Advertisement

T-type calcium channels in chronic pain: mouse models and specific blockers

  • Amaury François
  • Sophie Laffray
  • Anne Pizzoccaro
  • Alain Eschalier
  • Emmanuel BourinetEmail author
Invited Review

Abstract

Pain is a quite frequent complaint accompanying numerous pathologies. Among these pathological cases, neuropathies are retrieved with identified etiologies (chemotherapies, diabetes, surgeries…) and also more diffuse syndromes such as fibromyalgia. More broadly, pain is one of the first consequences of the majority of inherited diseases. Despite its importance for the quality of life, current pain management is limited to drugs that are either old or with a limited efficacy or that possess a bad benefit/risk ratio. As no new pharmacological concept has led to new analgesics in the last decades, the discovery of medications is needed, and to this aim the identification of new druggable targets in pain transmission is a first step. Therefore, studies of ion channels in pain pathways are extremely active. This is particularly true with ion channels in peripheral sensory neurons in dorsal root ganglia (DRG) known now to express unique sets of these channels. Moreover, both spinal and supraspinal levels are clearly important in pain modulation. Among these ion channels, we and others revealed the important role of low voltage-gated calcium channels in cellular excitability in different steps of the pain pathways. These channels, by being activated nearby resting membrane potential have biophysical characteristics suited to facilitate action potential generation and rhythmicity. In this review, we will review the current knowledge on the role of these channels in the perception and modulation of pain.

Keywords

Chronic pain Allodynia T-type calcium channel Mouse model Analgesia 

Notes

Acknowledgments

Pain-related work conducted in the authors’ laboratory is supported by the Agence Nationale pour la Recherche, Association Française pour les Myopathies, Institut UPSA de la Douleur, and the Fondation pour la Recherche Médicale.

References

  1. 1.
    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):483–489Google Scholar
  2. 2.
    Apkarian AV, Bushnell MC, Treede RD, Zubieta JK (2005) Human brain mechanisms of pain perception and regulation in health and disease. Eur J Pain 9(4):463–484. doi: 10.1016/j.ejpain.2004.11.001 PubMedGoogle Scholar
  3. 3.
    Bachy I, Franck MC, Li L, Abdo H, Pattyn A, Ernfors P (2011) The transcription factor Cux2 marks development of an A-delta sublineage of TrkA sensory neurons. Dev Biol 360(1):77–86. doi: 10.1016/j.ydbio.2011.09.007 PubMedGoogle Scholar
  4. 4.
    Bao J, Li JJ, Perl ER (1998) Differences in Ca2+ channels governing generation of miniature and evoked excitatory synaptic currents in spinal laminae I and II. J Neurosci 18(21):8740–8750PubMedGoogle Scholar
  5. 5.
    Barbara G, Alloui A, Nargeot J, Lory P, Eschalier A, Bourinet E, Chemin J (2009) T-type calcium channel inhibition underlies the analgesic effects of the endogenous lipoamino acids. J Neurosci 29(42):13106-–13114. doi: 10.1523/JNEUROSCI.2919-09.2009 PubMedGoogle Scholar
  6. 6.
    Basbaum AI, Bautista DM, Scherrer G, Julius D (2009) Cellular and molecular mechanisms of pain. Cell 139(2):267–284. doi: 10.1016/j.cell.2009.09.028 PubMedCentralPubMedGoogle Scholar
  7. 7.
    Basbaum AI, Braz JM (2010) Transgenic mouse models for the tracing of “pain” pathways. In: Kruger L, Light AR (eds) Translational Pain Research: From Mouse to Man. Frontiers in Neuroscience, Boca Raton, FLGoogle Scholar
  8. 8.
    Bender KJ, Ford CP, Trussell LO (2010) Dopaminergic modulation of axon initial segment calcium channels regulates action potential initiation. Neuron 68(3):500–511. doi: 10.1016/j.neuron.2010.09.026 PubMedCentralPubMedGoogle Scholar
  9. 9.
    Bender KJ, Trussell LO (2009) Axon initial segment Ca2+ channels influence action potential generation and timing. Neuron 61(2):259–271. doi: 10.1016/j.neuron.2008.12.004 PubMedCentralPubMedGoogle Scholar
  10. 10.
    Bergquist F, Nissbrandt H (2003) Influence of R-type (Cav2.3) and t-type (Cav3.1-3.3) antagonists on nigral somatodendritic dopamine release measured by microdialysis. Neuroscience 120(3):757–764PubMedGoogle Scholar
  11. 11.
    Bladen C, Zamponi GW (2012) Common mechanisms of drug interactions with sodium and T-type calcium channels. Mol Pharmacol 82(3):481–487. doi: 10.1124/mol.112.079715 PubMedGoogle Scholar
  12. 12.
    Blasius AL, Dubin AE, Petrus MJ, Lim BK, Narezkina A, Criado JR, Wills DN, Xia Y, Moresco EM, Ehlers C, Knowlton KU, Patapoutian A, Beutler B (2011) Hypermorphic mutation of the voltage-gated sodium channel encoding gene Scn10a causes a dramatic stimulus-dependent neurobehavioral phenotype. Proc Natl Acad Sci U S A 108(48):19413–19418. doi: 10.1073/pnas.1117020108 PubMedCentralPubMedGoogle Scholar
  13. 13.
    Bossu JL, Feltz A, Thomann JM (1985) Depolarization elicits two distinct calcium currents in vertebrate sensory neurones. Pflugers Arch 403(4):360–368PubMedGoogle Scholar
  14. 14.
    Bourdu S, Dapoigny M, Chapuy E, Artigue F, Vasson MP, Dechelotte P, Bommelaer G, Eschalier A, Ardid D (2005) Rectal instillation of butyrate provides a novel clinically relevant model of noninflammatory colonic hypersensitivity in rats. Gastroenterology 128(7):1996–2008PubMedGoogle Scholar
  15. 15.
