Deciphering in silico the Role of Mutated Na _V 1.1 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 Na_V1.1 sodium channels. The high level of expression of Na_V1.1 channels in peripheral trigeminal neurons may lead to abnormal nociceptive signaling thus contributing to migraine pain. Na_V1.1 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 Na_V1.1 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, Na_V1.1 channels efficiently participate in spike generation induced by ATP and 5-HT supported by Na_V1.6 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 Na_V1.1 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.

SUBMITTER: Suleimanova A 

PROVIDER: S-EPMC8200561 | biostudies-literature |

REPOSITORIES: biostudies-literature