. E., Guthrie, H., Murphy, T. H. & Snutch, T. P. P/Q-type calcium channels mediate the activity-dependent feedback of syntaxin-1A. Nature 401, 800–804 (1999).

    Article  CAS  PubMed  Google Scholar 

  43. Vecchia, D., Tottene, A., van den Maagdenberg, A. M. & Pietrobon, D. Abnormal cortical synaptic transmission in CaV2.1 knockin mice with the S218L missense mutation which causes a severe familial hemiplegic migraine syndrome in humans. Front. Cell Neurosci. 9, 8 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Nachbauer, W. et al. Episodic ataxia type 2: phenotype characteristics of a novel CACNA1A mutation and review of the literature. J. Neurol. 261, 983–991 (2014).

    Article  CAS  PubMed  Google Scholar 

  45. Saegusa, H. et al. Properties of human Cav2.1 channel with a spinocerebellar ataxia type 6 mutation expressed in Purkinje cells. Mol. Cell Neurosci. 34, 261–270 (2007).

    Article  CAS  PubMed  Google Scholar 

  46. Groen, J. L. et al. CACNA1B mutation is linked to unique myoclonus-dystonia syndrome. Hum. Mol. Genet. 24, 987–993 (2015).

    Article  CAS  PubMed  Google Scholar 

  47. Wu, L. G., Borst, J. G. & Sakmann, B. R-type Ca2+ currents evoke transmitter release at a rat central synapse. Proc. Natl Acad. Sci. USA 95, 4720–4725 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Ricoy, U. M. & Frerking, M. E. Distinct roles for Cav2.1–2.3 in activity-dependent synaptic dynamics. J. Neurophysiol. 111, 2404–2413 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Zaman, T. et al. Cav2.3 channels are critical for oscillatory burst discharges in the reticular thalamus and absence epilepsy. Neuron 70, 95–108 (2011).

    Article  CAS  PubMed  Google Scholar 

  50. Coulter, D. A., Huguenard, J. R. & Prince, D. A. Calcium currents in rat thalamocortical relay neurones: kinetic properties of the transient, low-threshold current. J. Physiol. 414, 587–604 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Molineux, M. L. et al. Specific T-type calcium channel isoforms are associated with distinct burst phenotypes in deep cerebellar nuclear neurons. Proc. Natl Acad. Sci. USA 103, 5555–5560 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Chemin, J., Monteil, A., Bourinet, E., Nargeot, J. & Lory, P. Alternatively spliced α1G (Cav3.1) intracellular loops promote specific T-type Ca2+ channel gating properties. Biophys. J. 80, 1238–1250 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Weiss, N. et al. A Cav3.2/syntaxin-1A signaling complex controls T-type channel activity and low-threshold exocytosis. J. Biol. Chem. 287, 2810–2818 (2012).

    Article  CAS  PubMed  Google Scholar 

  54. Fleckenstein, A., Kammermeier, H., Doring, H. J. & Freund, H. J. [On the method of action of new types of coronary dilatators with simultaneous oxygen-saving myocardial effects, prenylamine and iproveratril. 2]. Z. Kreislaufforsch. 56, 839–858 (1967).

    CAS  PubMed  Google Scholar 

  55. Doering, C. J. & Zamponi, G. W. Molecular pharmacology of high voltage-activated calcium channels. J. Bioenerg. Biomembr. 35, 491–505 (2003).

    Article  CAS  PubMed  Google Scholar 

  56. Glossmann, H., Ferry, D. R., Lubbecke, F., Mewes, R. & Hofmann, F. Identification of voltage operated calcium channels by binding studies: differentiation of subclasses of calcium antagonist drugs with 3H-nimodipine radioligand binding. J. Recept. Res. 3, 177–190 (1983).

    Article  CAS  PubMed  Google Scholar 

  57. Glossmann, H., Ferry, D. R., Goll, A. & Rombusch, M. Molecular pharmacology of the calcium channel: evidence for subtypes, multiple drug-receptor sites, channel subunits, and the development of a radioiodinated 1,4-dihydropyridine calcium channel label, [125I]iodipine. J. Cardiovasc. Pharmacol. 6 (Suppl. 4), 608–621 (1984).

    Article  CAS  Google Scholar 

  58. Benjamin, E. R. et al. Pharmacological characterization of recombinant N-type calcium channel (Cav2.2) mediated calcium mobilization using FLIPR. Biochem. Pharmacol. 72, 770–782 (2006).

    Article  CAS  PubMed  Google Scholar 

  59. Xie, X. et al. Validation of high throughput screening assays against three subtypes of Cav3 T-type channels using molecular and pharmacologic approaches. Assay Drug Dev. Technol. 5, 191–203 (2007).

    Article  CAS  PubMed  Google Scholar 

  60. Vetter, I. Development and optimization of FLIPR high throughput calcium assays for ion channels and GPCRs. Adv. Exp. Med. Biol. 740, 45–82 (2012).

    Article  CAS  PubMed  Google Scholar 

  61. Tao, H. et al. Efficient characterization of use-dependent ion channel blockers by real-time monitoring of channel state. Assay Drug Dev. Technol. 4, 57–64 (2006).

    Article  CAS  PubMed  Google Scholar 

  62. Dai, G. et al. A high-throughput assay for evaluating state dependence and subtype selectivity of Cav2 calcium channel inhibitors. Assay Drug Dev. Technol. 6, 195–212 (2008).

    Article  CAS  PubMed  Google Scholar 

  63. Belardetti, F. et al. A fluorescence-based high-throughput screening assay for the identification of T-type calcium channel blockers. Assay Drug Dev. Technol. 7, 266–280 (2009).

    Article  CAS  PubMed  Google Scholar 

  64. Balasubramanian, B. et al. Optimization of Cav1.2 screening with an automated planar patch clamp platform. J. Pharmacol. Toxicol. Methods 59, 62–72 (2009).

    Article  CAS  PubMed  Google Scholar 

  65. Kraus, R. et al. Identification of benz(othi)azepine-binding regions within L-type calcium channel α1 subunits. J. Biol. Chem. 271, 20113–20118 (1996).

    Article  CAS  PubMed  Google Scholar 

  66. Stotz, S. C., Jarvis, S. E. & Zamponi, G. W. Functional roles of cytoplasmic loops and pore lining transmembrane helices in the voltage-dependent inactivation of HVA calcium channels. J. Physiol. 554, 263–273 (2004).

    Article  CAS  PubMed  Google Scholar 

  67. Zamponi, G. W. et al. Unique structure-activity relationship for 4-isoxazolyl-1,4-dihydropyridines. J. Med. Chem. 46, 87–96 (2003).