    Bourinet E, Alloui A, Monteil A, Barrere C, Couette B, Poirot O, Pages A, McRory J, Snutch TP, Eschalier A, Nargeot J (2005) Silencing of the Cav3.2 T-type calcium channel gene in sensory neurons demonstrates its major role in nociception. Embo J 24(2):315–324PubMedCentralPubMedGoogle Scholar
  16. 16.
    Bourinet E, Soong TW, Sutton K, Slaymaker S, Mathews E, Monteil A, Zamponi GW, Nargeot J, Snutch TP (1999) Splicing of alpha 1A subunit gene generates phenotypic variants of P- and Q-type calcium channels. Nat Neurosci 2(5):407–415PubMedGoogle Scholar
  17. 17.
    Braz JM, Nassar MA, Wood JN, Basbaum AI (2005) Parallel “pain” pathways arise from subpopulations of primary afferent nociceptor. Neuron 47(6):787–793. doi: 10.1016/j.neuron.2005.08.015 PubMedGoogle Scholar
  18. 18.
    Cao XH, Byun HS, Chen SR, Pan HL (2011) Diabetic neuropathy enhances voltage-activated Ca2+ channel activity and its control by M4 muscarinic receptors in primary sensory neurons. J Neurochem 119(3):594–603. doi: 10.1111/j.1471-4159.2011.07456.x PubMedCentralPubMedGoogle Scholar
  19. 19.
    Carbone E, Lux HD (1984) A low voltage-activated, fully inactivating Ca channel in vertebrate sensory neurones. Nature 310(5977):501–502PubMedGoogle Scholar
  20. 20.
    Casey KL (1999) Forebrain mechanisms of nociception and pain: analysis through imaging. Proc Natl Acad Sci U S A 96(14):7668–7674PubMedCentralPubMedGoogle Scholar
  21. 21.
    Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D (1997) The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389(6653):816–824. doi: 10.1038/39807 PubMedGoogle Scholar
  22. 22.
    Catterall WA (2011) Voltage-gated calcium channels. Cold Spring Harb perspect biol 3(8):a003947. doi: 10.1101/cshperspect.a003947 PubMedCentralPubMedGoogle Scholar
  23. 23.
    Chemin J, Monteil A, Bourinet E, Nargeot J, Lory P (2001) Alternatively spliced alpha (1G) (Ca (V)3.1) intracellular loops promote specific T-type Ca (2+) channel gating properties. Biophys J 80(3):1238–1250PubMedCentralPubMedGoogle Scholar
  24. 24.
    Chen CC, Lamping KG, Nuno DW, Barresi R, Prouty SJ, Lavoie JL, Cribbs LL, England SK, Sigmund CD, Weiss RM, Williamson RA, Hill JA, Campbell KP (2003) Abnormal coronary function in mice deficient in alpha1H T-type Ca2+ channels. Science 302(5649):1416–1418PubMedGoogle Scholar
  25. 25.
    Chen WK, Liu IY, Chang YT, Chen YC, Chen CC, Yen CT, Shin HS (2010) Ca(v)3.2 T-type Ca2+ channel-dependent activation of ERK in paraventricular thalamus modulates acid-induced chronic muscle pain. J Neurosci 30(31):10360–10368. doi: 10.1523/JNEUROSCI.1041-10.2010 PubMedGoogle Scholar
  26. 26.
    Choe W, Messinger RB, Leach E, Eckle VS, Obradovic A, Salajegheh R, Jevtovic-Todorovic V, Todorovic SM (2011) TTA-P2 is a potent and selective blocker of T-type calcium channels in rat sensory neurons and a novel antinociceptive agent. Mol Pharmacol. doi: 10.1124/mol.111.073205 PubMedCentralPubMedGoogle Scholar
  27. 27.
    Choi S, Na HS, Kim J, Lee J, Lee S, Kim D, Park J, Chen CC, Campbell KP, Shin HS (2007) Attenuated pain responses in mice lacking Ca (V) 3.2 T-type channels. Genes Brain Behav 6(5):425–431PubMedGoogle Scholar
  28. 28.
    Comunanza V, Carbone E, Marcantoni A, Sher E, Ursu D (2011) Calcium-dependent inhibition of T-type calcium channels by TRPV1 activation in rat sensory neurons. Pflugers Arch 462(5):709–722. doi: 10.1007/s00424-011-1023-5 PubMedGoogle Scholar
  29. 29.
    Coste B, Crest M, Delmas P (2007) Pharmacological dissection and distribution of NaN/Nav1.9, T-type Ca2+ currents, and mechanically activated cation currents in different populations of DRG neurons. J Gen Physiol 129(1):57–77. doi: 10.1085/jgp.200609665 PubMedCentralPubMedGoogle Scholar
  30. 30.
    Cribbs LL, Lee JH, Yang J, Satin J, Zhang Y, Daud A, Barclay J, Williamson MP, Fox M, Rees M, Perez-Reyes E (1998) Cloning and characterization of alpha1H from human heart, a member of the T-type Ca2+ channel gene family. Circ Res 83(1):103–109PubMedGoogle Scholar
  31. 31.
    David LS, Garcia E, Cain SM, Thau E, Tyson JR, Snutch TP (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. doi: 10.4161/chan.4.5.12874 Google Scholar
  32. 32.
    Delfini MC, Mantilleri A, Gaillard S, Hao J, Reynders A, Malapert P, Alonso S, Francois A, Barrere C, Seal R, Landry M, Eschallier A, Alloui A, Bourinet E, Delmas P, Le Feuvre Y, Moqrich A (2013) TAFA4, a chemokine-like protein, modulates injury-induced mechanical and chemical pain hypersensitivity in mice. Cell Rep 5(2):378–388. doi: 10.1016/j.celrep.2013.09.013 PubMedGoogle Scholar
  33. 33.
