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INVESTIGATING THE MODULATION OF VOLTAGE-GATED SODIUM CHANNEL NAV1.1 NEURONAL EXCITABILITY BY FIBROBLAST GROWTH FACTOR HOMOLOGOUS FACTOR 2 AND IL-6

thesis
posted on 2024-01-03, 14:05 authored by Ashley Marie FrazeeAshley Marie Frazee

Migraine is a condition that has affected many for generations and yet remains poorly understood. Mutations to the Nav1.1 voltage gated sodium channels have been implicated in various diseases such as Familial Hemiplegic Migraine 3 (FHM3), epilepsy, and autism spectrum disorder (ASD). Various proteins have been found to modify the function of these channels. Fibroblast growth factor homologous factors (FHFs) have been found to regulate the activity of some voltage-gated sodium channels (Navs). More work is needed to determine which FHFs affect which Navs. Here I looked at FHF2A and FHF2B in Nav1.1 as well as an FHM3-causing mutation to this channel, F1774S. I found that FHF2A, but not 2B, induced long-term inactivation (LTI) in the wild-type (WT) Nav1.1 and that FHF2A induced LTI in the F1774S mutant channel to a greater extent. Several changes in channel function caused by the mutation were attenuated with the addition of FHF2A, including persistent currents, leading to a possible rescue in the mutant phenotype. By contrast, the P1894L mutation, which has been found to cause ASD, greatly attenuated LTI and other impacts of FHF2A on Nav1.1. The inflammatory cytokine IL-6 was also investigated as a possible modulator of the Nav1.1 channel. There does not appear to be any direct interaction between this cytokine and the channel. Overall, my data shows for the first time that FHF2A, but FHF2B or IL-6, might be a significant modulator of Nav1.1 and can differentially modulate disease mutations.

History

Degree Type

  • Doctor of Philosophy

Department

  • Biological Sciences

Campus location

  • Indianapolis

Advisor/Supervisor/Committee Chair

Dr. Theodore Cummins

Additional Committee Member 2

Dr. Nicolas Berbari

Additional Committee Member 3

Dr. A.J. Baucum

Additional Committee Member 4

Dr. Stephen Boehm

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