    Article  CAS  PubMed  Google Scholar 

  68. Catterall, W. A. & Swanson, T. M. Structural basis for pharmacology of voltage-gated sodium and calcium channels. Mol. Pharmacol. 88, 141–150 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Bladen, C., Gunduz, M. G., Simsek, R., Safak, C. & Zamponi, G. W. Synthesis and evaluation of 1,4-dihydropyridine derivatives with calcium channel blocking activity. Pflugers Arch. 466, 1355–1363 (2014).

    Article  CAS  PubMed  Google Scholar 

  70. Fujii, S., Kameyama, K., Hosono, M., Hayashi, Y. & Kitamura, K. Effect of cilnidipine, a novel dihydropyridine Ca++-channel antagonist, on N-type Ca++ channel in rat dorsal root ganglion neurons. J. Pharmacol. Exp. Ther. 280, 1184–1191 (1997).

    CAS  PubMed  Google Scholar 

  71. Kumar, P. P. et al. Synthesis and evaluation of a new class of nifedipine analogs with T-type calcium channel blocking activity. Mol. Pharmacol. 61, 649–658 (2002).

    Article  CAS  PubMed  Google Scholar 

  72. Basbaum, A. I., Bautista, D. M., Scherrer, G. & Julius, D. Cellular and molecular mechanisms of pain. Cell 139, 267–284 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Bourinet, E. et al. Calcium-permeable ion channels in pain signaling. Physiol. Rev. 94, 81–140 (2014).

    Article  CAS  PubMed  Google Scholar 

  74. Waxman, S. G. & Zamponi, G. W. Regulating excitability of peripheral afferents: emerging ion channel targets. Nat. Neurosci. 17, 153–163 (2014).

    Article  CAS  PubMed  Google Scholar 

  75. Cizkova, D. et al. Localization of N-type Ca2+ channels in the rat spinal cord following chronic constrictive nerve injury. Exp. Brain Res. 147, 456–463 (2002).

    Article  CAS  PubMed  Google Scholar 

  76. Marger, F. et al. T-type calcium channels contribute to colonic hypersensitivity in a rat model of irritable bowel syndrome. Proc. Natl Acad. Sci. USA 108, 11268–11273 (2011). This paper elegantly demonstrates that irritable bowel syndrome causes an upregulation of Cav3.2 channels in DRG neurons that innervate the colon.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Jagodic, M. M. et al. Upregulation of the T-type calcium current in small rat sensory neurons after chronic constrictive injury of the sciatic nerve. J. Neurophysiol. 99, 3151–3156 (2008).

    Article  CAS  PubMed  Google Scholar 

  78. Tedford, H. W. & Zamponi, G. W. Direct G protein modulation of Cav2 calcium channels. Pharmacol. Rev. 58, 837–862 (2006).

    Article  CAS  PubMed  Google Scholar 

  79. Jiang, Y. Q., Andrade, A. & Lipscombe, D. Spinal morphine but not ziconotide or gabapentin analgesia is affected by alternative splicing of voltage-gated calcium channel Cav2.2 pre-mRNA. Mol. Pain 9, 67 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Kuo, A., Wyse, B. D., Meutermans, W. & Smith, M. T. In vivo profiling of seven common opioids for antinociception, constipation and respiratory depression: no two opioids have the same profile. Br. J. Pharmacol. 172, 532–548 (2015).

    Article  CAS  PubMed  Google Scholar 

  81. Luo, Z. D. et al. Upregulation of dorsal root ganglion α2δ calcium channel subunit and its correlation with allodynia in spinal nerve-injured rats. J. Neurosci. 21, 1868–1875 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Bauer, C. S. et al. The increased trafficking of the calcium channel subunit α2δ-1 to presynaptic terminals in neuropathic pain is inhibited by the α2δ ligand pregabalin. J. Neurosci. 29, 4076–4088 (2009). This paper shows that gabapentinoids prevent synaptic targeting of calcium channels.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Bauer, C. S. et al. The anti-allodynic α2δ ligand pregabalin inhibits the trafficking of the calcium channel α2δ-1 subunit to presynaptic terminals in vivo. Biochem. Soc. Trans. 38, 525–528 (2010).

    Article  PubMed  Google Scholar 

  84. Hendrich, J., Bauer, C. S. & Dolphin, A. C. Chronic pregabalin inhibits synaptic transmission between rat dorsal root ganglion and dorsal horn neurons in culture. Channels 6, 124–132 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Johnson, R. W. & Rice, A. S. Clinical practice. Postherpetic neuralgia. N. Engl. J. Med. 371, 1526–1533 (2014).

    Article  CAS  PubMed  Google Scholar 

  86. Miljanich, G. P. Ziconotide: neuronal calcium channel blocker for treating severe chronic pain. Curr. Med. Chem. 11, 3029–3040 (2004).

    Article  CAS  PubMed  Google Scholar 

  87. Rauck, R. L., Wallace, M. S., Burton, A. W., Kapural, L. & North, J. M. Intrathecal ziconotide for neuropathic pain: a review. Pain Pract. 9, 327–337 (2009).

    Article  PubMed  Google Scholar 

  88. Staats, P. S. et al. Intrathecal ziconotide in the treatment of refractory pain in patients with cancer or AIDS: a randomized controlled trial. JAMA 291, 63–70 (2004). This important paper validates the use of N-type calcium channel blockers as a therapeutic strategy for treating pain in humans.

    Article  CAS  PubMed  Google Scholar 

  89. Smith, H. S. & Deer, T. R. Safety and efficacy of intrathecal ziconotide in the management of severe chronic pain. Ther. Clin. Risk Manag 5, 521–534 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Rauck, R. L. et al. A randomized, double-blind, placebo-controlled study of intrathecal ziconotide in adults with severe chronic pain. J. Pain Symptom Manage. 31, 393–406 (2006).

    Article  CAS  PubMed  Google Scholar 

  91. Wallace, M. S. et al. Intrathecal ziconotide in the treatment of chronic nonmalignant pain: a randomized, double-blind, placebo-controlled clinical trial. Neuromodulation 9, 75–86 (2006).

    Article  PubMed  Google Scholar 

  92. Feng, Z. P. et al. Determinants of inhibition of transiently expressed voltage-gated calcium channels by ω-conotoxins GVIA and MVIIA. J. Biol. Chem. 278, 20171–20178 (2003).

