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NeuroMolecular Medicine

, Volume 17, Issue 2, pp 158–169 | Cite as

The Domain II S4-S5 Linker in Nav1.9: A Missense Mutation Enhances Activation, Impairs Fast Inactivation, and Produces Human Painful Neuropathy

  • Chongyang Han
  • Yang Yang
  • Bianca T. A. de Greef
  • Janneke G. J. Hoeijmakers
  • Monique M. Gerrits
  • Camiel Verhamme
  • Jian Qu
  • Giuseppe Lauria
  • Ingemar S. J. Merkies
  • Catharina G. Faber
  • Sulayman D. Dib-Hajj
  • Stephen G. Waxman
Original Paper

Abstract

Painful small fiber neuropathy is a challenging medical condition with no effective treatment. Non-genetic causes can be identified in one half of the subjects. Gain-of-function variants of sodium channels Nav1.7 and Nav1.8 have recently been associated with painful small fiber neuropathy. More recently, mutations of sodium channel Nav1.9 have been linked to human pain disorders, with two gain-of-function mutations found in patients with painful small fiber neuropathy. Here we report a novel Nav1.9 mutation, a glycine 699 substitution by arginine (G699R) in the domain II S4-S5 linker, identified in a patient with painful small fiber neuropathy. In this study, we assayed the mutant channels by voltage-clamp in superior cervical ganglion neurons, which do not produce endogenous Nav1.8 or Nav1.9 currents, and provide a novel platform where Nav1.9 is expressed at relatively high levels. Voltage-clamp analysis showed that the mutation hyperpolarizes (−10.1 mV) channel activation, depolarizes (+6.3 mV) steady-state fast inactivation, slows deactivation, and enhances ramp responses compared with wild-type Nav1.9 channels. Current-clamp analysis showed that the G699R mutant channels render dorsal root ganglion neurons hyperexcitable, via depolarized resting membrane potential, reduced current threshold and increased evoked firing. These observations show that the domain II S4-S5 linker plays an important role in the gating of Nav1.9 and demonstrates that a mutation in this linker is linked to a common pain disorder.

Keywords

Sodium channel Nav1.9 DRG Pain 

Notes

Acknowledgments

We thank Lawrence J. Macala, Fadia Dib-Hajj, and Palak Shah for technical assistance. We thank Dr. Mark Estacion and Dr. Jianying Huang for valuable comments. This work was supported in part by Grants from the Rehabilitation Research Service and Medical Research Service, Department of Veterans Affairs (SGW and SDH), and Grant #602273 from the European Union Seventh Framework Programme FP7/2007-2013. The Center for Neuroscience & Regeneration Research is a Collaboration of the Paralyzed Veterans of America with Yale University.

Conflict of interest

The authors report no conflicts of interest.

