ArticleJournal of neurophysiology2015
Ca2+ toxicity due to reverse Na+/Ca2+ exchange contributes to degeneration of neurites of DRG neurons induced by a neuropathy-associated Nav1.7 mutation.
Article in Journal of neurophysiology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 50 citations in OpenAlex.
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- mGluR5 as a Potential Orchestrator of Astrocyte Interactions in Neurological Disorders.Neural plasticity · 2025Review
- Distinctive In Vitro Phenotypes in iPSC-Derived Neurons From Patients With Gain- and Loss-of-FunctionThe Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- From progression to progress: The future of multiple sclerosis.Journal of central nervous system disease · 2024Article
- Genetic Profiling of Sodium Channels in Diabetic Painful and Painless and Idiopathic Painful and Painless Neuropathies.International journal of molecular sciences · 2023Article
- Multiple sclerosis progression: time for a new mechanism-driven framework.The Lancet. Neurology · 2023Review
- Peripheral mechanisms of peripheral neuropathic pain.Frontiers in molecular neuroscience · 2023Review
- Investigating genotype-phenotype relationship of extreme neuropathic pain disorders in a UK national cohort.Brain communications · 2023Article
- Peripheral Ion Channel Genes Screening in Painful Small Fiber Neuropathy.International journal of molecular sciences · 2022Article
- Trigeminal Neuralgia TRPM8 Mutation: Enhanced Activation, Basal [CaNeurology. Genetics · 2021Article
- Enteric Neurodegeneration is Mediated Through Independent Neuritic and Somal Mechanisms in Rotenone and MPP+ Toxicity.Neurochemical research · 2018Article
- Sodium Channel SCN3A (NaNeuron · 2018Article
- Reducing CXCR4-mediated nociceptor hyperexcitability reverses painful diabetic neuropathy.The Journal of clinical investigation · 2018Article
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- Activity of NaJCI insight · 2016Article
- Nav1.7-A1632G Mutation from a Family with Inherited Erythromelalgia: Enhanced Firing of Dorsal Root Ganglia Neurons Evoked by Thermal Stimuli.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2016Article
Corrections and comments
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Authors and funding
9 authors at 5 institutions in 3 countries.
Funding
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.