Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Transcriptional channelopathies: An emerging class of disorders

Nature Reviews Neuroscience volume 2, pages 652–659 (2001)Cite this article

Key Points

  • In addition to genetic and autoimmune channelopathies, the two best-known types of this family of disorders, a new class has recently been recognized: transcriptional channelopathies, which are due to the dysregulated transcription of genes that encode normal channel proteins.

  • Transcription of sodium channel genes is a highly dynamic process; it is regulated throughout development, and it can be affected by the availability of neurotrophic factors. In addition, sodium channel transcription can change in response to physiological states such as changes in osmolarity.

  • Sodium channel transcription can also change in response to pathological states. Peripheral nerve injury provides a clear example. In a model of experimental nerve injury, reductions in the expression of some previously active sodium channel genes have been found. Similarly, another sodium channel gene that is normally silent in spinal sensory neurons is induced by nerve injury. These changes are thought to lead to hyperexcitability, and might contribute to the hyperalgesia and allodynia that are observed in cases of neuropathic pain.

  • Some of the signs that accompany multiple sclerosis, such as cerebellar ataxia, could be considered as transcriptional channelopathies. Although increased expression of sodium channels in multiple sclerosis seems to be a compensatory reaction to allow normal action potential conduction in demyelinated nerves, their anomalous expression in Purkinje cells might be responsible for some of the motor abnormalities seen in these patients.

  • There is evidence to suggest that the expression of potassium and calcium channels might also change in certain demyelinating conditions. In addition, other disorders, such as epilepsy, might also be accompanied by alterations in channel expression, raising the possibility that transcriptional channelopathies are a more widespread class of disorders than is appreciated at present.

Abstract

Two types of channelopathy are now well recognized: genetic, in which ion channels function abnormally or fail to function as a result of mutations, and autoimmune, in which antibodies perturb channel function. Recent studies have provided growing evidence for the existence of a third type — transcriptional channelopathies — which result from changes in the expression of non-mutated channel genes. A well-studied example is peripheral nerve injury, which causes spinal sensory neurons to turn off some active sodium channel genes and turn on others that were previously silent, a set of changes that can result in hyperexcitability of these cells. Recent studies have also shown upregulated expression of sensory-neuron-specific sodium channels in Purkinje cells, indicating that a transcriptional channelopathy might perturb cerebellar function in multiple sclerosis. It is probable that we will soon recognize further disorders that are characterized by dysregulation of channel gene expression in neurons. A better understanding of transcriptional channelopathies might provide us with new opportunities to treat these disorders.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Channelopathies can occur as a result of several types of molecular pathology.
Figure 2: Spinal sensory neurons and their axons can become hyperexcitable after nerve injury.
Figure 3: Sodium channel gene expression is altered in axotomized DRG neurons.
Figure 4: Levels of expression of the currents produced by Nav1.8, Nav1.9 and Nav1.3 are altered after transection of axons of spinal sensory neurons in sciatic nerve.
Figure 5: Expression of the SNS sodium channel Nav1.8 is upregulated in cerebellar Purkinje cells in patients with MS.
Figure 6: Upregulated expression of Nav1.8 channels can influence firing pattern and action potential configuration.

Similar content being viewed by others

References

  1. Rose, M. & Griggs, R. E. (eds) Channelopathies of the Nervous System (Butterworth–Heinemann, Oxford, 2001).

    Google Scholar 

  2. Escayg, A. et al. Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS+2. Nature Genet. 24, 343–345 (2000).

    Article  CAS  PubMed  Google Scholar 

  3. Kearney, J. A. et al. A gain-of-function in the sodium channel gene Scn2a results in seizures and behavioral abnormalities. Neuroscience 102, 307–317 (2001).

    Article  CAS  PubMed  Google Scholar 

  4. Sugawara, T. et al. A missense mutation of the Na+ channel αII subunit gene Nav1.2 in a patient with febrile and afebrile seizures causes channel dysfunction. Proc. Natl Acad. Sci. USA 98, 6384–6389 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Newsom-Davis, J. Autoantibody-mediated channelopathies at the neuromuscular junction. Neuroscientist 3, 337–346 (1997).