References

  1. Allen, A. S., Berkovic, S. F., Cossette, P., Delanty, N., Dlugos, D., Eichler, E. E., et al. (2013). De novo mutations in epileptic encephalopathies. Nature, 501(7466), 217–221. doi: 10.1038/Nature12439.CrossRefPubMedGoogle Scholar
  2. Amaya, F., Wang, H., Costigan, M., Allchorne, A. J., Hatcher, J. P., Egerton, J., et al. (2006). The voltage-gated sodium channel Na(v)1.9 is an effector of peripheral inflammatory pain hypersensitivity. Journal of Neuroscience, 26(50), 12852–12860. doi: 10.1523/JNEUROSCI.4015-06.2006.CrossRefPubMedGoogle Scholar
  3. Bendahhou, S., Cummins, T. R., Kula, R. W., Fu, Y. H., & Ptacek, L. J. (2002). Impairment of slow inactivation as a common mechanism for periodic paralysis in DIIS4-S5. Neurology, 58(8), 1266–1272.CrossRefPubMedGoogle Scholar
  4. Cannon, S. C. (2002). An expanding view for the molecular basis of familial periodic paralysis. Neuromuscular Disorders, 12(6), 533–543. doi: 10.1016/S0960-8966(02)00007-X.CrossRefPubMedGoogle Scholar
  5. Cummins, T. R., Dib-Hajj, S. D., Black, J. A., Akopian, A. N., Wood, J. N., & Waxman, S. G. (1999). A novel persistent tetrodotoxin-resistant sodium current in SNS-null and wild-type small primary sensory neurons. Journal of neuroscience, 19(24).Google Scholar
  6. Cummins, T. R., Dib-Hajj, S. D., & Waxman, S. G. (2004). Electrophysiological properties of mutant Nav1.7 sodium channels in a painful inherited neuropathy. Journal of Neuroscience, 24(38), 8232–8236. doi: 10.1523/JNEUROSCI.2695-04.2004.CrossRefPubMedGoogle Scholar
  7. Dib-Hajj, S., Black, J. A., Cummins, T. R., & Waxman, S. G. (2002). NaN/Nav1.9: a sodium channel with unique properties. Trends in Neurosciences, 25(5), 253–259.CrossRefPubMedGoogle Scholar
  8. Dib-Hajj, S. D., Choi, J. S., Macala, L. J., Tyrrell, L., Black, J. A., Cummins, T. R., et al. (2009). Transfection of rat or mouse neurons by biolistics or electroporation. Nature Protocols, 4(8), 1118–1126. doi: 10.1038/nprot.2009.90.CrossRefPubMedGoogle Scholar
  9. Dib-Hajj, S. D., Tyrrell, L., Black, J. A., & Waxman, S. G. (1998). NaN, a novel voltage-gated Na channel, is expressed preferentially in peripheral sensory neurons and down-regulated after axotomy. Proceedings of the National Academy of Sciences of the United States of America, 95(15), 8963–8968.CrossRefPubMedCentralPubMedGoogle Scholar
  10. Dib-Hajj, S. D., Tyrrell, L., Cummins, T. R., Black, J. A., Wood, P. M., & Waxman, S. G. (1999a). Two tetrodotoxin-resistant sodium channels in human dorsal root ganglion neurons. FEBS Letters, 462(1–2), 117–120.CrossRefPubMedGoogle Scholar
  11. Dib-Hajj, S. D., Tyrrell, L., Escayg, A., Wood, P. M., Meisler, M. H., & Waxman, S. G. (1999b). Coding sequence, genomic organization, and conserved chromosomal localization of the mouse gene Scn11a encoding the sodium channel NaN. Genomics, 59(3), 309–318. doi: 10.1006/geno.1999.5890.CrossRefPubMedGoogle Scholar
  12. Dib-Hajj, S. D., Yang, Y., Black, J. A., & Waxman, S. G. (2013). The Na(V)1.7 sodium channel: from molecule to man. Nature Reviews Neuroscience, 14(1), 49–62. doi: 10.1038/nrn3404.CrossRefPubMedGoogle Scholar
  13. Drenth, J. P., & Waxman, S. G. (2007). Mutations in sodium-channel gene SCN9A cause a spectrum of human genetic pain disorders. The Journal of Clinical Investigation, 117(12), 3603–3609. doi: 10.1172/JCI33297.CrossRefPubMedCentralPubMedGoogle Scholar
