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Sodium channel NaV1.9 mutations associated with insensitivity to pain dampen neuronal excitability
Jianying Huang, Carlos G. Vanoye, Alison Cutts, Y. Paul Goldberg, Sulayman D. Dib-Hajj, Charles J. Cohen, Stephen G. Waxman, Alfred L. George Jr.
Jianying Huang, Carlos G. Vanoye, Alison Cutts, Y. Paul Goldberg, Sulayman D. Dib-Hajj, Charles J. Cohen, Stephen G. Waxman, Alfred L. George Jr.
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Research Article Neuroscience

Sodium channel NaV1.9 mutations associated with insensitivity to pain dampen neuronal excitability

Abstract

Voltage-gated sodium channel (NaV) mutations cause genetic pain disorders that range from severe paroxysmal pain to a congenital inability to sense pain. Previous studies on NaV1.7 and NaV1.8 established clear relationships between perturbations in channel function and divergent clinical phenotypes. By contrast, studies of NaV1.9 mutations have not revealed a clear relationship of channel dysfunction with the associated and contrasting clinical phenotypes. Here, we have elucidated the functional consequences of a NaV1.9 mutation (L1302F) that is associated with insensitivity to pain. We investigated the effects of L1302F and a previously reported mutation (L811P) on neuronal excitability. In transfected heterologous cells, the L1302F mutation caused a large hyperpolarizing shift in the voltage-dependence of activation, leading to substantially enhanced overlap between activation and steady-state inactivation relationships. In transfected small rat dorsal root ganglion neurons, expression of L1302F and L811P evoked large depolarizations of the resting membrane potential and impaired action potential generation. Therefore, our findings implicate a cellular loss of function as the basis for impaired pain sensation. We further demonstrated that a U-shaped relationship between the resting potential and the neuronal action potential threshold explains why NaV1.9 mutations that evoke small degrees of membrane depolarization cause hyperexcitability and familial episodic pain disorder or painful neuropathy, while mutations evoking larger membrane depolarizations cause hypoexcitability and insensitivity to pain.

Authors

Jianying Huang, Carlos G. Vanoye, Alison Cutts, Y. Paul Goldberg, Sulayman D. Dib-Hajj, Charles J. Cohen, Stephen G. Waxman, Alfred L. George Jr.

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Mechanism of NaV1.9 pain insensitivity

Submitter: Ingo Kurth | ikurth@ukaachen.de

Authors: Enrico Leipold, Christian A. Hübner, Stefan H. Heinemann, and Ingo Kurth

Institute of Human Genetics, Medical Faculty, RWTH Aachen University, 52074, Aachen, Germany

Published June 27, 2017

Mutations enhancing the activity of voltage-gated sodium channel NaV1.9 can result both in painful neuropathy or pain insensitivity. Whereas neuronal hyperexcitability and pain are well understood consequences of enhanced NaV channel activity, it is less intuitive how NaV hyperactivity can also cause pain insensitivity.

In 2013, we identified the first disease-associated NaV1.9 mutation (L811P), which causes human analgesia.1 The mutation conferred gain-of-function properties to NaV1.9 and depolarized the resting membrane potential (RMP) in small-diameter DRG neurons obtained from engineered mice carrying the orthologous mutation. We hypothesized: “The p.L811P alteration increases the basal activity of NaV1.9 channels, resulting in excess sodium ion influx at rest and subsequent cell depolarization. Consequently, other ion channels such as NaV1.7, NaV1.8 and voltage-gated calcium ion channels that form the main constituents of the action potential in DRG neurons may undergo progressive inactivation, resulting in a conduction block”.1 We substantiated this hypothesis in a follow-up study2, however, it remained a matter of debate.3-5

In their current paper in JCI Huang and colleagues6 also address the mechanism of NaV1.9-associated pain insensitivity. They report that heterologous overexpression of NaV1.9-L811P channels in rat DRG neurons increases the cells RMP on average by 8.2 mV (versus a 6.7 mV increase in our genetic mouse model) with some cells displaying a RMP higher than –35 mV and some cells being hypoexcitable. Huang et al. conclude: “We posited that RMP depolarizations evoked by expression of L1302F or L811P caused inactivation of voltage-gated sodium channels, including NaV1.8, which contributes substantially to the action potential upstroke.” (…) ”the data support a primary loss of neuronal excitability as a direct consequence of a massively depolarized RMP (…).”