    Devor M (1999) Unexplained peculiarities of the dorsal root ganglion. Pain Suppl 6:S27–S35Google Scholar
  34. 34.
    Djouhri L, Lawson SN (2004) Abeta-fiber nociceptive primary afferent neurons: a review of incidence and properties in relation to other afferent A-fiber neurons in mammals. Brain Res Brain Res Rev 46(2):131–145. doi: 10.1016/j.brainresrev.2004.07.015 PubMedGoogle Scholar
  35. 35.
    Dogrul A, Gardell LR, Ossipov MH, Tulunay FC, Lai J, Porreca F (2003) Reversal of experimental neuropathic pain by T-type calcium channel blockers. Pain 105(1–2):159–168PubMedGoogle Scholar
  36. 36.
    Dreyfus FM, Tscherter A, Errington AC, Renger JJ, Shin HS, Uebele VN, Crunelli V, Lambert RC, Leresche N (2009) Selective T-type calcium channel block in thalamic neurons reveals channel redundancy and physiological impact of I(T)window. J Neurosci 30(1):99–109. doi: 10.1523/JNEUROSCI.4305-09.2010 Google Scholar
  37. 37.
    Dubel SJ, Altier C, Chaumont S, Lory P, Bourinet E, Nargeot J (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):29263–29269PubMedGoogle Scholar
  38. 38.
    Dubreuil AS, Boukhaddaoui H, Desmadryl G, Martinez-Salgado C, Moshourab R, Lewin GR, Carroll P, Valmier J, Scamps F (2004) Role of T-type calcium current in identified D-hair mechanoreceptor neurons studied in vitro. J Neurosci 24(39):8480–8484PubMedGoogle Scholar
  39. 39.
    Erlanger J (1927) The interpretation of the action potential in cutaneous and muscle nerves. Am J Physiol 1(82):11Google Scholar
  40. 40.
    Erlanger J, Gasser HS (1930) The action potential in fibers of slow conduction in spinal roots and somatic nerves. Am J Physiol 92(1):39Google Scholar
  41. 41.
    Fang X, McMullan S, Lawson SN, Djouhri L (2005) Electrophysiological differences between nociceptive and non-nociceptive dorsal root ganglion neurones in the rat in vivo. J Physiol 565(Pt 3):927–943. doi: 10.1113/jphysiol.2005.086199 PubMedCentralPubMedGoogle Scholar
  42. 42.
    Fedulova SA, Kostyuk PG, Veselovsky NS (1985) Two types of calcium channels in the somatic membrane of new-born rat dorsal root ganglion neurones. J Physiol 359:431–446PubMedCentralPubMedGoogle Scholar
  43. 43.
    Flatters SJ, Bennett GJ (2004) Ethosuximide reverses paclitaxel- and vincristine-induced painful peripheral neuropathy. Pain 109(1–2):150–161. doi: 10.1016/j.pain.2004.01.029 PubMedGoogle Scholar
  44. 44.
    Fox AP, Nowycky MC, Tsien RW (1987) Single-channel recordings of three types of calcium channels in chick sensory neurones. J Physiol 394:173–200PubMedCentralPubMedGoogle Scholar
  45. 45.
    Gackiere F, Bidaux G, Delcourt P, Van Coppenolle F, Katsogiannou M, Dewailly E, Bavencoffe A, Van Chuoi-Mariot MT, Mauroy B, Prevarskaya N, Mariot P (2008) CaV3.2 T-type calcium channels are involved in calcium-dependent secretion of neuroendocrine prostate cancer cells. J Biol Chem 283(15):10162–10173. doi: 10.1074/jbc.M707159200 PubMedGoogle Scholar
  46. 46.
    Gerke MB, Duggan AW, Xu L, Siddall PJ (2003) Thalamic neuronal activity in rats with mechanical allodynia following contusive spinal cord injury. Neuroscience 117(3):715–722PubMedGoogle Scholar
  47. 47.
    Graham BA, Brichta AM, Callister RJ (2007) Moving from an averaged to specific view of spinal cord pain processing circuits. J Neurophysiol 98(3):1057–1063. doi: 10.1152/jn.00581.2007 PubMedGoogle Scholar
  48. 48.
    Grubb MS, Burrone J (2010) Activity-dependent relocation of the axon initial segment fine-tunes neuronal excitability. Nature 465(7301):1070–1074. doi: 10.1038/nature09160 PubMedCentralPubMedGoogle Scholar
  49. 49.
    Hildebrand ME, Smith PL, Bladen C, Eduljee C, Xie JY, Chen L, Fee-Maki M, Doering CJ, Mezeyova J, Zhu Y, Belardetti F, Pajouhesh H, Parker D, Arneric SP, Parmar M, Porreca F, Tringham E, Zamponi GW, Snutch TP (2011) A novel slow-inactivation-specific ion channel modulator attenuates neuropathic pain. Pain 152(4):833–843. doi: 10.1016/j.pain.2010.12.035 PubMedGoogle Scholar
  50. 50.
    Huang Z, Lujan R, Kadurin I, Uebele VN, Renger JJ, Dolphin AC, Shah MM (2011) Presynaptic HCN1 channels regulate Cav3.2 activity and neurotransmission at select cortical synapses. Nat Neurosci 14(4):478–486. doi: 10.1038/nn.2757 PubMedCentralPubMedGoogle Scholar
  51. 51.
    Ikeda H, Heinke B, Ruscheweyh R, Sandkuhler J (2003) Synaptic plasticity in spinal lamina I projection neurons that mediate hyperalgesia. Science 299(5610):1237–1240PubMedGoogle Scholar
  52. 52.
