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J Neurophysiol. 2015 Sep;114(3):1554-64. doi: 10.1152/jn.00195.2015. Epub 2015 Jul 8.

Ca2+ toxicity due to reverse Na+/Ca2+ exchange contributes to degeneration of neurites of DRG neurons induced by a neuropathy-associated Nav1.7 mutation.

Author information

1
Department of Neurology, Yale University School of Medicine, New Haven, Connecticut; Center for Neuroscience and Regeneration Research, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut;
2
Department of Neurology, University Medical Center Maastricht, Maastricht, the Netherlands;
3
Department of Neurology, University Medical Center Maastricht, Maastricht, the Netherlands; Department of Neurology, Spaarne Hospital, Hoofddorp, the Netherlands; and.
4
Neuroalgology Unit IRCCS Foundation "Carlo Besta" Neurological Institute, Milan, Italy.
5
Department of Neurology, Yale University School of Medicine, New Haven, Connecticut; Center for Neuroscience and Regeneration Research, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut; Stephen.Waxman@yale.edu.

Abstract

Gain-of-function missense mutations in voltage-gated sodium channel Nav1.7 have been linked to small-fiber neuropathy, which is characterized by burning pain, dysautonomia and a loss of intraepidermal nerve fibers. However, the mechanistic cascades linking Nav1.7 mutations to axonal degeneration are incompletely understood. The G856D mutation in Nav1.7 produces robust changes in channel biophysical properties, including hyperpolarized activation, depolarized inactivation, and enhanced ramp and persistent currents, which contribute to the hyperexcitability exhibited by neurons containing Nav1.8. We report here that cell bodies and neurites of dorsal root ganglion (DRG) neurons transfected with G856D display increased levels of intracellular Na(+) concentration ([Na(+)]) and intracellular [Ca(2+)] following stimulation with high [K(+)] compared with wild-type (WT) Nav1.7-expressing neurons. Blockade of reverse mode of the sodium/calcium exchanger (NCX) or of sodium channels attenuates [Ca(2+)] transients evoked by high [K(+)] in G856D-expressing DRG cell bodies and neurites. We also show that treatment of WT or G856D-expressing neurites with high [K(+)] or 2-deoxyglucose (2-DG) does not elicit degeneration of these neurites, but that high [K(+)] and 2-DG in combination evokes degeneration of G856D neurites but not WT neurites. Our results also demonstrate that 0 Ca(2+) or blockade of reverse mode of NCX protects G856D-expressing neurites from degeneration when exposed to high [K(+)] and 2-DG. These results point to [Na(+)] overload in DRG neurons expressing mutant G856D Nav1.7, which triggers reverse mode of NCX and contributes to Ca(2+) toxicity, and suggest subtype-specific blockade of Nav1.7 or inhibition of reverse NCX as strategies that might slow or prevent axon degeneration in small-fiber neuropathy.

KEYWORDS:

axon degeneration; calcium transient; sodium channels; sodium-calcium exchanger

PMID:
26156380
PMCID:
PMC4561630
DOI:
10.1152/jn.00195.2015
[Indexed for MEDLINE]
Free PMC Article

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