    Article  CAS  Google Scholar 

  6. Gahring, L. C. & Rogers, S. W. Autoimmunity to glutamate receptors in Rasmussen's encephalitis: a rare finding or the tip of an iceberg? Neuroscientist 4, 373–379 (1998).

    Article  Google Scholar 

  7. Catterall, W. A. Cellular and molecular biology of voltage-gated sodium channels. Physiol. Rev. 72, 515–548 (1992).

    Article  Google Scholar 

  8. Plummer, W. & Meisler, M. H. Evolution and diversity of sodium channel genes. Genomics 57, 323–331 (1999).Reviews the structural differences between, and evolution of, the multiple sodium channels that have been cloned.

    Article  CAS  PubMed  Google Scholar 

  9. Goldin, A. L. et al. Nomenclature of voltage-gated sodium channels. Neuron 2, 365–368 (2000).Introduces a uniform nomenclature for voltage-gated sodium channels.

    Article  Google Scholar 

  10. Waxman, S. G. The neuron as a dynamic electrogenic machine: modulation of sodium channel expression as a basis for functional plasticity in neurons. Phil. Trans. R. Soc. Lond. B. 355, 199–213 (2000).

    Article  CAS  Google Scholar 

  11. Beckh, S., Noda, M., Lubbert, H. & Numa, S. Differential regulation of three sodium channel messenger RNAs in the rat central nervous system during development. EMBO J. 8, 3611–3616 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Brysch, W. Creutzfeldt, O. W., Luno, K., Schlingensiepen, R. & Schlingensiepen, K.-H. Regional and temporal expression of sodium channel messenger RNAs in the rat brain during development. Exp. Brain Res. 86, 562–567 (1991).

    Article  CAS  PubMed  Google Scholar 

  13. Felts, P. A., Yokoyama, S., Dib-Hajj, S., Black, J. A. & Waxman, S. G. Sodium channel α-subunit mRNAs I, II, III, NaG, Na6 and hNE: different expression patterns in developing rat nervous system. Brain Res. Mol. Brain Res. 45, 71–83 (1997).

    Article  CAS  PubMed  Google Scholar 

  14. Garcia, K. D., Sprunger, L. K., Meisler, M. M. & Beam, K. G. The sodium channel Scn8a is the major contributor to the postnatal developmental increase of sodium current density in spinal motoneurons. J. Neurosci. 18, 5234–5239 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Black, J. A., Langworthy, K., Hinson, A. W., Dib-Hajj, S. D. & Waxman, S. G. NGF has opposing effects on Na+ channel III and SNS gene expression in spinal sensory neurons. Neuroreport 8, 2331–2335 (1997).

    Article  CAS  PubMed  Google Scholar 

  16. Dib-Hajj, S. D. et al. Rescue of α-SNS/PN3 sodium channel expression in small dorsal root ganglion neurons after axotomy by nerve growth factor in vivo. J. Neurophysiol. 79, 2668–2676 (1998).

    Article  CAS  PubMed  Google Scholar 

  17. Fjell, J., Cummins, T. R., Fried, K., Black, J. A. & Waxman, S. G. In vivo NGF deprivation reduces SNS/PN3 expression and TTX-R sodium currents in IB4-negative DRG neurons. J. Neurophysiol. 81, 803–911 (1999).

    Article  CAS  PubMed  Google Scholar 

  18. Cummins, T. R., Black, J. A., Dib-Hajj, S. D. & Waxman, S. G. Glial-derived neurotrophic factor upregulates expression of functional SNS and NaN sodium channels and their currents in axotomized dorsal root ganglion neurons. J. Neurosci. 20, 8754–8761 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Fjell, J. et al. Differential role of GDNF and NGF in the maintenance of two TTX-resistant sodium channels in adult DRG neurons. Brain Res. Mol. Brain Res. 67, 267–282 (1999).

