Deciphering in silico the Role of Mutated NaV1.1 Sodium Channels in Enhancing Trigeminal Nociception in Familial Hemiplegic Migraine Type 3

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.

Inhibition of 2-AG hydrolysis alleviates posttraumatic headache attributed to mild traumatic brain injury

“…It has been reported that anandamide (AEA) can activate the transient receptor potential vanilloid receptor (TRPV1) to trigger the release of CGRP and promote nociceptive signaling [ 72 ]. In the TGVS, many pain-related ion channels are located in the meningeal afferents and can be targeted by 2-AG and AEA [ 73 , 74 ]. Since the activity of most ion channels depends on membrane lipids such as phosphatidylinositol 4,5-bisphosphate (PIP2) and specific fatty acids [ 75 , 76 ], the endocannabinoid-metabolized lipid profile allows them to modulate mechanosensitive ion channels through noncanonical lipid signaling.…”

A hyperthermic seizure unleashes a surge of spreading depolarizations in Scn1a-deficient mice

“…52 ). The dissociation of these phenotypes may have several explanations: The pain threshold may be higher in Dravet syndrome because of a deficiency of peripheral Scn1a /Nav1.1 channels maintaining sensory nerve excitation ( 53 ), whereas FHM3-linked Scn1a gain-of-function mutations might reduce this threshold ( 54 ) and intensify headache sensation. FHM may represent a rare form of migraine linked to high SD susceptibility involving motor-related cortical regions, and SD generated in epilepsy may accompany distinct focal functional impairment depending on the affected brain region ( 55 ).…”

Pathology of pain and its implications for therapeutic interventions

“… 166 Additionally, the Nav1.1 channel with L263V missense mutation enhances spike activity induced by P2X3 and 5-HT3 receptors, increasing the excitability of peripheral trigeminal neurons and contributing to migraine pain . 167 …”