    Article  CAS  PubMed  Google Scholar 

  93. Zamponi, G. W. et al. Scaffold-based design and synthesis of potent N-type calcium channel blockers. Bioorg. Med. Chem. Lett. 19, 6467–6472 (2009).

    Article  CAS  PubMed  Google Scholar 

  94. Swensen, A. M. et al. Characterization of the substituted N-triazole oxindole TROX-1, a small-molecule, state-dependent inhibitor of CaV2 calcium channels. Mol. Pharmacol. 81, 488–497 (2012).

    Article  CAS  PubMed  Google Scholar 

  95. Ryder, T. R. et al. Multiple parallel synthesis of N,N-dialkyldipeptidylamines as N-type calcium channel blockers. Bioorg. Med. Chem. Lett. 9, 1813–1818 (1999).

    Article  CAS  PubMed  Google Scholar 

  96. Subasinghe, N. L. et al. A novel series of pyrazolylpiperidine N-type calcium channel blockers. Bioorg. Med. Chem. Lett. 22, 4080–4083 (2012).

    Article  CAS  PubMed  Google Scholar 

  97. Shao, P. P. et al. Aminopiperidine sulfonamide Cav2.2 channel inhibitors for the treatment of chronic pain. J. Med. Chem. 55, 9847–9855 (2012).

    Article  CAS  PubMed  Google Scholar 

  98. Hu, L. Y. et al. Synthesis and biological evaluation of substituted 4-(OBz)phenylalanine derivatives as novel N-type calcium channel blockers. Bioorg. Med. Chem. Lett. 9, 1121–1126 (1999).

    Article  CAS  PubMed  Google Scholar 

  99. Yamamoto, T. et al. Discovery and evaluation of selective N-type calcium channel blockers: 6-unsubstituted-1,4-dihydropyridine-5-carboxylic acid derivatives. Bioorg. Med. Chem. Lett. 22, 3639–3642 (2012).

    Article  CAS  PubMed  Google Scholar 

  100. Scott, V. E. et al. A-1048400 is a novel, orally active, state-dependent neuronal calcium channel blocker that produces dose-dependent antinociception without altering hemodynamic function in rats. Biochem. Pharmacol. 83, 406–418 (2012).

    Article  CAS  PubMed  Google Scholar 

  101. Cheng, J. K., Lin, C. S., Chen, C. C., Yang, J. R. & Chiou, L. C. Effects of intrathecal injection of T-type calcium channel blockers in the rat formalin test. Behav. Pharmacol. 18, 1–8 (2007).

    Article  CAS  PubMed  Google Scholar 

  102. Bourinet, E. et al. Silencing of the Cav3.2 T-type calcium channel gene in sensory neurons demonstrates its major role in nociception. EMBO J. 24, 315–324 (2005). This paper demonstrates that in vivo siRNA knockdown of Cav3.2 channels mediates analgesia in inflammatory and neuropathic pain models, thus validating these channels as important drug targets for pain.

    Article  CAS  PubMed  Google Scholar 

  103. Berger, N. D. et al. NMP-7 inhibits chronic inflammatory and neuropathic pain via block of Cav3.2 T-type calcium channels and activation of CB2 receptors. Mol. Pain 10, 77 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Bladen, C. et al. Characterization of novel cannabinoid based T-type calcium channel blockers with analgesic effects. ACS Chem. Neurosci. 6, 277–287 (2015).

    Article  CAS  PubMed  Google Scholar 

  105. Gadotti, V. M. et al. Analgesic effect of a mixed T-type channel inhibitor/CB2 receptor agonist. Mol. Pain 9, 32 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Bladen, C. et al. 1,4-dihydropyridine derivatives with T-type calcium channel blocking activity attenuate inflammatory and neuropathic pain. Pflugers Arch. 467, 1237–1247 (2014).

    Article  CAS  PubMed  Google Scholar 

  107. Lee, M. J. et al. KST5468, a new T-type calcium channel antagonist, has an antinociceptive effect on inflammatory and neuropathic pain models. Pharmacol. Biochem. Behav. 97, 198–204 (2010).

    Article  CAS  PubMed  Google Scholar 

  108. Choe, W. et al. TTA-P2 is a potent and selective blocker of T-type calcium channels in rat sensory neurons and a novel antinociceptive agent. Mol. Pharmacol. 80, 900–910 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Chemin, J., Monteil, A., Perez-Reyes, E., Nargeot, J. & Lory, P. Direct inhibition of T-type calcium channels by the endogenous cannabinoid anandamide. EMBO J. 20, 7033–7040 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Gilmore, A. J., Heblinski, M., Reynolds, A., Kassiou, M. & Connor, M. Inhibition of human recombinant T-type calcium channels by N-arachidonoyl 5-HT. Br. J. Pharmacol. 167, 1076–1088 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Hildebrand, M. E. et al. A novel slow-inactivation-specific ion channel modulator attenuates neuropathic pain. Pain 152, 833–843 (2011).

    Article  CAS  PubMed  Google Scholar 

  112. Lee, M. Z944: a first in class T-type calcium channel modulator for the treatment of pain. J. Peripher Nerv. Syst. 19 (Suppl. 2), 11–12 (2014).

    Article  Google Scholar 

  113. Ziegler, D., Duan, W. R., An, G., Thomas, J. W. & Nothaft, W. A randomized double-blind, placebo-, and active-controlled study of T-type calcium channel blocker ABT-639 in patients with diabetic peripheral neuropathic pain. Pain 156, 2013–2020 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Terashima, T., Xu, Q., Yamaguchi, S. & Yaksh, T. L. Intrathecal P/Q and R-type calcium channel blockade of spinal substance P release and c-Fos expression. Neuropharmacology 75, 1–8 (2013).

    Article  CAS  PubMed  Google Scholar 

  115. Matthews, E. A., Bee, L. A., Stephens, G. J. & Dickenson, A. H. The Cav2.3 calcium channel antagonist SNX-482 reduces dorsal horn neuronal responses in a rat model of chronic neuropathic pain. Eur. J. Neurosci. 25, 3561–3569 (2007).

    Article  PubMed  Google Scholar 

  116. Murakami, M. et al. Antinociceptive effect of different types of calcium channel inhibitors and the distribution of various calcium channel α1 subunits in the dorsal horn of spinal cord in mice. Brain Res. 1024, 122–129 (2004).