    Article  CAS  PubMed  Google Scholar 

  20. Boucher, T. J. et al. Potent analgesic effects of GDNF in neuropathic pain states. Science 290, 124–127 (2000).

    Article  CAS  PubMed  Google Scholar 

  21. Offord, J. & Catterall, W. A. Electrical activity, cAMP, and cytosolic calcium regulate mRNA encoding sodium channel α subunits in rat muscle cells. Neuron 2, 1447–1452 (1989).

    Article  CAS  PubMed  Google Scholar 

  22. Sashihara, S., Greer, C. A., Oh, Y. & Waxman, S. G. Cell specific differential expression of Na+ channel β1 subunit mRNA in the olfactory system during postnatal development and following denervation. J. Neurosci. 16, 702–714 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Sashihara, S., Waxman, S. G. & Greer, C. A. Down-regulation of Na+ channel mRNA following sensory deprivation of tufted cells in the neonatal rat olfactory bulb. Neuroreport 8, 1289–1293 (1997).

    Article  CAS  PubMed  Google Scholar 

  24. Kaplan, M. R. et al. Differential control of clustering of the sodium channels Nav1.2 and Nav1.6 at developing CNS nodes of Ranvier. Neuron 30, 105–119 (2001).

    Article  CAS  PubMed  Google Scholar 

  25. Andrew, R. D. & Dudek, F. E. Burst discharge in mammalian neuroendocrine cells involves an intrinsic regenerative mechanism. Science 221, 1050–1052 (1983).

    Article  CAS  PubMed  Google Scholar 

  26. Inenaga, K., Nagamoto, T., Kannan, H. & Yamashita, H. Inward sodium current involvement in regenerative bursting activity of rat magnocellular supraoptic neurons in vitro. J. Physiol. (Lond.) 465, 289–301 (1993).

    Article  CAS  Google Scholar 

  27. Li, Z. & Hatton, G. I. Oscillatory bursting of physically firing rat supraoptic neurones in low-Ca2+ medium: Na+ influx, cytosolic Ca2+ and gap junctions. J. Physiol. (Lond.) 496, 397–394 (1996).

    Article  Google Scholar 

  28. Tanaka, M. et al. Molecular and functional remodeling of electrogenic membrane of hypothalamic neurons in response to changes in their input. Proc. Natl Acad. Sci. USA 96, 1088–109 (1999).Demonstration of plasticity of sodium channel gene expression in the normal adult central nervous system.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Devor, M. & Seltzer, Z. in Textbook of Pain 4th edn (eds Wall, P. D. & Melzack, R.) 129–164 (Churchill Livingstone, Edinburgh, 1999).

    Google Scholar 

  30. Zhang, J.-M., Donnelly, D. F., Song, X.-J. & LaMotte, R. H. Axotomy increases the excitability of dorsal root ganglion cells with unmyelinated axons. J. Neurophysiol. 78, 2790–2794 (1997).

    Article  CAS  PubMed  Google Scholar 

  31. Wood, J. N. & Perl, E. R. Pain. Curr. Opin. Genet. Dev. 9, 328–332 (1999).

    Article  CAS  PubMed  Google Scholar 

  32. Kocsis, J. D. & Waxman, S. G. Long-term regenerated nerve fibres retain sensitivity to potassium channel blocking agents. Nature 304, 640–642 (1983).Demonstration of altered ion channel activity in previously injured nerves.

    Article  CAS  PubMed  Google Scholar 

  33. Kocsis, J. D., Ruiz, J. A. & Waxman, S. G. Maturation of mammalian myelinated fibers: changes in action potential characteristics following 4-aminopyridine application. J. Neurophysiol. 50, 449–463 (1983).

    Article  CAS  PubMed  Google Scholar 

  34. Black, J. A. et al. Spinal sensory neurons express multiple sodium channel α-subunit mRNAs. Brain Res. Mol. Brain Res. 43, 117–132 (1996).

    Article  CAS  PubMed  Google Scholar 

  35. Akopian, A. N., Sivilotti, L. & Wood, J. N. A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature 379, 257–262 (1996).