  14. Estacion, M., & Waxman, S. G. (2013). The response of Na(V)1.3 sodium channels to ramp stimuli: multiple components and mechanisms. Journal of Neurophysiology, 109(2), 306–314. doi: 10.1152/jn.00438.2012.CrossRefPubMedGoogle Scholar
  15. Faber, C. G., Hoeijmakers, J. G. J., Ahn, H. S., Cheng, X. Y., Han, C. Y., Choi, J. S., et al. (2012a). Gain of function NaV1.7 mutations in idiopathic small fiber neuropathy. Annals of Neurology, 71(1), 26–39. doi: 10.1002/Ana.22485.CrossRefPubMedGoogle Scholar
  16. Faber, C. G., Lauria, G., Merkies, I. S. J., Cheng, X. Y., Han, C. Y., Ahn, H. S., et al. (2012b). Gain-of-function Na(v)1.8 mutations in painful neuropathy. Proceedings of the National Academy of Sciences of the United States of America, 109(47), 19444–19449. doi: 10.1073/pnas.1216080109.CrossRefPubMedCentralPubMedGoogle Scholar
  17. Fjell, J., Hjelmstrom, P., Hormuzdiar, W., Milenkovic, M., Aglieco, F., Tyrrell, L., et al. (2000). Localization of the tetrodotoxin-resistant sodium channel NaN in nociceptors. NeuroReport, 11(1), 199–202. doi: 10.1097/00001756-200001170-00039.CrossRefPubMedGoogle Scholar
  18. Han, C., Hoeijmakers, J. G., Ahn, H. S., Zhao, P., Shah, P., Lauria, G., et al. (2012). Nav1.7-related small fiber neuropathy: impaired slow-inactivation and DRG neuron hyperexcitability. Neurology, 78(21), 1635–1643. doi: 10.1212/WNL.0b013e3182574f12.CrossRefPubMedGoogle Scholar
  19. Han, C., Rush, A. M., Dib-Hajj, S. D., Li, S., Xu, Z., Wang, Y., et al. (2006). Sporadic onset of erythermalgia: a gain-of-function mutation in Nav1.7. Annals of Neurology, 59(3), 553–558. doi: 10.1002/ana.20776.CrossRefPubMedGoogle Scholar
  20. Han, C., Vasylyev, D., Macala, L. J., Gerrits, M. M., Hoeijmakers, J. G., Bekelaar, K. J., et al. (2014). The G1662S NaV1.8 mutation in small fibre neuropathy: impaired inactivation underlying DRG neuron hyperexcitability. Journal of Neurology, Neurosurgery and Psychiatry, 85(5), 499–505. doi: 10.1136/jnnp-2013-306095.CrossRefPubMedGoogle Scholar
  21. Hockley, J. R., Boundouki, G., Cibert-Goton, V., McGuire, C., Yip, P. K., Chan, C., et al. (2014). Multiple roles for NaV1.9 in the activation of visceral afferents by noxious inflammatory, mechanical, and human disease-derived stimuli. Pain, 155(10), 1962–1975, doi: 10.1016/j.pain.2014.06.015.
  22. Hoeijmakers, J. G., Faber, C. G., Lauria, G., Merkies, I. S., & Waxman, S. G. (2012a). Small-fibre neuropathies-advances in diagnosis, pathophysiology and management. Nature Reviews Neurology, 8(7), 369–379. doi: 10.1038/nrneurol.2012.97.CrossRefPubMedGoogle Scholar
  23. Hoeijmakers, J. G., Han, C., Merkies, I. S., Macala, L. J., Lauria, G., Gerrits, M. M., et al. (2012b) Small nerve fibres, small hands and small feet: a new syndrome of pain, dysautonomia and acromesomelia in a kindred with a novel NaV1.7 mutation. Brain, 135(Pt 2), 345–358, doi: 10.1093/brain/awr349
  24. Huang, J., Han, C., Estacion, M., Vasylyev, D., Hoeijmakers, J. G., Gerrits, M. M., et al. (2014). Gain-of-function mutations in sodium channel Na(V)1.9 in painful neuropathy. Brain, 137, 1627–1642. doi: 10.1093/Brain/Awu079.CrossRefPubMedGoogle Scholar
  25. Huang, J., Yang, Y., Zhao, P., Gerrits, M. M., Hoeijmakers, J. G., Bekelaar, K., et al. (2013). Small-fiber neuropathy Nav1.8 mutation shifts activation to hyperpolarized potentials and increases excitability of dorsal root ganglion neurons. Journal of Neuroscience, 33(35), 14087–14097. doi: 10.1523/JNEUROSCI.2710-13.2013.CrossRefPubMedGoogle Scholar
