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

  • Molecular and cellular mechanisms of disease
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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.

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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).

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Authors and Affiliations

  1. Institute of Physiology, Uniklinik RWTH Aachen, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany

    Luisa Kaluza, Jannis E. Meents, Martin Hampl, Corinna Rösseler, Petra A. I. Hautvast & Angelika Lampert

  2. Institute of Physiology and Pathophysiology, Friedrich-Alexander University Erlangen-Nürnberg, 91054, Erlangen, Germany

    Martin Hampl

  3. Department of Molecular Pharmacology, RWTH Aachen University, 52074, Aachen, Germany

    Silvia Detro-Dassen, Ralf Hausmann & Günther Schmalzing

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  1. Luisa Kaluza
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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.

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Kaluza, L., Meents, J.E., Hampl, M. et al. Loss-of-function of Nav1.8/D1639N linked to human pain can be rescued by lidocaine. Pflugers Arch - Eur J Physiol 470, 1787–1801 (2018). https://doi.org/10.1007/s00424-018-2189-x

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