    Article  CAS  PubMed  Google Scholar 

  117. Saegusa, H. et al. Altered pain responses in mice lacking α1E subunit of the voltage-dependent Ca2+ channel. Proc. Natl Acad. Sci. USA 97, 6132–6137 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Bourinet, E. et al. Interaction of SNX482 with domains III and IV inhibits activation gating of α1E (Cav2.3) calcium channels. Biophys. J. 81, 79–88 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Ide, S. et al. Association between genetic polymorphisms in Cav2.3 (R-type) Ca2+ channels and fentanyl sensitivity in patients undergoing painful cosmetic surgery. PLoS ONE 8, e70694 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Herman, S. T. Epilepsy after brain insult: targeting epileptogenesis. Neurology 59, S21–S26 (2002).

    Article  PubMed  Google Scholar 

  121. Blumenfeld, H. Cellular and network mechanisms of spike-wave seizures. Epilepsia 46 (Suppl. 9), 21–33 (2005).

    Article  CAS  PubMed  Google Scholar 

  122. Noebels, J. L. The biology of epilepsy genes. Annu. Rev. Neurosci. 26, 599–625 (2003).

    Article  CAS  PubMed  Google Scholar 

  123. Heron, S. E., Scheffer, I. E., Berkovic, S. F., Dibbens, L. M. & Mulley, J. C. Channelopathies in idiopathic epilepsy. Neurotherapeutics 4, 295–304 (2007).

    Article  CAS  PubMed  Google Scholar 

  124. Khosravani, H. & Zamponi, G. W. Voltage-gated calcium channels and idiopathic generalized epilepsies. Physiol. Rev. 86, 941–966 (2006).

    Article  CAS  PubMed  Google Scholar 

  125. Luttjohann, A. & van Luijtelaar, G. Dynamics of networks during absence seizure's on- and offset in rodents and man. Front. Physiol. 6, 16 (2015).

    PubMed  PubMed Central  Google Scholar 

  126. Cheong, E. & Shin, H. S. T-type Ca2+ channels in absence epilepsy. Pflugers Arch. 466, 719–734 (2014).

    Article  CAS  PubMed  Google Scholar 

  127. Tscherter, A. et al. Minimal alterations in T-type calcium channel gating markedly modify physiological firing dynamics. J. Physiol. 589, 1707–1724 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Song, I. et al. Role of the α1G T-type calcium channel in spontaneous absence seizures in mutant mice. J. Neurosci. 24, 5249–5257 (2004). This paper reveals an upregulation of T-type calcium channels in several mouse models of epilepsy, and shows that deletion of Cav3.1 channels protects from absence seizures.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Powell, K. L. et al. 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, 371–380 (2009). This important paper reveals that Cav3.2 mutations linked to epilepsy manifest their physiological effects in a channel splice isoform-dependent manner.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Zamponi, G. W., Lory, P. & Perez-Reyes, E. Role of voltage-gated calcium channels in epilepsy. Pflugers Arch. 460, 395–403 (2010).

    Article  CAS  PubMed  Google Scholar 

  131. Heron, S. E. et al. Extended spectrum of idiopathic generalized epilepsies associated with CACNA1H functional variants. Ann. Neurol. 62, 560–568 (2007).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  133. Vitko, I. et al. The I-II loop controls plasma membrane expression and gating of Cav3.2 T-type Ca2+ channels: a paradigm for childhood absence epilepsy mutations. J. Neurosci. 27, 322–330 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Eckle, V. S. et al. Mechanisms by which a CACNA1H mutation in epilepsy patients increases seizure susceptibility. J. Physiol. 592, 795–809 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Ernst, W. L., Zhang, Y., Yoo, J. W., Ernst, S. J. & Noebels, J. L. Genetic enhancement of thalamocortical network activity by elevating α1g-mediated low-voltage-activated calcium current induces pure absence epilepsy. J. Neurosci. 29, 1615–1625 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Kim, D. et al. Lack of the burst firing of thalamocortical relay neurons and resistance to absence seizures in mice lacking α1G T-type Ca2+ channels. Neuron 31, 35–45 (2001).

    Article  CAS  PubMed  Google Scholar 

  137. Cain, S. M. & Snutch, T. P. Contributions of T-type calcium channel isoforms to neuronal firing. Channels 4, 475–482 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Astori, S. et al. The Cav3.3 calcium channel is the major sleep spindle pacemaker in thalamus. Proc. Natl Acad. Sci. USA 108, 13823–13828 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  139. Lee, S. E. et al. Rebound burst firing in the reticular thalamus is not essential for pharmacological absence seizures in mice. Proc. Natl Acad. Sci. USA 111, 11828–11833 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Huguenard, J. R. Block of T -type Ca2+ channels is an important action of succinimide antiabsence drugs. Epilepsy Curr. 2, 49–52 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  141. Gomora, J. C., Daud, A. N., Weiergraber, M. & Perez-Reyes, E. Block of cloned human T-type calcium channels by succinimide antiepileptic drugs. Mol. Pharmacol. 60, 1121–1132 (2001).

    Article  CAS  PubMed  Google Scholar 

  142. Todorovic, S. M. & Lingle, C. J. Pharmacological properties of T-type Ca2+ current in adult rat sensory neurons: effects of anticonvulsant and anesthetic agents. J. Neurophysiol. 79, 240–252 (1998).

    Article  CAS  PubMed  Google Scholar 

  143. Ziyatdinova, S. et al. Spontaneous epileptiform discharges in a mouse model of Alzheimer's disease are suppressed by antiepileptic drugs that block sodium channels. Epilepsy Res. 94, 75–85 (2011).

    Article  CAS  PubMed  Google Scholar 

  144. Gottlicher, M. et al. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J. 20, 6969–6978 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Matar, N. et al. Zonisamide block of cloned human T-type voltage-gated calcium channels. Epilepsy Res. 83, 224–234 (2009).

    Article  CAS  PubMed  Google Scholar 

  146. Tanabe, M., Murakami, T. & Ono, H. Zonisamide suppresses pain symptoms of formalin-induced inflammatory and streptozotocin-induced diabetic neuropathy. J. Pharmacol. Sci. 107, 213–220 (2008).

    Article  CAS  PubMed  Google Scholar 

  147. Tringham, E. et al. T-type calcium channel blockers that attenuate thalamic burst firing and suppress absence seizures. Sci. Transl. Med. 4, 121ra19 (2012). This elegant paper identifies novel T-type calcium channel blockers and assesses their efficacy in seizure models.

    Article  CAS  PubMed  Google Scholar 

  148. Johannessen Landmark, C., Beiske, G., Baftiu, A., Burns, M. L. & Johannessen, S. I. Experience from therapeutic drug monitoring and gender aspects of gabapentin and pregabalin in clinical practice. Seizure 28, 88–91 (2015).