    Article  CAS  PubMed  Google Scholar 

  36. Sangameswaren, L. et al. Structure and function of a novel voltage-gated tetrodotoxin-resistant sodium channel specific to sensory neurons. J. Biol. Chem. 271, 5953–5956 (2000).

    Article  Google Scholar 

  37. Dib-Hajj, S. D., Tyrrell, L., Black, J. A. & Waxman, S. G. NaN, a novel voltage-gated Na channel preferentially expressed in peripheral sensory neurons and down-regulated following axotomy. Proc. Natl Acad. Sci. USA 95, 8963–8968 (1998).References 35–37 report the cloning and sequencing of two sodium channels — Na v 1.8 and Na v 1.9 — that are preferentially expressed in DRG neurons.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Dib-Hajj, S., Black, J. A., Felts, P. & Waxman, S. G. Down-regulation of transcripts for Na channel α-SNS in spinal sensory neurons following axotomy. Proc. Natl Acad. Sci. USA 93, 14950–14954 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Sleeper, A. A. et al. Changes in expression of two tetrodotoxin-resistant sodium channels and their currents in dorsal root ganglion neurons after sciatic nerve injury but not rhizotomy. J. Neurosci. 20, 7279–7289 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Waxman, S. G., Kocsis, J. D. & Black, J. A. Type III sodium channel mRNA is expressed in embryonic but not adult spinal sensory neurons, and is re-expressed following axotomy. J. Neurophysiol. 72, 466–471 (1994).References 38 and 40 report the dysregulation of sodium channel mRNA in peripherally axotomized DRG neurons. Reference 39 demonstrates parallel changes in the sodium channel proteins and currents.

    Article  CAS  PubMed  Google Scholar 

  41. Black, J. A. et al. Upregulation of a silent sodium channel after peripheral, but not central, nerve injury in DRG neurons. J. Neurophysiol. 82, 2776–2785 (1999).

    Article  CAS  PubMed  Google Scholar 

  42. Cummins, T. R. & Waxman, S. G. Down-regulation of tetrodotoxin-resistant sodium currents and up-regulation of a rapidly repriming tetrodotoxin-sensitive sodium current in small spinal sensory neurons following nerve injury. J. Neurosci. 17, 3503–3514 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Cummins, T. R. et al. Nav1.3 sodium channels: rapid repriming and slow closed-state inactivation display quantitative differences after expression in a mammalian cell line and in spinal sensory neurons. J. Neurosci. 21, 5952–5961 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Cummins, T. R. et al. GDNF and NGF reverse changes in repriming kinetics of TTX-S currents following peripheral axotomy of DRG neurons. Soc. Neurosci. Abstr. (in the press).

  45. Lewin, G. R., Ritter, A. M. & Mendell, L. M. On the role of nerve growth factor in the development of myelinated nociceptors. J. Neurosci. 12, 1896–1905 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Ritter, A. M. & Mendell, L. M. Soma membrane properties of physiologically identified sensory neurons in the rat: effects of nerve growth factor. J. Neurophysiol. 68, 2033–2041 (1992).

    Article  CAS  PubMed  Google Scholar 

  47. Dib-Hajj, S. D. et al. Plasticity of sodium channel expression in DRG neurons in the chronic constriction injury model of neuropathic pain. Pain 83, 591–600 (1999).

    Article  CAS  PubMed  Google Scholar 

  48. Waxman, S. G., Dib-Hajj, S., Cummins, T. R. & Black, J. A. Sodium channels and pain. Proc. Natl Acad. Sci. USA 96, 7635–7639 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Kocsis, J. D. & Waxman, S. G. Ionic channel organization of normal and regenerating mammalian axons. Prog. Brain Res. 71, 89–102 (1987).

    Article  CAS  PubMed  Google Scholar 

  50. Coward, K. et al. Immunolocalization of SNS/PN3 and NaN/SNS2 sodium channels in human pain states. Pain 85, 41–50 (2000).

