Ca2+ toxicity due to reverse Na+/Ca2+ exchange contributes to degeneration of neurites of DRG neurons induced by a neuropathy-associated Nav1.7 mutation
Articolo
Data di Pubblicazione:
2015
Citazione:
Ca2+ toxicity due to reverse Na+/Ca2+ exchange contributes to degeneration of neurites of DRG neurons induced by a neuropathy-associated Nav1.7 mutation / M. Estacion, B..P..S. Vohra, S. Liu, J. Hoeijmakers, C..G. Faber, I..S..J. Merkies, G. LAURIA PINTER, J..A. Black, S..G. Waxman. - In: JOURNAL OF NEUROPHYSIOLOGY. - ISSN 0022-3077. - 114:3(2015 Jul 08), pp. 1554-1564.
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 [Ca2+]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 [Ca2+] 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 0Ca2+ 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 Ca2+ 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.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
axon degeneration; calcium transient; sodium channels; sodium-calcium exchanger; animals; calcium; cells, cultured; erythromelalgia; ganglia, spinal; humans; nav1.3 voltage-gated sodium channel; neurites; potassium; rats; rats, sprague-dawley; sodium; sodium channels; sodium-calcium exchanger; mutation, missense; neuroscience (all); physiology
Elenco autori:
M. Estacion, B..P..S. Vohra, S. Liu, J. Hoeijmakers, C..G. Faber, I..S..J. Merkies, G. LAURIA PINTER, J..A. Black, S..G. Waxman
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