    Article  PubMed  Google Scholar 

  149. Iyer, A. & Marson, A. Pharmacotherapy of focal epilepsy. Expert Opin. Pharmacother. 15, 1543–1551 (2014).

    Article  CAS  PubMed  Google Scholar 

  150. Glauser, T. A. et al. Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy: initial monotherapy outcomes at 12 months. Epilepsia 54, 141–155 (2013).

    Article  CAS  PubMed  Google Scholar 

  151. Hainsworth, A. H., McNaughton, N. C., Pereverzev, A., Schneider, T. & Randall, A. D. Actions of sipatrigine, 202W92 and lamotrigine on R-type and T-type Ca2+ channel currents. Eur. J. Pharmacol. 467, 77–80 (2003).

    Article  CAS  PubMed  Google Scholar 

  152. Dibue, M. et al. Cav 2.3 (R-type) calcium channels are critical for mediating anticonvulsive and neuroprotective properties of lamotrigine in vivo. Epilepsia 54, 1542–1550 (2013).

    Article  CAS  PubMed  Google Scholar 

  153. Kuzmiski, J. B., Barr, W., Zamponi, G. W. & MacVicar, B. A. Topiramate inhibits the initiation of plateau potentials in CA1 neurons by depressing R-type calcium channels. Epilepsia 46, 481–489 (2005).

    Article  CAS  PubMed  Google Scholar 

  154. Radzicki, D. et al. Temperature-sensitive Cav1.2 calcium channels support intrinsic firing of pyramidal neurons and provide a target for the treatment of febrile seizures. J. Neurosci. 33, 9920–9931 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Furukawa, T. et al. Five different profiles of dihydropyridines in blocking T-type Ca2+ channel subtypes (Cav3.1 (α1G), Cav3.2 (α1H), and Cav3.3 (α1I)) expressed in Xenopus oocytes. Eur. J. Pharmacol. 613, 100–107 (2009).

    Article  CAS  PubMed  Google Scholar 

  156. Sirven, J. I., Noe, K., Hoerth, M. & Drazkowski, J. Antiepileptic drugs 2012: recent advances and trends. Mayo Clin. Proc. 87, 879–889 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Sulzer, D. & Surmeier, D. J. Neuronal vulnerability, pathogenesis, and Parkinson's disease. Mov. Disord. 28, 715–724 (2013).

    Article  PubMed  Google Scholar 

  158. Zahodne, L. B. & Fernandez, H. H. Pathophysiology and treatment of psychosis in Parkinson's disease: a review. Drugs Aging 25, 665–682 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Connolly, B. S. & Lang, A. E. Pharmacological treatment of Parkinson disease: a review. JAMA 311, 1670–1683 (2014).

    Article  CAS  PubMed  Google Scholar 

  160. Kalia, L. V., Kalia, S. K., McLean, P. J., Lozano, A. M. & Lang, A. E. α-synuclein oligomers and clinical implications for Parkinson disease. Ann. Neurol. 73, 155–169 (2013).

    Article  CAS  PubMed  Google Scholar 

  161. Nuytemans, K., Theuns, J., Cruts, M. & Van Broeckhoven, C. Genetic etiology of Parkinson disease associated with mutations in the SNCA, PARK2, PINK1, PARK7, and LRRK2 genes: a mutation update. Hum. Mutat. 31, 763–780 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Abdel-Salam, O. M. The paths to neurodegeneration in genetic Parkinson's disease. CNS Neurol. Disord. Drug Targets 13, 1485–1512 (2014).

    Article  CAS  PubMed  Google Scholar 

  163. Putzier, I., Kullmann, P. H., Horn, J. P. & Levitan, E. S. Cav1.3 channel voltage dependence, not Ca2+ selectivity, drives pacemaker activity and amplifies bursts in nigral dopamine neurons. J. Neurosci. 29, 15414–15419 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Guzman, J. N., Sánchez-Padilla, J., Chan, C. S. & Surmeier, D. J. Robust pacemaking in substantia nigra dopaminergic neurons. J. Neurosci. 29, 11011–11019 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Chan, C. S., Gertler, T. S. & Surmeier, D. J. A molecular basis for the increased vulnerability of substantia nigra dopamine neurons in aging and Parkinson's disease. Mov. Disord. 25 (Suppl. 1), 63–70 (2010).

    Article  Google Scholar 

  166. Guzman, J. N. et al. Oxidant stress evoked by pacemaking in dopaminergic neurons is attenuated by DJ-1. Nature 468, 696–700 (2010). This important study links pacemaker activity in dopaminergic substantia nigra neurons to L-type calcium channel-mediated increases in oxidative stress and cell damage.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Hurley, M. J., Brandon, B., Gentleman, S. M. & Dexter, D. T. Parkinson's disease is associated with altered expression of Cav1 channels and calcium-binding proteins. Brain 136, 2077–2097 (2013).

    Article  PubMed  Google Scholar 

  168. Dragicevic, E. et al. Cav1.3 channels control D2-autoreceptor responses via NCS-1 in substantia nigra dopamine neurons. Brain 137, 2287–2302 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  169. Anzalone, A. et al. Dual control of dopamine synthesis and release by presynaptic and postsynaptic dopamine D2 receptors. J. Neurosci. 32, 9023–9034 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Parkinson Study Group. Phase II safety, tolerability, and dose selection study of isradipine as a potential disease-modifying intervention in early Parkinson's disease (STEADY-PD). Mov. Disord. 28, 1823–1831 (2013). This clinical trial supports the administration of the L-type channel blocker isradipine as a possible therapeutic strategy for Parkinson disease.

  171. Striessnig, J., Pinggera, A., Kaur, G., Bock, G. & Tuluc, P. L-type Ca2+ channels in heart and brain. Wiley Interdiscip. Rev. Membr. Transp. Signal 3, 15–38 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Kang, S. et al. CaV1.3-selective L-type calcium channel antagonists as potential new therapeutics for Parkinson's disease. Nat. Commun. 3, 1146 (2012).

    Article  CAS  PubMed  Google Scholar 

  173. Huang, H. et al. Modest CaV1.342-selective inhibition by compound 8 is β-subunit dependent. Nat. Commun. 5, 4481 (2014).

    Article  CAS  PubMed  Google Scholar 

  174. Ortner, N. J. et al. Pyrimidine-2,4,6-triones are a new class of voltage-gated L-type Ca2+ channel activators. Nat. Commun. 5, 3897 (2014).