    Iwata M, LeBlanc BW, Kadasi LM, Zerah ML, Cosgrove RG, Saab CY (2011) High-frequency stimulation in the ventral posterolateral thalamus reverses electrophysiologic changes and hyperalgesia in a rat model of peripheral neuropathic pain. Pain 152(11):2505–2513. doi: 10.1016/j.pain.2011.07.011 PubMedGoogle Scholar
  53. 53.
    Jacus MO, Uebele VN, Renger JJ, Todorovic SM (2012) Presynaptic Cav3.2 channels regulate excitatory neurotransmission in nociceptive dorsal horn neurons. J Neurosci 32(27):9374–9382. doi: 10.1523/JNEUROSCI.0068-12.2012 PubMedCentralPubMedGoogle Scholar
  54. 54.
    Jagodic MM, Pathirathna S, Joksovic PM, Lee W, Nelson MT, Naik AK, Su P, Jevtovic-Todorovic V, Todorovic SM (2008) Upregulation of the T-type calcium current in small rat sensory neurons after chronic constrictive injury of the sciatic nerve. J Neurophysiol 99(6):3151–3156PubMedCentralPubMedGoogle Scholar
  55. 55.
    Jagodic MM, Pathirathna S, Nelson MT, Mancuso S, Joksovic PM, Rosenberg ER, Bayliss DA, Jevtovic-Todorovic V, Todorovic SM (2007) Cell-specific alterations of T-type calcium current in painful diabetic neuropathy enhance excitability of sensory neurons. J Neurosci 27(12):3305–3316PubMedGoogle Scholar
  56. 56.
    Jeanmonod D, Magnin M, Morel A (1996) Low-threshold calcium spike bursts in the human thalamus. Common physiopathology for sensory, motor and limbic positive symptoms. Brain 119(Pt 2):363–375PubMedGoogle Scholar
  57. 57.
    Jones EG (1998) Viewpoint: the core and matrix of thalamic organization. Neuroscience 85(2):331–345PubMedGoogle Scholar
  58. 58.
    Julius D, Basbaum AI (2001) Molecular mechanisms of nociception. Nature 413(6852):203–210PubMedGoogle Scholar
  59. 59.
    Kawabata A (2013) Targeting Ca(v)3.2 T-type calcium channels as a therapeutic strategy for chemotherapy-induced neuropathic pain. Nihon yakurigaku zasshi Folia pharmacol Jpn 141(2):81–84Google Scholar
  60. 60.
    Kerckhove N, Mallet C, Francois A, Boudes M, Chemin J, Voets T, Bourinet E, Alloui A, Eschalier A (2014) Cav3.2 calcium channels: the key protagonist of the supraspinal effect of paracetamol. Pain. doi: 10.1016/j.pain.2014.01.015 PubMedGoogle Scholar
  61. 61.
    Khosravani H, Altier C, Simms B, Hamming KS, Snutch TP, Mezeyova J, McRory JE, Zamponi GW (2004) Gating effects of mutations in the Cav3.2 T-type calcium channel associated with childhood absence epilepsy. J Biol Chem 279(11):9681–9684PubMedGoogle Scholar
  62. 62.
    Khosravani H, Zamponi GW (2006) Voltage-gated calcium channels and idiopathic generalized epilepsies. Physiol Rev 86(3):941–966. doi: 10.1152/physrev.00002.2006 PubMedGoogle Scholar
  63. 63.
    Kim D, Park D, Choi S, Lee S, Sun M, Kim C, Shin HS (2003) Thalamic control of visceral nociception mediated by T-type Ca2+ channels. Science 302(5642):117–119PubMedGoogle Scholar
  64. 64.
    Kim D, Song I, Keum S, Lee T, Jeong MJ, Kim SS, McEnery MW, Shin HS (2001) Lack of the burst firing of thalamocortical relay neurons and resistance to absence seizures in mice lacking alpha(1G) T-type Ca(2+) channels. Neuron 31(1):35–45PubMedGoogle Scholar
  65. 65.
    Ku WH, Schneider SP (2011) Multiple T-type Ca2+ current subtypes in electrophysiologically characterized hamster dorsal horn neurons: possible role in spinal sensory integration. J Neurophysiol 106(5):2486–2498. doi: 10.1152/jn.01083.2010 PubMedCentralPubMedGoogle Scholar
  66. 66.
    Lallemend F, Ernfors P (2012) Molecular interactions underlying the specification of sensory neurons. Trends Neurosci 35(6):373–381. doi: 10.1016/j.tins.2012.03.006 PubMedGoogle Scholar
  67. 67.
    Latham JR, Pathirathna S, Jagodic MM, Choe WJ, Levin ME, Nelson MT, Lee WY, Krishnan K, Covey DF, Todorovic SM, Jevtovic-Todorovic V (2009) Selective T-type calcium channel blockade alleviates hyperalgesia in ob/ob mice. Diabetes 58(11):2656–2665. doi: 10.2337/db08-1763 PubMedCentralPubMedGoogle Scholar
  68. 68.
    Lee JH, Daud AN, Cribbs LL, Lacerda AE, Pereverzev A, Klockner U, Schneider T, Perez-Reyes E (1999) Cloning and expression of a novel member of the low voltage-activated T- type calcium channel family. J Neurosci 19(6):1912–1921PubMedGoogle Scholar
  69. 69.
    Lee WY, Orestes P, Latham J, Naik AK, Nelson MT, Vitko I, Perez-Reyes E, Jevtovic-Todorovic V, Todorovic SM (2009) Molecular mechanisms of lipoic acid modulation of T-type calcium channels in pain pathway. J Neurosci 29(30):9500–9509. doi: 10.1523/JNEUROSCI.5803-08.2009 PubMedCentralPubMedGoogle Scholar
  70. 70.
