Atypical changes in DRG neuron excitability and complex pain phenotype associated with a Nav1.7 mutation that massively hyperpolarizes activation

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 gain-of-function mutation, however, is linked to a dual clinical presentation of episodic...

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Autores principales:	Jianying Huang, Malgorzata A. Mis, Brian Tanaka, Talia Adi, Mark Estacion, Shujun Liu, Suellen Walker, Sulayman D. Dib-Hajj, Stephen G. Waxman
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/8eca63acbcfb47469d32f11de63ac492
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spelling	oai:doaj.org-article:8eca63acbcfb47469d32f11de63ac4922021-12-02T15:08:17ZAtypical changes in DRG neuron excitability and complex pain phenotype associated with a Nav1.7 mutation that massively hyperpolarizes activation10.1038/s41598-018-20221-72045-2322https://doaj.org/article/8eca63acbcfb47469d32f11de63ac4922018-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-20221-7https://doaj.org/toc/2045-2322Abstract 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 gain-of-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 >−40 mV 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 confirmed 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 fire. Our results demonstrate how a Nav1.7 mutation that produces channel gain-of-function can contribute to a dual clinical presentation that includes loss of pain sensation at the clinical level.Jianying HuangMalgorzata A. MisBrian TanakaTalia AdiMark EstacionShujun LiuSuellen WalkerSulayman D. Dib-HajjStephen G. WaxmanNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-13 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jianying Huang Malgorzata A. Mis Brian Tanaka Talia Adi Mark Estacion Shujun Liu Suellen Walker Sulayman D. Dib-Hajj Stephen G. Waxman Atypical changes in DRG neuron excitability and complex pain phenotype associated with a Nav1.7 mutation that massively hyperpolarizes activation
description	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 gain-of-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 >−40 mV 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 confirmed 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 fire. Our results demonstrate how a Nav1.7 mutation that produces channel gain-of-function can contribute to a dual clinical presentation that includes loss of pain sensation at the clinical level.
format	article
author	Jianying Huang Malgorzata A. Mis Brian Tanaka Talia Adi Mark Estacion Shujun Liu Suellen Walker Sulayman D. Dib-Hajj Stephen G. Waxman
author_facet	Jianying Huang Malgorzata A. Mis Brian Tanaka Talia Adi Mark Estacion Shujun Liu Suellen Walker Sulayman D. Dib-Hajj Stephen G. Waxman
author_sort	Jianying Huang
title	Atypical changes in DRG neuron excitability and complex pain phenotype associated with a Nav1.7 mutation that massively hyperpolarizes activation
title_short	Atypical changes in DRG neuron excitability and complex pain phenotype associated with a Nav1.7 mutation that massively hyperpolarizes activation
title_full	Atypical changes in DRG neuron excitability and complex pain phenotype associated with a Nav1.7 mutation that massively hyperpolarizes activation
title_fullStr	Atypical changes in DRG neuron excitability and complex pain phenotype associated with a Nav1.7 mutation that massively hyperpolarizes activation
title_full_unstemmed	Atypical changes in DRG neuron excitability and complex pain phenotype associated with a Nav1.7 mutation that massively hyperpolarizes activation
title_sort	atypical changes in drg neuron excitability and complex pain phenotype associated with a nav1.7 mutation that massively hyperpolarizes activation
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/8eca63acbcfb47469d32f11de63ac492
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Atypical changes in DRG neuron excitability and complex pain phenotype associated with a Nav1.7 mutation that massively hyperpolarizes activation

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