    Article  CAS  PubMed  Google Scholar 

  175. Tai, C. H., Yang, Y. C., Pan, M. K., Huang, C. S. & Kuo, C. C. Modulation of subthalamic T-type Ca2+ channels remedies locomotor deficits in a rat model of Parkinson disease. J. Clin. Invest. 121, 3289–3305 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Scott, C. K., Dennis, M. L., Laudet, A., Funk, R. R. & Simeone, R. S. Surviving drug addiction: the effect of treatment and abstinence on mortality. Am. J. Publ. Health 101, 737–744 (2011).

    Article  Google Scholar 

  177. Buttner, A. Review: the neuropathology of drug abuse. Neuropathol. Appl. Neurobiol. 37, 118–134 (2011).

    Article  CAS  PubMed  Google Scholar 

  178. Fowler, J. S., Volkow, N. D., Kassed, C. A. & Chang, L. Imaging the addicted human brain. Sci. Pract. Perspect. 3, 4–16 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  179. Nestler, E. J. The neurobiology of cocaine addiction. Sci. Pract. Perspect. 3, 4–10 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  180. Kosten, T. R. & George, T. P. The neurobiology of opioid dependence: implications for treatment. Sci. Pract. Perspect. 1, 13–20 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  181. Pierce, R. C. & Kumaresan, V. The mesolimbic dopamine system: the final common pathway for the reinforcing effect of drugs of abuse? Neurosci. Biobehav Rev. 30, 215–238 (2006).

    Article  CAS  PubMed  Google Scholar 

  182. Chen, B. T., Hopf, F. W. & Bonci, A. Synaptic plasticity in the mesolimbic system: therapeutic implications for substance abuse. Ann. NY Acad. Sci. 1187, 129–139 (2010).

    Article  CAS  PubMed  Google Scholar 

  183. Adinoff, B. Neurobiologic processes in drug reward and addiction. Harv. Rev. Psychiatry 12, 305–320 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  184. Koob, G. F. & Volkow, N. D. Neurocircuitry of addiction. Neuropsychopharmacology 35, 217–238 (2010).

    Article  PubMed  Google Scholar 

  185. Rosse, R. B. et al. Nimodipine pharmacotherapeutic adjuvant therapy for inpatient treatment of cocaine dependence. Clin. Neuropharmacol. 17, 348–358 (1994).

    Article  CAS  PubMed  Google Scholar 

  186. Reimer, A. R. & Martin-Iverson, M. T. Nimodipine and haloperidol attenuate behavioural sensitization to cocaine but only nimodipine blocks the establishment of conditioned locomotion induced by cocaine. Psychopharmacol. 113, 404–410 (1994).

    Article  CAS  Google Scholar 

  187. Pierce, R. C., Quick, E. A., Reeder, D. C., Morgan, Z. R. & Kalivas, P. W. Calcium-mediated second messengers modulate the expression of behavioral sensitization to cocaine. J. Pharmacol. Exp. Ther. 286, 1171–1176 (1998).

    CAS  PubMed  Google Scholar 

  188. De Beun, R., Schneider, R., Klein, A., Lohmann, A. & De Vry, J. Effects of nimodipine and other calcium channel antagonists in alcohol-preferring AA rats. Alcohol 13, 263–271 (1996).

    Article  CAS  PubMed  Google Scholar 

  189. Giordano, T. P., Satpute, S. S., Striessnig, J., Kosofsky, B. E. & Rajadhyaksha, A. M. Up-regulation of dopamine D2L mRNA levels in the ventral tegmental area and dorsal striatum of amphetamine-sensitized C57BL/6 mice: role of Cav1.3 L-type Ca2+ channels. J. Neurochem. 99, 1197–1206 (2006).

    Article  CAS  PubMed  Google Scholar 

  190. Giordano, T. P. et al. Molecular switch from L-type Cav1.3 to Cav1.2 Ca2+ channel signaling underlies long-term psychostimulant-induced behavioral and molecular plasticity. J. Neurosci. 30, 17051–17062 (2010). This paper elegantly links L-type calcium channels to drug addiction.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Schierberl, K. et al. Cav1.3 L-type Ca2+ channels mediate long-term adaptation in dopamine D2L-mediated GluA1 trafficking in the dorsal striatum following cocaine exposure. Channels 6, 11–17 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Schierberl, K. et al. Cav1.2 L-type Ca2+ channels mediate cocaine-induced GluA1 trafficking in the nucleus accumbens, a long-term adaptation dependent on ventral tegmental area Cav1.3 channels. J. Neurosci. 31, 13562–13575 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Rajadhyaksha, A. et al. L-type Ca2+ channels mediate adaptation of extracellular signal-regulated kinase 1/2 phosphorylation in the ventral tegmental area after chronic amphetamine treatment. J. Neurosci. 24, 7464–7476 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Liu, Y. et al. Cav1.2 and Cav1.3 L-type calcium channels regulate dopaminergic firing activity in the mouse ventral tegmental area. J. Neurophysiol. 112, 1119–1130 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Shulman, A., Jagoda, J., Laycock, G. & Kelly, H. Calcium channel blocking drugs in the management of drug dependence, withdrawal and craving. A clinical pilot study with nifedipine and verapamil. Aust. Fam. Physician 27 (Suppl. 1), 19–24 (1998).

    Google Scholar 

  196. Jimenez-Lerma, J. M. et al. Nimodipine in opiate detoxification: a controlled trial. Addiction 97, 819–824 (2002).

    Article  PubMed  Google Scholar 

  197. Newton, P. M. et al. A blocker of N- and T-type voltage-gated calcium channels attenuates ethanol-induced intoxication, place preference, self-administration, and reinstatement. J. Neurosci. 28, 11712–11719 (2008). This paper links the blockade of T-type and N-type channels to relief from alcohol addiction.

    Article  PubMed  PubMed Central  Google Scholar 

  198. Bhutada, P. et al. Cilnidipine, an L/N-type calcium channel blocker prevents acquisition and expression of ethanol-induced locomotor sensitization in mice. Neurosci. Lett. 514, 91–95 (2012).

    Article  CAS  PubMed  Google Scholar 

  199. Ferreira, M. A. et al. Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nat. Genet. 40, 1056–1058 (2008). This important study identifies Cav1.2 channels as a risk factor in psychiatric disorders.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Cross-Disorder Group of the Psychiatric Genomics Consortium. Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet 381, 1371–1379 (2013).

  201. Wang, F., McIntosh, A. M., He, Y., Gelernter, J. & Blumberg, H. P. The association of genetic variation in CACNA1C with structure and function of a frontotemporal system. Bipolar Disord. 13, 696–700 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Paulus, F. M. et al. Association of rs1006737 in CACNA1C with alterations in prefrontal activation and fronto-hippocampal connectivity. Hum. Brain Mapp. 35, 1190–1200 (2014).