    Lenz FA, Gracely RH, Rowland LH, Dougherty PM (1994) A population of cells in the human thalamic principal sensory nucleus respond to painful mechanical stimuli. Neurosci Lett 180(1):46–50PubMedGoogle Scholar
  71. 71.
    Lenz FA, Kwan HC, Dostrovsky JO, Tasker RR (1989) Characteristics of the bursting pattern of action potentials that occurs in the thalamus of patients with central pain. Brain Res 496(1–2):357–360PubMedGoogle Scholar
  72. 72.
    Li L, Rutlin M, Abraira VE, Cassidy C, Kus L, Gong S, Jankowski MP, Luo W, Heintz N, Koerber HR, Woodbury CJ, Ginty DD (2011) The functional organization of cutaneous low-threshold mechanosensory neurons. Cell 147(7):1615–1627. doi: 10.1016/j.cell.2011.11.027 PubMedCentralPubMedGoogle Scholar
  73. 73.
    Lipscombe D, Andrade A, Allen SE (2012) Alternative splicing: functional diversity among voltage-gated calcium channels and behavioral consequences. Biochim Biophys Acta. doi: 10.1016/j.bbamem.2012.09.018 PubMedGoogle Scholar
  74. 74.
    Liu Y, Yang FC, Okuda T, Dong X, Zylka MJ, Chen CL, Anderson DJ, Kuner R, Ma Q (2008) Mechanisms of compartmentalized expression of Mrg class G-protein-coupled sensory receptors. J Neurosci 28(1):125–132. doi: 10.1523/JNEUROSCI.4472-07.2008 PubMedGoogle Scholar
  75. 75.
    Llinas RR, Ribary U, Jeanmonod D, Kronberg E, Mitra PP (1999) Thalamocortical dysrhythmia: a neurological and neuropsychiatric syndrome characterized by magnetoencephalography. Proc Natl Acad Sci U S A 96(26):15222–15227PubMedCentralPubMedGoogle Scholar
  76. 76.
    Luo W, Wickramasinghe SR, Savitt JM, Griffin JW, Dawson TM, Ginty DD (2007) A hierarchical NGF signaling cascade controls Ret-dependent and Ret-independent events during development of nonpeptidergic DRG neurons. Neuron 54(5):739–754. doi: 10.1016/j.neuron.2007.04.027 PubMedGoogle Scholar
  77. 77.
    Maeda Y, Aoki Y, Sekiguchi F, Matsunami M, Takahashi T, Nishikawa H, Kawabata A (2009) Hyperalgesia induced by spinal and peripheral hydrogen sulfide: evidence for involvement of Cav3.2 T-type calcium channels. Pain 142(1–2):127–132PubMedGoogle Scholar
  78. 78.
    Marger F, Gelot A, Alloui A, Matricon J, Ferrer JF, Barrere C, Pizzoccaro A, Muller E, Nargeot J, Snutch TP, Eschalier A, Bourinet E, Ardid D (2011) T-type calcium channels contribute to colonic hypersensitivity in a rat model of irritable bowel syndrome. Proc Natl Acad Sci U S A 108(27):11268–11273. doi: 10.1073/pnas.1100869108 PubMedCentralPubMedGoogle Scholar
  79. 79.
    Marmigere F, Ernfors P (2007) Specification and connectivity of neuronal subtypes in the sensory lineage. Nat Rev Neurosci 8(2):114–127. doi: 10.1038/nrn2057 PubMedGoogle Scholar
  80. 80.
    Matsunami M, Kirishi S, Okui T, Kawabata A (2011) Chelating luminal zinc mimics hydrogen sulfide-evoked colonic pain in mice: possible involvement of T-type calcium channels. Neuroscience 181:257–264. doi: 10.1016/j.neuroscience.2011.02.044 PubMedGoogle Scholar
  81. 81.
    McKay BE, McRory JE, Molineux ML, Hamid J, Snutch TP, Zamponi GW, Turner RW (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. doi: 10.1111/j.1460-9568.2006.05136.x PubMedGoogle Scholar
  82. 82.
    Messinger RB, Naik AK, Jagodic MM, Nelson MT, Lee WY, Choe WJ, Orestes P, Latham JR, Todorovic SM, Jevtovic-Todorovic V (2009) In vivo silencing of the Ca(V)3.2 T-type calcium channels in sensory neurons alleviates hyperalgesia in rats with streptozocin-induced diabetic neuropathy. Pain 145(1-2):184–195. doi: 10.1016/j.pain.2009.06.012 PubMedCentralPubMedGoogle Scholar
  83. 83.
    Millan MJ (2002) Descending control of pain. Prog neurobiol 66(6):355–474PubMedGoogle Scholar
  84. 84.
    Modesti LM, Waszak M (1975) Firing pattern of cells in human thalamus during dorsal column stimulation. Appl neurophys 38(4):251–258Google Scholar
  85. 85.
    Molliver DC, Radeke MJ, Feinstein SC, Snider WD (1995) Presence or absence of TrkA protein distinguishes subsets of small sensory neurons with unique cytochemical characteristics and dorsal horn projections. J Comp Neurol 361(3):404–416. doi: 10.1002/cne.903610305 PubMedGoogle Scholar
  86. 86.
    Molliver DC, Wright DE, Leitner ML, Parsadanian AS, Doster K, Wen D, Yan Q, Snider WD (1997) IB4-binding DRG neurons switch from NGF to GDNF dependence in early postnatal life. Neuron 19(4):849–861, doi:S0896-6273 (00) 80966-6 [pii]PubMedGoogle Scholar
  87. 87.
