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Pflügers Archiv - European Journal of Physiology

, Volume 470, Issue 12, pp 1787–1801 | Cite as

Loss-of-function of Nav1.8/D1639N linked to human pain can be rescued by lidocaine

  • Luisa Kaluza
  • Jannis E. Meents
  • Martin Hampl
  • Corinna Rösseler
  • Petra A. I. Hautvast
  • Silvia Detro-Dassen
  • Ralf Hausmann
  • Günther Schmalzing
  • Angelika Lampert
Molecular and cellular mechanisms of disease
  • 230 Downloads
Part of the following topical collections:
  1. Molecular and cellular mechanisms of disease

Abstract

Mutations in voltage-gated sodium channels are associated with altered pain perception in humans. Most of these mutations studied to date present with a direct and intuitive link between the altered electrophysiological function of the channel and the phenotype of the patient. In this study, we characterize a variant of Nav1.8, D1639N, which has been previously identified in a patient suffering from the chronic pain syndrome “small fiber neuropathy”. Using a heterologous expression system and patch-clamp analysis, we show that Nav1.8/D1639N reduces current density without altering biophysical gating properties of Nav1.8. Therefore, the D1639N variant causes a loss-of-function of the Nav1.8 sodium channel in a patient suffering from chronic pain. Using immunocytochemistry and biochemical approaches, we show that Nav1.8/D1639N impairs trafficking of the channel to the cell membrane. Neither co-expression of β1 or β3 subunit, nor overnight incubation at 27 °C rescued current density of the D1639N variant. On the other hand, overnight incubation with lidocaine fully restored current density of Nav1.8/D1639N most likely by overcoming the trafficking defect, whereas phenytoin failed to do so. Since lidocaine rescues the loss-of-function of Nav1.8/D1639N, it may offer a future therapeutic option for the patient carrying this variant. These results demonstrate that the D1639N variant, identified in a patient suffering from chronic pain, causes loss-of-function of the channel due to impaired cell surface trafficking and that this trafficking defect can be rescued by lidocaine.

Keywords

Small fiber neuropathy Inherited pain syndromes Local anesthetics Patch-clamp Mutagenesis Trafficking 

Notes

Acknowledgments

We thank Brigitte Hoch for excellent technical assistance. This work was supported by the Core Facility Flow Cytometry, a Core Facility of the Interdisciplinary Center for Clinical Research (IZKF) Aachen within the Faculty of Medicine at RWTH Aachen University.

Funding

This study was funded in parts by the DFG (HA 6095/1-2 to RH, LA 2740/3-1 to AL).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted. This article does not contain any studies with human participants performed by any of the authors.

Supplementary material

424_2018_2189_MOESM1_ESM.docx (380 kb)
ESM 1 (DOCX 380 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Luisa Kaluza
    • 1
  • Jannis E. Meents
    • 1
  • Martin Hampl
    • 1
    • 2
  • Corinna Rösseler
    • 1
  • Petra A. I. Hautvast
    • 1
  • Silvia Detro-Dassen
    • 3
  • Ralf Hausmann
    • 3
  • Günther Schmalzing
    • 3
  • Angelika Lampert
    • 1
  1. 1.Institute of PhysiologyUniklinik RWTH Aachen, RWTH Aachen UniversityAachenGermany
  2. 2.Institute of Physiology and PathophysiologyFriedrich-Alexander University Erlangen-NürnbergErlangenGermany
  3. 3.Department of Molecular PharmacologyRWTH Aachen UniversityAachenGermany

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