    Article  PubMed  Google Scholar 

  203. Erk, S. et al. Replication of brain function effects of a genome-wide supported psychiatric risk variant in the CACNA1C gene and new multi-locus effects. Neuroimage 94, 147–154 (2014).

    Article  CAS  PubMed  Google Scholar 

  204. Ament, S. A. et al. Rare variants in neuronal excitability genes influence risk for bipolar disorder. Proc. Natl Acad. Sci. USA 112, 3576–3581 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Gershon, E. S. et al. A rare mutation of CACNA1C in a patient with bipolar disorder, and decreased gene expression associated with a bipolar-associated common SNP of CACNA1C in brain. Mol. Psychiatry 19, 890–894 (2014).

    Article  CAS  PubMed  Google Scholar 

  206. Yoshimizu, T. et al. Functional implications of a psychiatric risk variant within CACNA1C in induced human neurons. Mol. Psychiatry 20, 284 (2015).

    Article  CAS  PubMed  Google Scholar 

  207. Ostacher, M. J. et al. Pilot investigation of isradipine in the treatment of bipolar depression motivated by genome-wide association. Bipolar Disord. 16, 199–203 (2014).

    Article  CAS  PubMed  Google Scholar 

  208. Splawski, I. et al. CaV1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell 119, 19–31 (2004). This manuscript reports on the devastating effects of a de novo mutation in Cav1.2 channels in patients with Timothy syndrome.

    Article  CAS  PubMed  Google Scholar 

  209. Splawski, I. et al. Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations. Proc. Natl Acad. Sci. USA 102, 8089–8096; discussion 8086–8088 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Tian, Y. et al. Alteration in basal and depolarization induced transcriptional network in iPSC derived neurons from Timothy syndrome. Genome Med. 6, 75 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Krey, J. F. et al. Timothy syndrome is associated with activity-dependent dendritic retraction in rodent and human neurons. Nat. Neurosci. 16, 201–209 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Pinggera, A. et al. CACNA1D de novo mutations in autism spectrum disorders activate Cav1.3 L-type calcium channels. Biol. Psychiatry 77, 816–822 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Breitenkamp, A. F. et al. Rare mutations of CACNB2 found in autism spectrum disease-affected families alter calcium channel function. PLoS ONE 9, e95579 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Lu, A. T., Dai, X., Martinez-Agosto, J. A. & Cantor, R. M. Support for calcium channel gene defects in autism spectrum disorders. Mol. Autism 3, 18 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Splawski, I. et al. CACNA1H mutations in autism spectrum disorders. J. Biol. Chem. 281, 22085–22091 (2006).

    Article  CAS  PubMed  Google Scholar 

  216. Duval, E. R., Javanbakht, A. & Liberzon, I. Neural circuits in anxiety and stress disorders: a focused review. Ther. Clin. Risk Manag 11, 115–126 (2015).

    PubMed  PubMed Central  Google Scholar 

  217. Fox, A. S., Oler, J. A., Tromp, D. P., Fudge, J. L. & Kalin, N. H. Extending the amygdala in theories of threat processing. Trends Neurosci. 38, 319–329 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Felix-Ortiz, A. C. et al. BLA to vHPC inputs modulate anxiety-related behaviors. Neuron 79, 658–664 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Ricord, M. Academy of Medicine: Paris. Prov. Med. Surg. J. 2, 96–97 (1841).

    CAS  Google Scholar 

  220. Nasca, C. et al. Exposure to predator odor and resulting anxiety enhances the expression of the α2δ subunit of voltage-sensitive calcium channels in the amygdala. J. Neurochem. 125, 649–656 (2013).

    Article  CAS  PubMed  Google Scholar 

  221. Strawn, J. R. & Geracioti, T. D. Jr. The treatment of generalized anxiety disorder with pregabalin, an atypical anxiolytic. Neuropsychiatr. Dis. Treat. 3, 237–243 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Shinnick-Gallagher, P., McKernan, M. G., Xie, J. & Zinebi, F. L-type voltage-gated calcium channels are involved in the in vivo and in vitro expression of fear conditioning. Ann. NY Acad. Sci. 985, 135–149 (2003).

    Article  CAS  PubMed  Google Scholar 

  223. Lee, A. S. et al. Forebrain elimination of cacna1c mediates anxiety-like behavior in mice. Mol. Psychiatry 17, 1054–1055 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Dao, D. T. et al. Mood disorder susceptibility gene CACNA1C modifies mood-related behaviors in mice and interacts with sex to influence behavior in mice and diagnosis in humans. Biol. Psychiatry 68, 801–810 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Fulga, I. G. & Stroescu, V. Experimental research on the effect of calcium channel blockers nifedipine and verapamil on the anxiety in mice. Rom. J. Physiol. 34, 127–136 (1997).

    CAS  PubMed  Google Scholar 

  226. Busquet, P. et al. CaV1.3 L-type Ca2+ channels modulate depression-like behaviour in mice independent of deaf phenotype. Int. J. Neuropsychopharmacol. 13, 499–513 (2010).

    Article  CAS  PubMed  Google Scholar 

  227. Saegusa, H. et al. Suppression of inflammatory and neuropathic pain symptoms in mice lacking the N-type Ca2+ channel. EMBO J. 20, 2349–2356 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. Cassidy, J. S., Ferron, L., Kadurin, I., Pratt, W. S. & Dolphin, A. C. Functional exofacially tagged N-type calcium channels elucidate the interaction with auxiliary α2δ-1 subunits. Proc. Natl Acad. Sci. USA 111, 8979–8984 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Murakami, M. et al. Modified behavioral characteristics following ablation of the voltage-dependent calcium channel β3 subunit. Brain Res. 1160, 102–112 (2007).

    Article  CAS  PubMed  Google Scholar 

  230. Lee, J. & Shin, H. S. T-type calcium channels and thalamocortical rhythms in sleep: a perspective from studies of T-type calcium channel knockout mice. CNS Neurol. Disord. Drug Targets 6, 63–69 (2007).

    Article  CAS  PubMed  Google Scholar 

  231. Amer, A. & Maher, T. J. Nasal administration of the calcium channel blocker diltiazem decreases food intake and attenuates weight gain in rats. Pharmacol. Biochem. Behav. 82, 379–387 (2005).

    Article  CAS  PubMed  Google Scholar 

  232. Bell, T. J., Thaler, C., Castiglioni, A. J., Helton, T. D. & Lipscombe, D. Cell-specific alternative splicing increases calcium channel current density in the pain pathway. Neuron 41, 127–138 (2004).