We were very surprised that the authors then claim that, “by contrast”… “a different interpretation of the mechanisms responsible for this effect was offered. Specifically, Leipold and colleagues1 argued for a conduction block secondary to inactivation of NaV1.7, NaV1.8, and neuronal calcium channels as the central basis for impaired nociception.” We would like to point out that the data presented by Huang et al.6 strongly support our initial hypothesis and they do not provide an alternative mechanism as implied in their discussion. Using different cellular models the three studies give novel insight into how gain-of-function alterations of NaV1.9 can result in loss-of-function at the cellular level and they have interesting implications for NaV1.9 as pharmacological target.

 

1. Leipold E, et al. A de novo gain-of-function mutation in SCN11A causes loss of pain perception. Nat Genet. 2013;45(11):1399–1404.

2. Leipold E, et al. Cold-aggravated pain in humans caused by a hyperactive NaV1.9 channel mutant. Nat Commun. 2015;6:10049. doi: 10.1038/ncomms10049.

3. Huang J, et al., Gain-of-function mutations in sodium channel NaV1.9 in painful neuropathy. Brain. 2014;137(Pt 6):1627-42.

4. Dib-Hajj SD, Black JA, Waxman SG. NaV1.9: a sodium channel linked to human pain. Nat Rev Neurosci. 2015;16(9):511-9.

5. Dib-Hajj SD, Geha P, Waxman SG. Sodium channels in pain disorders: pathophysiology and prospects for treatment. Pain. 2017;158 Suppl 1:S97-S107.

6. Huang J, et al., Sodium channel NaV1.9 mutations associated with insensitivity to pain dampen neuronal excitability. J Clin Invest. 2017; pii: 92373. doi: 10.1172/JCI92373. [Epub ahead of print]

Response to Kurth et al.

Submitter: Alfred L. George, Jr. | al.george@northwestern.edu

Authors: Jianying Huang, Carlos G. Vanoye, Alison Cutts, Y. Paul Goldberg, Sulayman D. Dib-Hajj, Charles J. Cohen, Stephen G. Waxman, and Alfred L. George Jr.

Northwestern University

Published June 27, 2017

We appreciate the letter from Kurth and colleagues sharing their perspectives on the mechanism responsible for insensitivity to pain associated with gain-of-function NaV1.9 mutations. As we note in our paper, their group deserves credit for discovering the first NaV1.9 mutation and performing its functional characterization (1). However, despite this initial work there remained confusion about the cellular mechanism for impaired sensibility to pain, largely because gain-of-function NaV1.9 mutations were also associated with paroxysmal pain disorders (2-4). The association of NaV1.9 mutations that enhance channel function with both insensitivity to pain and paroxysmal pain seemed incongruous and clear evidence about the cellular mechanism was clearly needed to resolve this matter.

Our study provided definitive evidence that severe gain-of-function NaV1.9 mutations produce a level of membrane depolarization incompatible with action potential generation and hence a primary loss of excitability (5). Conduction block, which was implicated by Kurth and colleagues (1), is a term traditionally used to describe the focal block of action potentials generated elsewhere along a neuron. Our data are most consistent with a primary failure to generate action potentials rather than a defect in action potential propagation.

Importantly, we also demonstrated a U-shaped relationship between resting membrane potential and neuronal excitability that fully explains why mild gain-of-function NaV1.9 mutations cause enhanced excitability of DRG neurons in paroxysmal pain disorders whereas severe gain-of-function mutations lead to reduced excitability in these cells and insensitivity to pain (see Figure 6 in the published paper). This relationship provides a new mechanistic explanation for the genotype-phenotype complexity associated with NaV1.9 mutations.

 

REFERENCES

1.   Leipold E, et al.   A de novo gain-of-function mutation in SCN11A causes loss of pain perception. Nat Genet. 2013;45(11):1399-1404. 

2.   Zhang XY, et al.   Gain-of-function mutations in SCN11A cause familial episodic pain. Am J Hum Genet. 2013;93(5):957-966.

3.   Huang J, et al.   Gain-of-function mutations in sodium channel NaV1.9 in painful neuropathy. Brain. 2014;137(Pt 6):1627-1642.

4.   Han C, et al.   Familial gain-of-function NaV1.9 mutation in a painful channelopathy. J Neurol Neurosurg Psychiatry. 2017;(88):233-240.

5.   Huang J, et al.   Sodium channel NaV1.9 mutations associated with insensitivity to pain dampen neuronal excitability. J Clin Invest. 2017 May 22. pii: 92373. doi: 10.1172/JCI92373. [Epub ahead of print]

 

 

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