  26. Lauria, G., Merkies, I. S., & Faber, C. G. (2012). Small fibre neuropathy. Current Opinion in Neurology, 25(5), 542–549. doi: 10.1097/WCO.0b013e32835804c5.CrossRefPubMedGoogle Scholar
  27. Leipold, E., Liebmann, L., Korenke, G. C., Heinrich, T., Giesselmann, S., Baets, J., et al. (2013). A de novo gain-of-function mutation in SCN11A causes loss of pain perception. Nature Genetics, 45(11), 1399–1404. doi: 10.1038/ng.2767.CrossRefPubMedGoogle Scholar
  28. Lerche, H., Peter, W., Fleischha, R., Pika-Hartlaub, U., Malina, T., Mitrovic, N., et al. (1997). Role in fast inactivation of the IV/S4-S5 loop of the human muscle Na+ channel probed by cysteine mutagenesis. Journal of Physiology, 505(2), 345–352.CrossRefPubMedCentralPubMedGoogle Scholar
  29. Lolignier, S., Amsalem, M., Maingret, F., Padilla, F., Gabriac, M., Chapuy, E., et al. (2011). Nav1.9 channel contributes to mechanical and heat pain hypersensitivity induced by subacute and chronic inflammation. PLoS ONE, 6(8), e23083. doi: 10.1371/journal.pone.0023083.CrossRefPubMedCentralPubMedGoogle Scholar
  30. McPhee, J. C., Ragsdale, D. S., Scheuer, T., & Catterall, W. A. (1998). A critical role for the S4-S5 intracellular loop in domain IV of the sodium channel alpha-subunit in fast inactivation. The Journal of biological chemistry, 273(2), 1121–1129.CrossRefPubMedGoogle Scholar
  31. Niimura, H., Matsunaga, A., Kumagai, K., Ohwaki, K., Ogawa, M., Noguchi, H., et al. (2004). Genetic analysis of Brugada syndrome in western Japan - Two novel mutations. Circulation Journal, 68(8), 740–746. doi: 10.1253/Circj.68.740.CrossRefPubMedGoogle Scholar
  32. Ostman, J. A., Nassar, M. A., Wood, J. N., & Baker, M. D. (2008). GTP up-regulated persistent Na+ current and enhanced nociceptor excitability require NaV1.9. Journal of Physiology, 586(4), 1077–1087. doi: 10.1113/jphysiol.2007.147942.CrossRefPubMedCentralPubMedGoogle Scholar
  33. Payandeh, J., El-Din, T. M. G., Scheuer, T., Zheng, N., & Catterall, W. A. (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
  34. Payandeh, J., Scheuer, T., Zheng, N., & Catterall, W. A. (2011). The crystal structure of a voltage-gated sodium channel. Nature, 475(7356), 353–358. doi: 10.1038/Nature10238.CrossRefPubMedCentralPubMedGoogle Scholar
  35. Persson, A. K., Black, J. A., Gasser, A., Cheng, X. Y., Fischer, T. Z., & Waxman, S. G. (2010). Sodium-calcium exchanger and multiple sodium channel isoforms in intra-epidermal nerve terminals. Molecular Pain, 6, doi: 10.1186/1744-8069-6-84
  36. Plassart-Schiess, E., Lhuillier, L., George, A. L., Fontaine, B., & Tabti, N. (1998). Functional expression of the Ile693Thr Na+ channel mutation associated with paramyotonia congenita in a human cell line. Journal of Physiology, 507(3), 721–727. doi: 10.1111/j.1469-7793.1998.721bs.x.CrossRefPubMedCentralPubMedGoogle Scholar
  37. Priest, B. T., Murphy, B. A., Lindia, J. A., Diaz, C., Abbadie, C., Ritter, A. M., et al. (2005). Contribution of the tetrodotoxin-resistant voltage-gated sodium channel NaV1.9 to sensory transmission and nociceptive behavior. Proceedings of the National Academy of Sciences of the United States of America, 102(26), 9382–9387. doi: 10.1073/pnas.0501549102.CrossRefPubMedCentralPubMedGoogle Scholar