    Article  CAS  PubMed  Google Scholar 

  233. Altier, C. et al. Differential role of N-type calcium channel splice isoforms in pain. J. Neurosci. 27, 6363–6373 (2007). This study follows up on findings in reference 232 and shows that a unique Cav2.2 splice variant that is selectively expressed in nociceptive fibres is critical for pain transmission.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. Chang, S. Y. et al. Age and gender-dependent alternative splicing of P/Q-type calcium channel EF-hand. Neuroscience 145, 1026–1036 (2007).

    Article  CAS  PubMed  Google Scholar 

  235. Michailidis, I. E. et al. Age-related homeostatic midchannel proteolysis of neuronal L-type voltage-gated Ca2+ channels. Neuron 82, 1045–1057 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. Schrauwen, I. et al. A mutation in CABP2, expressed in cochlear hair cells, causes autosomal-recessive hearing impairment. Am. J. Hum. Genet. 91, 636–645 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Yang, P. S. et al. Switching of Ca2+-dependent inactivation of Cav1.3 channels by calcium binding proteins of auditory hair cells. J. Neurosci. 26, 10677–10689 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  238. Kuryshev, Y. A., Brown, A. M., Duzic, E. & Kirsch, G. E. Evaluating state dependence and subtype selectivity of calcium channel modulators in automated electrophysiology assays. Assay Drug Dev. Technol. 12, 110–119 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Brittain, J. M. et al. Suppression of inflammatory and neuropathic pain by uncoupling CRMP-2 from the presynaptic Ca2+ channel complex. Nat. Med. 17, 822–829 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Garcia-Caballero, A. et al. The deubiquitinating enzyme USP5 modulates neuropathic and inflammatory pain by enhancing Cav3.2 channel activity. Neuron 83, 1144–1158 (2014). This study identifies deubiquitylation of Cav3.2 channels as a critical factor in the development of chronic pain, and shows that interfering with this process can be exploited to develop new analgesics.

    Article  CAS  PubMed  Google Scholar 

  241. Gadotti, V. M. et al. Small organic molecule disruptors of Cav3.2–USP5 interactions reverse inflammatory and neuropathic pain. Mol. Pain 11, 12 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  242. Inagaki, A., Frank, C. A., Usachev, Y. M., Benveniste, M. & Lee, A. Pharmacological correction of gating defects in the voltage-gated Cav2.1 Ca2+ channel due to a familial hemiplegic migraine mutation. Neuron 81, 91–102 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. Fischer, T. Z. et al. A novel Nav1.7 mutation producing carbamazepine-responsive erythromelalgia. Ann. Neurol. 65, 733–741 (2009). The authors of this paper identify a sodium channel mutation in a patient with erythromelalgia, study the effect of the mutation in a recombinant expression system, and then use this information to design customized treatment of the patient.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

G.W.Z. holds a Canada Research Chair, and work in his laboratory is supported by grants from the Canadian Institutes of Health Research, Alberta Innovates: Health Solutions, and the Natural Sciences and Engineering Research Council of Canada.

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Correspondence to Gerald W. Zamponi.

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Glossary

Calcium channels

A group of membrane proteins that allow entry of calcium into cells.

Alternative splicing

A process by which one gene can create different variants of one protein.

Parkinson disease

A neurological disorder caused by a loss of dopaminergic neurons.

Epilepsy

A neurological disorder in which patients present with seizures.

Dihydropyridines

A class of drug molecules that often act on calcium channels.

Phenylalkylamines

A specific class of small organic molecules that block calcium channels.

Use-dependence

A process by which an ion-channel-blocking drug becomes more effective during repetitive activation of the channel.

Opioid

A molecule that activates opioid receptors.

Gabapentinoids

A class of compounds that acts on the ancillary calcium channel Cavα2δ subunit. Gabapentinoids are used as analgesics.

Gabapentin

A compound that is used in the treatment of neuropathic pain.

Pregabalin

A compound that is used in the treatment of neuropathic pain.

Neuropathic pain

A chronic pain condition arising from a peripheral nerve injury.

Ziconotide

A synthetic version of ω-conotoxin MIIA that is used for pain treatment.

Z160

A blocker of N-type calcium channels that was explored as an analgesic.

TROX-1

A blocker of N-type calcium channels that was developed by Merck.

Neuropathy

A disease or dysfunction of peripheral nerves.

Ethosuximide

A type of anti-epileptic drug that acts on T-type calcium channels.

Z944

A drug molecule that potently blocks T-type calcium channels.

SNX-482

A blocker of R-type calcium channels that is isolated from tarantula venom.

Dorsal root ganglion

(DRG). A cluster of nerve cell bodies comprising primary afferent sensory fibres.

Polymorphisms

The presence of genetic variations in a given population.

nRT neurons

Reticular thalamic nucleus neurons; a specific group of neurons within the thalamus.

Thalamus

A specific brain region involved in functions such as sleep.

Trafficking

The process by which proteins are transported to specific loci in cells.

Valproate

An anti-epileptic drug with multiple molecular targets.

Lamotrigine

An anti-epileptic drug with multiple molecular targets.

Topiramate

An anti-epileptic drug with multiple cellular targets.

Nimodipine

A blocker of L-type calcium channels from the dihydropyridine class.

Neurodegenerative disorders

Disorders caused by the loss of nerve cells during disease.

Striatum

A specific subcortical part of the forebrain.

Tremor

Uncontrolled trembling and shaking motion of the limbs.

Dopamine

A neurotransmitter that acts on dopamine receptors.

Isradipine

A dihydropyridine that is used as an antihypertensive and currently being explored as a drug for Parkinson disease.

Ventral tegmental area

A collection of specific neurons in the midbrain that is part of the reward system.

Nucleus accumbens

A specific brain region that is involved in reward behaviour.

Nifedipine

A blocker of L-type calcium channels from the dihydropyridine class.

Cilnidipine

A specific dihydropyridine that blocks both N-type and L-type calcium channels.

Bipolar disorder

A neuropsychiatric condition marked by alternating bouts of elation and depression.

Schizophrenia

A common neuropsychiatric disorder.

Amygdala

A specific brain region known to be involved in fear.

Channelopathies

A group of conditions in which mutations in specific ion channels give rise to disease.

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Zamponi, G. Targeting voltage-gated calcium channels in neurological and psychiatric diseases. Nat Rev Drug Discov 15, 19–34 (2016). https://doi.org/10.1038/nrd.2015.5

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