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Deciphering in silico the Role of Mutated Na<inf>V</inf>1.1 Sodium Channels in Enhancing Trigeminal Nociception in Familial Hemiplegic Migraine Type 3

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dc.contributor.author Suleimanova A.
dc.contributor.author Talanov M.
dc.contributor.author van den Maagdenberg A.M.J.M.
dc.contributor.author Giniatullin R.
dc.date.accessioned 2022-02-09T20:38:37Z
dc.date.available 2022-02-09T20:38:37Z
dc.date.issued 2021
dc.identifier.issn 1662-5102
dc.identifier.uri https://dspace.kpfu.ru/xmlui/handle/net/169524
dc.description.abstract Familial hemiplegic migraine type 3 (FHM3) is caused by gain-of-function mutations in the SCN1A gene that encodes the α1 subunit of voltage-gated NaV1.1 sodium channels. The high level of expression of NaV1.1 channels in peripheral trigeminal neurons may lead to abnormal nociceptive signaling thus contributing to migraine pain. NaV1.1 dysfunction is relevant also for other neurological disorders, foremost epilepsy and stroke that are comorbid with migraine. Here we used computer modeling to test the functional role of FHM3-mutated NaV1.1 channels in mechanisms of trigeminal pain. The activation of Aδ-fibers was studied for two algogens, ATP and 5-HT, operating through P2X3 and 5-HT3 receptors, respectively, at trigeminal nerve terminals. In WT Aδ-fibers of meningeal afferents, NaV1.1 channels efficiently participate in spike generation induced by ATP and 5-HT supported by NaV1.6 channels. Of the various FHM3 mutations tested, the L263V missense mutation, with a longer activation state and lower activation voltage, resulted in the most pronounced spiking activity. In contrast, mutations that result in a loss of NaV1.1 function largely reduced firing of trigeminal nerve fibers. The combined activation of P2X3 and 5-HT3 receptors and branching of nerve fibers resulted in very prolonged and high-frequency spiking activity in the mutants compared to WT. We identified, in silico, key determinants of long-lasting nociceptive activity in FHM3-mutated Aδ-fibers that naturally express P2X3 and 5-HT3 receptors and suggest mutant-specific correction options. Modeled trigeminal nerve firing was significantly higher for FHM3 mutations, compared to WT, suggesting that pronounced nociceptive signaling may contribute to migraine pain.
dc.relation.ispartofseries Frontiers in Cellular Neuroscience
dc.subject 5-HT
dc.subject ATP
dc.subject FHM3
dc.subject meninges
dc.subject migraine
dc.subject model
dc.subject Na V
dc.subject trigeminal nerve
dc.title Deciphering in silico the Role of Mutated Na<inf>V</inf>1.1 Sodium Channels in Enhancing Trigeminal Nociception in Familial Hemiplegic Migraine Type 3
dc.type Article
dc.relation.ispartofseries-volume 15
dc.collection Публикации сотрудников КФУ
dc.source.id SCOPUS16625102-2021-15-SID85107900817


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  • Публикации сотрудников КФУ Scopus [24551]
    Коллекция содержит публикации сотрудников Казанского федерального (до 2010 года Казанского государственного) университета, проиндексированные в БД Scopus, начиная с 1970г.

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