    Nelson MT, Joksovic PM, Su P, Kang HW, Van Deusen A, Baumgart JP, David LS, Snutch TP, Barrett PQ, Lee JH, Zorumski CF, Perez-Reyes E, Todorovic SM (2007) Molecular mechanisms of subtype-specific inhibition of neuronal T-type calcium channels by ascorbate. J Neurosci 27(46):12577–12583PubMedGoogle Scholar
  88. 88.
    Nelson MT, Woo J, Kang HW, Vitko I, Barrett PQ, Perez-Reyes E, Lee JH, Shin HS, Todorovic SM (2007) Reducing agents sensitize C-type nociceptors by relieving high-affinity zinc inhibition of T-type calcium channels. J Neurosci 27(31):8250–8260PubMedGoogle Scholar
  89. 89.
    Nowycky MC, Fox AP, Tsien RW (1985) Three types of neuronal calcium channel with different calcium agonist sensitivity. Nature 316(6027):440–443PubMedGoogle Scholar
  90. 90.
    Okayama S, Imagawa K, Naya N, Iwama H, Somekawa S, Kawata H, Horii M, Nakajima T, Uemura S, Saito Y (2006) Blocking T-type Ca2+ channels with efonidipine decreased plasma aldosterone concentration in healthy volunteers. Hypertens res : off j Jpn Soc Hypertens 29(7):493–497. doi: 10.1291/hypres.29.493 Google Scholar
  91. 91.
    Okubo K, Takahashi T, Sekiguchi F, Kanaoka D, Matsunami M, Ohkubo T, Yamazaki J, Fukushima N, Yoshida S, Kawabata A (2011) Inhibition of T-type calcium channels and hydrogen sulfide-forming enzyme reverses paclitaxel-evoked neuropathic hyperalgesia in rats. Neuroscience 188:148–156. doi: 10.1016/j neuroscience.2011.05.004 PubMedGoogle Scholar
  92. 92.
    Orestes P, Osuru HP, McIntire WE, Jacus MO, Salajegheh R, Jagodic MM, Choe W, Lee J, Lee SS, Rose KE, Poiro N, Digruccio MR, Krishnan K, Covey DF, Lee JH, Barrett PQ, Jevtovic-Todorovic V, Todorovic SM (2013) Reversal of neuropathic pain in diabetes by targeting glycosylation of CaV3.2 T-type calcium channels. Diabetes. doi: 10.2337/db13-0813 PubMedGoogle Scholar
  93. 93.
    Park C, Kim JH, Yoon BE, Choi EJ, Lee CJ, Shin HS (2010) T-type channels control the opioidergic descending analgesia at the low threshold-spiking GABAergic neurons in the periaqueductal gray. Proc Natl Acad Sci U S A 107(33):14857–14862. doi: 10.1073/pnas.1009532107 PubMedCentralPubMedGoogle Scholar
  94. 94.
    Payandeh J, Gamal El-Din TM, Scheuer T, Zheng N, Catterall WA (2012) Crystal structure of a voltage-gated sodium channel in two potentially inactivated states. Nature 486(7401):135–139. doi: 10.1038/nature11077 PubMedCentralPubMedGoogle Scholar
  95. 95.
    Payandeh J, Scheuer T, Zheng N, Catterall WA (2011) The crystal structure of a voltage-gated sodium channel. Nature 475(7356):353–358. doi: 10.1038/nature10238 PubMedCentralPubMedGoogle Scholar
  96. 96.
    Peier AM, Moqrich A, Hergarden AC, Reeve AJ, Andersson DA, Story GM, Earley TJ, Dragoni I, McIntyre P, Bevan S, Patapoutian A (2002) A TRP channel that senses cold stimuli and menthol. Cell 108(5):705–715, doi:S0092867402006529 [pii]PubMedGoogle Scholar
  97. 97.
    Perez-Reyes E (2003) Molecular physiology of low-voltage-activated t-type calcium channels. Physiol Rev 83(1):117–161PubMedGoogle Scholar
  98. 98.
    Perez-Reyes E, Cribbs LL, Daud A, Lacerda AE, Barclay J, Williamson MP, Fox M, Rees M, Lee JH (1998) Molecular characterization of a neuronal low-voltage-activated T-type calcium channel. Nature 391(6670):896–900PubMedGoogle Scholar
  99. 99.
    Perl ER (2007) Ideas about pain, a historical view. Nat Rev Neurosci 8(1):71–80. doi: 10.1038/nrn2042 PubMedGoogle Scholar
  100. 100.
    Pinchenko VO, Kostyuk PG, Kostyuk EP (2005) Influence of external pH on two types of low-voltage-activated calcium currents in primary sensory neurons of rats. Biochim Biophys Acta 1724(1–2):1–7. doi: 10.1016/j.bbagen.2005.04.008 PubMedGoogle Scholar
  101. 101.
    Powell KL, Cain SM, Ng C, Sirdesai S, David LS, Kyi M, Garcia E, Tyson JR, Reid CA, Bahlo M, Foote SJ, Snutch TP, O”Brien TJ (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. doi: 10.1523/JNEUROSCI.5295-08.2009 PubMedGoogle Scholar
  102. 102.
    Reed-Geaghan EG, Maricich SM (2011) Peripheral somatosensation: a touch of genetics. Curr opin genet dev 21(3):240–248. doi: 10.1016/j.gde.2010.12.009 PubMedCentralPubMedGoogle Scholar
  103. 103.
    Reeh PW (1986) Sensory receptors in mammalian skin in an in vitro preparation. Neurosci Lett 66(2):141–146PubMedGoogle Scholar
  104. 104.