    Article  CAS  PubMed  Google Scholar 

  51. McDonald, W. I. Remyelination in relation to clinical lesions of the central nervous system. Br. Med. Bull. 30, 186–189 (1974).

    Article  CAS  PubMed  Google Scholar 

  52. Waxman, S. G. Demyelinating diseases: new pathological insights, new therapeutic targets. N. Engl. J. Med. 338, 323–325 (1998).

    CAS  PubMed  Google Scholar 

  53. Trapp, B. D. et al. Axonal transection in the lesions of multiple sclerosis. N. Engl. J. Med. 338, 278–285 (1998).

    Article  CAS  PubMed  Google Scholar 

  54. Ferguson, B., Matyszak, M. K., Esiri, M. M. & Perry, V. H. Axonal damage in acute multiple sclerosis lesions. Brain 120, 393–399 (1997).

    Article  PubMed  Google Scholar 

  55. Narayan, S. et al. Imaging of axonal damage in multiple sclerosis: spatial distribution of magnetic resonance imaging lesions. Ann. Neurol. 41, 385–391 (1997).

    Article  Google Scholar 

  56. McDonald, W. I., Miller, D. H. & Barnes, D. The pathological evolution of multiple sclerosis. Neuropathol. Appl. Neurobiol. 18, 319–334 (1992).

    Article  CAS  PubMed  Google Scholar 

  57. Davie, C. A. et al. Persistent functional deficit in multiple sclerosis and autosomal dominant cerebellar ataxia is associated with axon loss. Brain 118, 1583–1592 (1995).References 53–57 describe axonal degeneration and its clinical consequences in MS.

    Article  PubMed  Google Scholar 

  58. Waxman, S. G. Conduction in myelinated, unmyelinated, and demyelinated fibers. Arch. Neurol. 34, 585–590 (1977).

    Article  CAS  PubMed  Google Scholar 

  59. Ritchie, J. M. & Rogart, R. B. The density of sodium channels in mammalian myelinated nerve fibers and the nature of the axonal membrane under the myelin sheath. Proc. Natl Acad. Sci. USA 74, 211–215 (1977).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Bostock, H. & Sears, T. A. The internodal axon membrane: electrical excitability and continuous conduction in segmental demyelination. J. Physiol. (Lond.) 280, 273–301 (1978).

    Article  CAS  PubMed Central  Google Scholar 

  61. Foster, R. E., Whalen, C. C. & Waxman, S. G. Reorganization of the axonal membrane of demyelinated nerve fibers: morphological evidence. Science 210, 661–663 (1980).

    Article  CAS  PubMed  Google Scholar 

  62. England, J. D., Gamboni, F. & Levinson, S. R. Increased numbers of sodium channels form along demyelinated axons. Brain Res. 548, 334–337 (1991).

    Article  CAS  PubMed  Google Scholar 

  63. Felts, P. A., Baker, T. A. & Smith, K. J. Conduction in segmentally demyelinated mammalian central axons. J. Neurosci. 17, 7267–7277 (1997).References 60–63 show the acquisition of higher-than-normal density of sodium channels along chronically demyelinated axons, a form of molecular plasticity that can restore action potential conduction.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Waxman, S. G. in Molecular Neurobiology in Neurology and Psychiatry (ed. Kandel, E. R.) 7–37 (Raven Press, New York, 1987).

    Google Scholar 

  65. Boiko, T. et al. Compact myelin dictates the differential targeting of two sodium channel isoforms in the same axon. Neuron 30, 91–104 (2001).

    Article  CAS  PubMed  Google Scholar 

  66. Black, J. A. et al. Abnormal expression of SNS/PN3 sodium channel in cerebellar Purkinje cells following loss of myelin in the taiep rat. Neuroreport 10, 913–918 (1999).

    Article  CAS  PubMed  Google Scholar 

  67. Duncan, I. D., Lunn, K. F., Holmgren, B., Urba-Holmgren, R. & Brignolo-Holmes, L. The taiep rat: a myelin mutant with an associated oligodendrocyte microtubular defect. J. Neurocytol. 21, 870–884 (1992).

