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Reverse pharmacogenomics: carbamazepine normalizes activation and attenuates thermal hyperexcitability of sensory neurons due to Nav 1.7 mutation I234T.

ABSTRACT: BACKGROUND AND PURPOSE:Pharmacotherapy for pain currently involves trial and error. A previous study on inherited erythromelalgia (a genetic model of neuropathic pain due to mutations in the sodium channel, Nav 1.7) used genomics, structural modelling and biophysical and pharmacological analyses to guide pharmacotherapy and showed that carbamazepine normalizes voltage dependence of activation of the Nav 1.7-S241T mutant channel, reducing pain in patients carrying this mutation. However, whether this approach is applicable to other Nav channel mutants is still unknown. EXPERIMENTAL APPROACH:We used structural modelling, patch clamp and multi-electrode array (MEA) recording to assess the effects of carbamazepine on Nav 1.7-I234T mutant channels and on the firing of dorsal root ganglion (DRG) sensory neurons expressing these mutant channels. KEY RESULTS:In a reverse engineering approach, structural modelling showed that the I234T mutation is located in atomic proximity to the carbamazepine-responsive S241T mutation and that activation of Nav 1.7-I234T mutant channels, from patients who are known to respond to carbamazepine, is partly normalized with a clinically relevant concentration (30 ?M) of carbamazepine. There was significantly higher firing in intact sensory neurons expressing Nav 1.7-I234T channels, compared with neurons expressing the normal channels (Nav 1.7-WT). Pre-incubation with 30 ?M carbamazepine also significantly reduced the firing of intact DRG sensory neurons expressing Nav 1.7-I234T channels. Although the expected use-dependent inhibition of Nav 1.7-WT channels by carbamazepine was confirmed, carbamazepine did not enhance use-dependent inhibition of Nav 1.7-I234T mutant channels. CONCLUSION AND IMPLICATIONS:These results support the utility of a pharmacogenomic approach to treatment of pain in patients carrying sodium channel variants. LINKED ARTICLES:This article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc.

SUBMITTER: Yang Y

PROVIDER: S-EPMC5980548 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Reverse pharmacogenomics: carbamazepine normalizes activation and attenuates thermal hyperexcitability of sensory neurons due to Na<sub>v</sub> 1.7 mutation I234T.

Yang Yang Y Adi Talia T Effraim Philip R PR Chen Lubin L Dib-Hajj Sulayman D SD Waxman Stephen G SG

British journal of pharmacology 20170730 12

<h4>Background and purpose</h4>Pharmacotherapy for pain currently involves trial and error. A previous study on inherited erythromelalgia (a genetic model of neuropathic pain due to mutations in the sodium channel, Na<sub>v</sub> 1.7) used genomics, structural modelling and biophysical and pharmacological analyses to guide pharmacotherapy and showed that carbamazepine normalizes voltage dependence of activation of the Na<sub>v</sub> 1.7-S241T mutant channel, reducing pain in patients carrying th ...[more]

PMID: 28658526

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Project description:Huwentoxin-IV (HwTx-IV), a peptide discovered in the venom of the Chinese bird spider Cyriopagopus schmidti, has been reported to be a potent antinociceptive compound due to its action on the genetically-validated NaV1.7 pain target. Using this peptide for antinociceptive applications in vivo suffers from one major drawback, namely its negative impact on the neuromuscular system. Although studied only recently, this effect appears to be due to an interaction between the peptide and the NaV1.6 channel subtype located at the presynaptic level. The aim of this work was to investigate how HwTx-IV could be modified in order to alter the original human (h) NaV1.7/NaV1.6 selectivity ratio of 23. Nineteen HwTx-IV analogues were chemically synthesized and tested for their blocking effects on the Na+ currents flowing through these two channel subtypes stably expressed in cell lines. Dose-response curves for these analogues were generated, thanks to the use of an automated patch-clamp system. Several key amino acid positions were targeted owing to the information provided by earlier structure-activity relationship (SAR) studies. Among the analogues tested, the potency of HwTx-IV E4K was significantly improved for hNaV1.6, leading to a decreased hNaV1.7/hNaV1.6 selectivity ratio (close to 1). Similar decreased selectivity ratios, but with increased potency for both subtypes, were observed for HwTx-IV analogues that combine a substitution at position 4 with a modification of amino acid 1 or 26 (HwTx-IV E1G/E4G and HwTx-IV E4K/R26Q). In contrast, increased selectivity ratios (>46) were obtained if the E4K mutation was combined to an additional double substitution (R 26A/Y33W) or simply by further substituting the C-terminal amidation of the peptide by a carboxylated motif, linked to a marked loss of potency on hNaV1.6 in this latter case. These results demonstrate that it is possible to significantly modulate the selectivity ratio for these two channel subtypes in order to improve the potency of a given analogue for hNaV1.6 and/or hNaV1.7 subtypes. In addition, selective analogues for hNaV1.7, possessing better safety profiles, were produced to limit neuromuscular impairments.

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Reverse pharmacogenomics: carbamazepine normalizes activation and attenuates thermal hyperexcitability of sensory neurons due to Nav 1.7 mutation I234T.

Publications

Reverse pharmacogenomics: carbamazepine normalizes activation and attenuates thermal hyperexcitability of sensory neurons due to Na<sub>v</sub> 1.7 mutation I234T.

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Reverse pharmacogenomics: carbamazepine normalizes activation and attenuates thermal hyperexcitability of sensory neurons due to Nav 1.7 mutation I234T.

Publications

Reverse pharmacogenomics: carbamazepine normalizes activation and attenuates thermal hyperexcitability of sensory neurons due to Na&lt;sub&gt;v&lt;/sub&gt; 1.7 mutation I234T.

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OmicsDI is part of the ELIXIR infrastructure

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Reverse pharmacogenomics: carbamazepine normalizes activation and attenuates thermal hyperexcitability of sensory neurons due to Na<sub>v</sub> 1.7 mutation I234T.