    Rinaldi PC, Young RF, Albe-Fessard D, Chodakiewitz J (1991) Spontaneous neuronal hyperactivity in the medial and intralaminar thalamic nuclei of patients with deafferentation pain. J Neurosurg 74(3):415–421. doi: 10.3171/jns.1991.74.3.0415 PubMedGoogle Scholar
  105. 105.
    Sarnthein J, Stern J, Aufenberg C, Rousson V, Jeanmonod D (2006) Increased EEG power and slowed dominant frequency in patients with neurogenic pain. Brain 129(Pt 1):55–64. doi: 10.1093/brain/awh631 PubMedGoogle Scholar
  106. 106.
    Scroggs RS, Fox AP (1992) Calcium current variation between acutely isolated adult rat dorsal root ganglion neurons of different size. J Physiol 445:639–658PubMedCentralPubMedGoogle Scholar
  107. 107.
    Seal RP, Wang X, Guan Y, Raja SN, Woodbury CJ, Basbaum AI, Edwards RH (2009) Injury-induced mechanical hypersensitivity requires C-low threshold mechanoreceptors. Nature 462(7273):651–655. doi: 10.1038/nature08505 PubMedCentralPubMedGoogle Scholar
  108. 108.
    Senatore A, Spafford JD (2012) Gene transcription and splicing of T-type channels are evolutionarily-conserved strategies for regulating channel expression and gating. PloS one 7(6):e37409. doi: 10.1371/journal.pone.0037409 PubMedCentralPubMedGoogle Scholar
  109. 109.
    Serra J (2010) Microneurography: an opportunity for translational drug development in neuropathic pain. Neurosci Lett 470(3):155–157. doi: 10.1016/j.neulet.2009.12.065 PubMedGoogle Scholar
  110. 110.
    Shelton L, Becerra L, Borsook D (2012) Unmasking the mysteries of the habenula in pain and analgesia. Prog neurobiol 96(2):208–219. doi: 10.1016/j.pneurobio.2012.01.004 PubMedCentralPubMedGoogle Scholar
  111. 111.
    Shen Y, Yu D, Hiel H, Liao P, Yue DT, Fuchs PA, Soong TW (2006) Alternative splicing of the Ca(v)1.3 channel IQ domain, a molecular switch for Ca2 + -dependent inactivation within auditory hair cells. J Neurosci 26(42):10690–10699. doi: 10.1523/JNEUROSCI.2093-06.2006 PubMedGoogle Scholar
  112. 112.
    Shin JB, Martinez-Salgado C, Heppenstall PA, Lewin GR (2003) A T-type calcium channel required for normal function of a mammalian mechanoreceptor. Nat Neurosci 6(7):724–730. doi: 10.1038/nn1076 PubMedGoogle Scholar
  113. 113.
    Splawski I, Yoo DS, Stotz SC, Cherry A, Clapham DE, Keating MT (2006) CACNA1H mutations in autism spectrum disorders. J Biol Chem 281(31):22085–22091PubMedGoogle Scholar
  114. 114.
    Steriade M, McCormick DA, Sejnowski TJ (1993) Thalamocortical oscillations in the sleeping and aroused brain. Science 262(5134):679–685PubMedGoogle Scholar
  115. 115.
    Takahashi T, Aoki Y, Okubo K, Maeda Y, Sekiguchi F, Mitani K, Nishikawa H, Kawabata A (2010) Upregulation of Ca(v)3.2 T-type calcium channels targeted by endogenous hydrogen sulfide contributes to maintenance of neuropathic pain. Pain 150(1):183–191. doi: 10.1016/j.pain.2010.04.022 PubMedGoogle Scholar
  116. 116.
    Talley EM, Cribbs LL, Lee JH, Daud A, Perez-Reyes E, Bayliss DA (1999) Differential distribution of three members of a gene family encoding low voltage-activated (T-type) calcium channels. J Neurosci 19(6):1895–1911PubMedGoogle Scholar
  117. 117.
    Tan GM, Yu D, Wang J, Soong TW (2012) Alternative splicing at C terminus of Ca(V)1.4 calcium channel modulates calcium-dependent inactivation, activation potential, and current density. J Biol Chem 287(2):832–847. doi: 10.1074/jbc.M111.268722 PubMedCentralPubMedGoogle Scholar
  118. 118.
    Tandrup T (1995) Are the neurons in the dorsal root ganglion pseudounipolar? A comparison of the number of neurons and number of myelinated and unmyelinated fibres in the dorsal root. J Comp Neurol 357(3):341–347. doi: 10.1002/cne.903570302 PubMedGoogle Scholar
  119. 119.
    Tang ZZ, Liang MC, Lu S, Yu D, Yu CY, Yue DT, Soong TW (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. doi: 10.1074/jbc.M407023200 PubMedGoogle Scholar
  120. 120.
    Todorovic SM, Jevtovic-Todorovic V (2006) The role of T-type calcium channels in peripheral and central pain processing. CNS Neurol Disord Drug Targets 5(6):639–653PubMedGoogle Scholar
  121. 121.
    Todorovic SM, Jevtovic-Todorovic V (2013) Neuropathic pain: role for presynaptic T-type channels in nociceptive signaling. Pflugers Arch 465(7):921–927. doi: 10.1007/s00424-012-1211-y PubMedGoogle Scholar
  122. 122.
    Todorovic SM, Jevtovic-Todorovic V, Meyenburg A, Mennerick S, Perez-Reyes E, Romano C, Olney JW, Zorumski CF (2001) Redox modulation of T-type calcium channels in rat peripheral nociceptors. Neuron 31(1):75–85PubMedGoogle Scholar
  123. 123.
    Tscherter A, David F, Ivanova T, Deleuze C, Renger JJ, Uebele VN, Shin HS, Bal T, Leresche N, Lambert RC (2011) Minimal alterations in T-type calcium channel gating markedly modify physiological firing dynamics. J Physiol 589(Pt 7):1707–1724. doi: 10.1113/jphysiol.2010.203836 PubMedCentralPubMedGoogle Scholar
  124. 124.