    Article  CAS  PubMed  Google Scholar 

  68. Black, J. A. et al. Sensory neuron specific sodium channel SNS is abnormally expressed in the brains of mice with experimental allergic encephalomyelitis and humans with multiple sclerosis. Proc. Natl Acad. Sci. USA 97, 11598–11602 (2000).Demonstration of a channelopathy in an animal model of MS and in human MS.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Baker, D. et al. Induction of chronic relapsing experimental allergic encephalomyelitis in biozzi mice. J. Neuroimmunol. 28, 261–270 (1990).

    Article  CAS  PubMed  Google Scholar 

  70. Baker, D. et al. Cannabinoids control spasticity and tremor in a multiple sclerosis model. Nature 404, 84–87 (2000).

    Article  CAS  PubMed  Google Scholar 

  71. Renganathan, M., Cummins, T. R. & Waxman, S. G. The contribution of Nav1.8 sodium channels to action potential electrogenesis in DRG neurons. J. Neurophysiol. (in the press).

  72. Elliott, A. A. & Elliott, J. R. Characterization of TTX-sensitive and TTX-resistant sodium currents in small cells from adult rat dorsal root ganglia. J. Physiol. (Lond.) 463, 39–56 (1993).

    Article  CAS  Google Scholar 

  73. Dib-Hajj, S. D., Ishikawa, I., Cummins, T. R. & Waxman, S. G. Insertion of an SNS-specific tetrapeptide in the S3–S4 linker of D4 accelerates recovery from inactivation of skeletal muscle voltage-gated Na channel μ1 in HEK293 cells. FEBS Lett. 416, 11–14 (1997).

    Article  CAS  PubMed  Google Scholar 

  74. Llinas, R. & Sugimori, M. Electrophysiological properties of in vitro Purkinje cell somata in mammalian cerebellar slices. J. Physiol. (Lond.) 305, 171–195 (1980).

    Article  CAS  Google Scholar 

  75. Stuart, G. & Hausser, M. Initiation and spread of sodium action potentials in cerebellar purkinje cells. Neuron 13, 703–712 (1994).

    Article  CAS  PubMed  Google Scholar 

  76. Raman, I. M. & Bean, B. P. Resurgent sodium current and action potential formation in dissociated cerebellar Purkinje neurons. J. Neurosci. 17, 4517–4526 (1997).References 74–76 illustrate the presence and functional roles of multiple sodium currents in Purkinje neurons.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Raman, I. M., Sprunger, L. K., Meisler, M. H. & Bean, B. P. Altered subthreshold sodium currents and disrupted firing patterns in Purkinje neurons of Scn81 mutant mice. Neuron 19, 881–891 (1997).

    Article  CAS  PubMed  Google Scholar 

  78. Kohrman, D. C., Smith, M. R., Goldin, A. L., Harris, J. & Meisler, M. H. A missense mutation in the sodium channel Scn8a is responsible for cerebellar ataxia in the mouse mutant jolting. J. Neurosci. 16, 5993–5999 (1996).References 76 and 77 show that sodium channel mutations can perturb cerebellar function.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Akopian, A. N. et al. The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways. Nature Neurosci. 2, 541–548 (1999).

    Article  CAS  PubMed  Google Scholar 

  80. Scroggs, R. S. & Fox, A. P. Multiple Ca2+ currents elicited by action potential waveforms in acutely isolated adult rat dorsal root ganglion neurons. J. Neurosci. 12, 1789–1801 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Westenbroek, R. E., Noebels, J. L. & Catterall, W. A. Elevated expression of type II Na+ channels in hypomyelinated axons of shiverer mouse brain. J. Neurosci. 12, 2259–2267 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Wang, H., Allen, M. L., Grigg, J. J., Noebels, J. L. & Tempel, B. L. Hypomyelination alters K+ channel expression in mouse mutants shiverer and trembler. Neuron 15, 1337–1347 (1995).

