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

Alina Suleimanova,Arn M J M Van Den Maagdenberg,Max Talanov,Rashid Giniatullin

doi:10.3389/fncel.2021.644047

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.

Highlights

The generation of disabling migraine pain involves the activation of the meningeal trigeminovascular system (Moskowitz, 2008; Messlinger, 2009), but the underlying pro-nociceptive mechanisms remain largely unknown
The main result of this study is to provide a mechanistical explanation of peripheral mechanisms of enhanced nociceptive firing activity in trigeminal neurons and the whole nerve when in silico modeling the effect of Familial hemiplegic migraine type 3 (FHM3) mutations
Our data suggest that compounds affecting NaV1.1 channels in Aδ-fibers of peripheral nerves in a mutation-specific manner, may be a promising avenue for novel type analgesic anti-migraine therapy

Summary

Introduction

The generation of disabling migraine pain involves the activation of the meningeal trigeminovascular system (Moskowitz, 2008; Messlinger, 2009), but the underlying pro-nociceptive mechanisms remain largely unknown. The observation that incubation at lower temperature and expression in neurons rescued folding/trafficking issues firmly established that FHM3 is caused by a gain of NaV1.1 function (Dhifallah et al, 2018), whereas earlier studies suggested foremost loss-offunction effects of FHM3 mutations when overexpressed in heterologous expression systems (Dichgans et al, 2005; Kahlig et al, 2008). As NaV1.1 channels are strongly expressed in peripheral Aδ-fibers of the trigeminal nerve (Ho and O’Leary, 2011; Osteen et al, 2016), their modified activity may underlie the activation of peripheral trigeminal neurons leading to migraine pain. It can be expected that a gain-of-function enhances excitability of peripheral nerve fibers expressing modified NaV1.1 channels, providing a high pro-nociceptive activity delivered to second order neurons

Methods

Results

Conclusion