  38. Qiu, F., Jiang, Y., Zhang, H., Liu, Y., & Mi, W. (2012). Increased expression of tetrodotoxin-resistant sodium channels Nav1.8 and Nav1.9 within dorsal root ganglia in a rat model of bone cancer pain. Neuroscience Letters, 512(2), 61–66. doi: 10.1016/j.neulet.2012.01.069.CrossRefPubMedGoogle Scholar
  39. Rugiero, F., Mistry, M., Sage, D., Black, J. A., Waxman, S. G., Crest, M., et al. (2003). Selective expression of a persistent tetrodotoxin-resistant Na+ current and NaV1.9 subunit in myenteric sensory neurons. Journal of Neuroscience, 23(7), 2715–2725.PubMedGoogle Scholar
  40. Rush, A. M., Dib-Hajj, S. D., Liu, S., Cummins, T. R., Black, J. A., & Waxman, S. G. (2006). A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons. Proceedings of the National Academy of Sciences of the United States of America, 103(21), 8245–8250. doi: 10.1073/pnas.0602813103.CrossRefPubMedCentralPubMedGoogle Scholar
  41. Smith, M. R., & Goldin, A. L. (1997). Interaction between the sodium channel inactivation linker and domain III S4-S5. Biophysical Journal, 73(4), 1885–1895.CrossRefPubMedCentralPubMedGoogle Scholar
  42. Waxman, S. G., & Zamponi, G. W. (2014). Regulating excitability of peripheral afferents: emerging ion channel targets. Nature Neuroscience, 17(2), 153–163. doi: 10.1038/nn.3602.CrossRefPubMedGoogle Scholar
  43. Yang, Y., Wang, Y., Li, S., Xu, Z., Li, H., Ma, L., et al. (2004). Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia. Journal of Medical Genetics, 41(3), 171–174. doi: 10.1136/jmg.2003.012153.CrossRefPubMedCentralPubMedGoogle Scholar
  44. Zhang, X., Ren, W. L., DeCaen, P., Yan, C. Y., Tao, X., Tang, L., et al. (2012). Crystal structure of an orthologue of the NaChBac voltage-gated sodium channel. Nature, 486(7401), 130–134. doi: 10.1038/Nature11054.PubMedCentralPubMedGoogle Scholar
  45. Zhang, X. Y., Wen, J., Yang, W., Wang, C., Gao, L., Zheng, L. H., et al. (2013). Gain-of-function mutations in SCN11A cause familial episodic pain. American Journal of Human Genetics, 93(5), 957–966. doi: 10.1016/j.ajhg.2013.09.016.CrossRefPubMedCentralPubMedGoogle Scholar
  46. Zuberi, S. M., Brunklaus, A., Birch, R., Reavey, E., Duncan, J., & Forbes, G. H. (2011). Genotype-phenotype associations in SCN1A-related epilepsies. Neurology, 76(7), 594–600. doi: 10.1212/Wnl.0b013e31820c309b.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Chongyang Han
    • 1
    • 2
  • Yang Yang
    • 1
    • 2
  • Bianca T. A. de Greef
    • 3
  • Janneke G. J. Hoeijmakers
    • 3
  • Monique M. Gerrits
    • 4
  • Camiel Verhamme
    • 5
  • Jian Qu
    • 1
    • 2
  • Giuseppe Lauria
    • 6
  • Ingemar S. J. Merkies
    • 3
    • 7
  • Catharina G. Faber
    • 3
  • Sulayman D. Dib-Hajj
    • 1
    • 2
  • Stephen G. Waxman
    • 1
    • 2
  1. 1.Department of NeurologyYale University School of MedicineNew HavenUSA
  2. 2.Center for Neuroscience and Regeneration ResearchVeterans Affairs Medical CenterWest HavenUSA
  3. 3.Department of NeurologyUniversity Medical Centre MaastrichtMaastrichtThe Netherlands
  4. 4.Department of Clinical GeneticsUniversity Medical Centre MaastrichtMaastrichtThe Netherlands
  5. 5.Department of NeurologyAmsterdam Medical CenterAmsterdamThe Netherlands
  6. 6.Neuromuscular Diseases Unit and Bioinformatics UnitIRCCS FoundationMilanItaly
  7. 7.Department of NeurologySpaarne HospitalHoofddorpThe Netherlands

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