    Article  CAS  PubMed  Google Scholar 

  83. Kornek, B. et al. Distribution of a calcium channel subunit in dystrophic axons in multiple sclerosis and experimental autoimmune encephalomyelitis. Brain 124, 1114–1124 (2000).

    Article  Google Scholar 

  84. Ishikawa, K., Tanaka, M., Black, J. A. & Waxman, S. G. Changes in expression of voltage-gated potassium channels in dorsal root ganglion neurons following axotomy. Muscle Nerve 22, 502–507 (1999).

    Article  CAS  PubMed  Google Scholar 

  85. Everill, B. & Kocsis, J. D. Reduction in potassium currents in identified cutaneous afferent dorsal root ganglion neurons after axotomy. J. Neurophysiol. 82, 700–708 (1999).

    Article  CAS  PubMed  Google Scholar 

  86. Baccei, M. L. & Kocsis, J. D. Voltage-gated calcium currents in axotomized adult rat cutaneous afferent neurons. J. Neurophysiol. 83, 2227–2238 (2000).

    Article  CAS  PubMed  Google Scholar 

  87. Oyelese, A. A. & Kocsis, J. D. GABAA-receptor-mediated conductance and action potential waveform in cutaneous and muscle afferent neurons of the adult rat: differential expression and response to nerve injury. J. Neurophysiol. 76, 2383–2392 (1996).

    Article  CAS  PubMed  Google Scholar 

  88. Oyelese, A. A., Rizzo, M. A., Waxman, S. G. & Kocsis, J. D. Differential effects of NGF and BDNF on axotomy-induced changes in GABAA-receptor-mediated conductance and sodium currents in cutaneous afferent neurons. J. Neurophysiol. 78, 31–42 (1997).

    Article  CAS  PubMed  Google Scholar 

  89. Okuse, K. et al. Regulation of expression of the sensory neuron-specific sodium channel SNS in inflammatory and neuropathic pain. Mol. Cell. Neurosci. 10, 196–207 (1997).

    Article  CAS  PubMed  Google Scholar 

  90. Chaplan, S. R., Calcutt, N. & Higuera, E. S. Sodium channel type III is upregulated in three mechanistically different models of experimental allodynia. J. Pain 2 (Suppl. 2), 21 (2001).

    Google Scholar 

  91. Gastaldi, M. et al. Increase in mRNAs encoding neonatal II and III sodium channel α-isoforms during kainate-induced seizures in adult rat hippocampus. Brain Res. Mol. Brain Res. 44, 179–190 (1997).

    Article  CAS  PubMed  Google Scholar 

  92. Vreugdenhil, M., Faas, G. C. & Wadman, W. J. Sodium currents in isolated rat CA1 neurons after kindling epileptogenesis. Neuroscience 86, 99–107 (1998).

    Article  CAS  PubMed  Google Scholar 

  93. Kraner, S. D., Chong, J. A., Tsay, H.-J. & Mandel, G. Silencing the type II sodium channel gene: a model for neural-specific gene regulation. Neuron 9, 37–44 (1992).

    Article  CAS  PubMed  Google Scholar 

  94. Mori, N., Schoenherr, C., Vandenbergh, D. J. & Anderson, D. J. A common silencer element in the SCG10 and type II Na+ channel genes binds a factor present in nonneuronal cells but not in neuronal cells. Neuron 9, 45–54 (1992).

    Article  CAS  PubMed  Google Scholar 

  95. Toledo-Aral, J. J., Brehm, P., Halegoua, S. & Mendell, G. A single pulse of nerve growth factor triggers long-term neuronal excitability through sodium channel gene induction. Neuron 14, 607–611 (1995).