    Vallbo AB, Olausson H, Wessberg J (1999) Unmyelinated afferents constitute a second system coding tactile stimuli of the human hairy skin. J Neurophysiol 81(6):2753–2763PubMedGoogle Scholar
  125. 125.
    Vitko I, Bidaud I, Arias JM, Mezghrani A, Lory P, Perez-Reyes E (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):322–330PubMedGoogle Scholar
  126. 126.
    Walsh MA, Graham BA, Brichta AM, Callister RJ (2009) Evidence for a critical period in the development of excitability and potassium currents in mouse lumbar superficial dorsal horn neurons. J Neurophysiol 101(4):1800–1812. doi: 10.1152/jn.90755.2008 PubMedGoogle Scholar
  127. 127.
    Walton KD, Llinas RR (2010) Central pain as a thalamocortical dysrhythmia: a thalamic efference disconnection? In: Kruger L, Light AR (eds) Translational Pain Research: From Mouse to Man. Frontiers in Neuroscience, Boca Raton, FLGoogle Scholar
  128. 128.
    Wang R, Lewin GR (2011) The Cav3.2 T-type calcium channel regulates temporal coding in mouse mechanoreceptors. J Physiol 589(Pt 9):2229–2243. doi: 10.1113/jphysiol.2010.203463 PubMedCentralPubMedGoogle Scholar
  129. 129.
    Weiss N, Black SA, Bladen C, Chen L, Zamponi GW (2013) Surface expression and function of Ca3.2 T-type calcium channels are controlled by asparagine-linked glycosylation. Pflugers Arch. doi: 10.1007/s00424-013-1259-3 Google Scholar
  130. 130.
    Weiss N, Hameed S, Fernandez-Fernandez JM, Fablet K, Karmazinova M, Poillot C, Proft J, Chen L, Bidaud I, Monteil A, Huc-Brandt S, Lacinova L, Lory P, Zamponi GW, De Waard M (2012) A Ca(v)3.2/syntaxin-1A signaling complex controls T-type channel activity and low-threshold exocytosis. J Biol Chem 287(4):2810–2818. doi: 10.1074/jbc.M111.290882 PubMedCentralPubMedGoogle Scholar
  131. 131.
    Weiss N, Zamponi GW (2012) Control of low-threshold exocytosis by T-type calcium channels. Biochim Biophys Acta. doi: 10.1016/j.bbamem.2012.07.031 Google Scholar
  132. 132.
    Wen XJ, Xu SY, Chen ZX, Yang CX, Liang H, Li H (2010) The roles of T-type calcium channel in the development of neuropathic pain following chronic compression of rat dorsal root ganglia. Pharmacol 85(5):295–300. doi: 10.1159/000276981 Google Scholar
  133. 133.
    Wheeler DG, Groth RD, Ma H, Barrett CF, Owen SF, Safa P, Tsien RW (2012) Ca(V)1 and Ca(V)2 channels engage distinct modes of Ca(2+) signaling to control CREB-dependent gene expression. Cell 149(5):1112–1124. doi: 10.1016/j.cell.2012.03.041 PubMedCentralPubMedGoogle Scholar
  134. 134.
    Wu H, Williams J, Nathans J (2012) Morphologic diversity of cutaneous sensory afferents revealed by genetically directed sparse labeling. eLife 1:e00181. doi: 10.7554/eLife.00181 PubMedCentralPubMedGoogle Scholar
  135. 135.
    Yue J, Liu L, Liu Z, Shu B, Zhang Y (2013) Upregulation of T-type Ca2+ channels in primary sensory neurons in spinal nerve injury. Spine 38(6):463–470. doi: 10.1097/BRS.0b013e318272fbf8 PubMedGoogle Scholar
  136. 136.
    Zamponi GW, Lory P, Perez-Reyes E (2010) Role of voltage-gated calcium channels in epilepsy. Pflugers Arch 460(2):395–403. doi: 10.1007/s00424-009-0772-x PubMedCentralPubMedGoogle Scholar
  137. 137.
    Zimmermann K, Hein A, Hager U, Kaczmarek JS, Turnquist BP, Clapham DE, Reeh PW (2009) Phenotyping sensory nerve endings in vitro in the mouse. Nat Protoc 4(2):174–196. doi: 10.1038/nprot.2008.223 PubMedGoogle Scholar
  138. 138.
    Zotterman Y (1939) Touch, pain and tickling: an electro-physiological investigation on cutaneous sensory nerves. J Physiol 95(1):1–28PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Amaury François
    • 1
    • 2
    • 3
    • 4
  • Sophie Laffray
    • 1
    • 2
    • 3
    • 4
  • Anne Pizzoccaro
    • 1
    • 2
    • 3
    • 4
  • Alain Eschalier
    • 5
    • 6
    • 7
  • Emmanuel Bourinet
    • 1
    • 2
    • 3
    • 4
    Email author
  1. 1.Laboratories of Excellence, Ion Channel Science and TherapeuticsInstitut de Génomique FonctionnelleMontpellierFrance
  2. 2.CNRS UMR5203MontpellierFrance
  3. 3.INSERM U661MontpellierFrance
  4. 4.IFR3 Universités Montpellier I & IIMontpellierFrance
  5. 5.Clermont Université, Université d’Auvergne, Pharmacologie Fondamentale et Clinique de la DouleurClermont-FerrandFrance
  6. 6.Neuro-DolINSERM U1107Clermont-FerrandFrance
  7. 7.CHU Clermont-Ferrand, Service de PharmacologieClermont-FerrandFrance

Personalised recommendations