Huang, J;
Mis, MA;
Tanaka, B;
Adi, T;
Estacion, M;
Liu, S;
Walker, S;
... Waxman, SG; + view all
(2018)
Atypical changes in DRG neuron excitability and complex pain phenotype associated with a Na(v)1.7 mutation that massively hyperpolarizes activation.
Scientific Reports
, 8
, Article 1811. 10.1038/s41598-018-20221-7.
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Abstract
Sodium channel Nav1.7 plays a central role in pain-signaling: gain-of-function Nav1.7 mutations usually cause severe pain and loss-of-function mutations produce insensitivity to pain. The Nav1.7 I234T gainof-function mutation, however, is linked to a dual clinical presentation of episodic pain, together with absence of pain following fractures, and corneal anesthesia. How a Nav1.7 mutation that produces gain-of-function at the channel level causes clinical loss-of-function has remained enigmatic. We show by current-clamp that expression of I234T in dorsal root ganglion (DRG) neurons produces a range of membrane depolarizations including a massive shift to >−40mV that reduces excitability in a small number of neurons. Dynamic-clamp permitted us to mimic the heterozygous condition via replacement of 50% endogenous wild-type Nav1.7 channels by I234T, and confrmed that the I234T conductance could drastically depolarize DRG neurons, resulting in loss of excitability. We conclude that attenuation of pain sensation by I234T is caused by massively depolarized membrane potential of some DRG neurons which is partly due to enhanced overlap between activation and fast-inactivation, impairing their ability to fre. Our results demonstrate how a Nav1.7 mutation that produces channel gain-offunction can contribute to a dual clinical presentation that includes loss of pain sensation at the clinical level.
| Type: | Article |
|---|---|
| Title: | Atypical changes in DRG neuron excitability and complex pain phenotype associated with a Na(v)1.7 mutation that massively hyperpolarizes activation |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1038/s41598-018-20221-7 |
| Publisher version: | http://dx.doi.org/10.1038/s41598-018-20221-7 |
| Language: | English |
| Additional information: | Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
| Keywords: | Science & Technology, Multidisciplinary Sciences, Science & Technology - Other Topics, OF-FUNCTION MUTATION, SODIUM-CHANNELS, SENSORY NEURONS, SCN9A MUTATION, ERYTHROMELALGIA, DISORDER, GAIN, INSENSITIVITY, FAMILY, ONSET |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Neurosciences Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10044167 |
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