    Article  CAS  PubMed  Google Scholar 

  96. Tanaka, M. et al. SNS Na+ channel expression increases in dorsal root ganglion neurons in the carrageenan inflammatory pain model. Neuroreport 9, 967–972 (1998).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Research in the author's laboratory has been supported, in part, by grants from the National Multiple Sclerosis Society, the Medical Research Service and Rehabilitation Research Service, the Department of Veterans Affairs, the Eastern Paralyzed Veterans Association, the Paralyzed Veterans of America and the Nancy Davis Foundation. I thank my colleagues Joel Black, Sulayman Dib-Hajj, Ted Cummins and M. Renganathan for important molecular and biophysical insights into the transcriptional channelopathies, and Jeffery Kocsis, whose physiological expertise provided early evidence for altered channel activity in injured peripheral nerves.

Author information

Authors and Affiliations

  1. Department of Neurology LCI 707, Yale University School of Medicine, P.O. Box 208018, 333 Cedar Street, New Haven, 06520-8018, Connecticut, USA

    Stephen G. Waxman

Authors
  1. Stephen G. Waxman
    View author publications

    You can also search for this author in PubMed Google Scholar

Related links

Related links

DATABASE LINKS

voltage-gated sodium channels

generalized epilepsy with febrile seizures plus

NGF

GDNF

multiple sclerosis

Kv1.1

Kv1.2

myelin basic protein

trigeminal neuralgia

FURTHER INFORMATION

The ion channel web page

Families of transport proteins

Glossary

GEFS+2

An autosomal-dominant disorder characterized by febrile seizures in children and afebrile seizures in adults. Its penetrance is incomplete, and a large intrafamilial phenotypic variability is observed.

LAMBERT–EATON MYASTHENIC SYNDROME

An adult-onset condition characterized by muscular weakness and fatigue that is often associated with lung cancer. It is related to decreased transmitter release at the neuromuscular junction, which is caused by antibodies against presynaptic calcium channels.

RASMUSSEN'S ENCEPHALITIS

A progressive neurological disorder characterized by frequent and severe seizures, loss of motor skills and speech, paralysis on one side of the body, inflammation of the brain, dementia and mental deterioration. The disorder, which affects a single cerebral hemisphere, generally occurs in children under the age of 10, and is related to the production of glutamate receptor autoantibodies.

NEUROPATHIC PAIN

Pain due to injury of a nerve. Neuropathic pain is sometimes described as 'burning' or 'electric' in nature. The underlying dysfunction might involve deafferentation within the peripheral nervous system (neuropathy), deafferentation within the central nervous system (stroke), an imbalance between the two (phantom limb pain) or a channelopathy.

PARAESTHESIAE

Spontaneously occurring abnormal tingling sensations, sometimes described as pins and needles. They may reflect partial damage to a peripheral nerve, but can also result from damage to sensory fibres in the spinal cord.

ALLODYNIA

The perception of a stimulus as painful when previously the same stimulus was reported to be non-painful.

CHRONIC CONSTRICTION NERVE-INJURY MODEL

A model for the study of pain in which a nerve is ligated. As a result, the animal experiences hyperalgesia and allodynia. This model has been useful for the study of conditions such as neuropathic pain.

CEREBELLAR ATAXIA

Loss of muscle coordination caused by disorders of the cerebellum.

TAIEP RATS

Rats with an autosomal-recessive mutation that causes massive accumulation of microtubules in oligodendrocytes, resulting in progressive demyelination.

CHRONIC RELAPSING EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS

A rodent autoimmune model of multiple sclerosis. It is produced by transferring special T-cell lines into the rodents to induce inflammation and demyelination in susceptible animals.

SHIVERER

A mouse strain in which the gene for myelin basic protein is mutated, leading to a defect in myelination. These animals are characterized by the presence of ataxia, tremor and cerebral atrophy.

KINDLING

An experimental model of epilepsy in which an increased susceptibility to seizures arises after daily focal stimulation of specific brain areas (for example, the amygdala), stimulation that does not reach the threshold to elicit a seizure by itself.

SILENCER ELEMENT

A DNA sequence at which repressor factors bind and mediate silencing of promoters through interaction with the basal transcriptional machinery or the enhancer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Waxman, S. Transcriptional channelopathies: An emerging class of disorders. Nat Rev Neurosci 2, 652–659 (2001). https://doi.org/10.1038/35090026

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/35090026

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing