A-type FHFs mediate resurgent currents through TTX-resistant voltage-gated sodium channels.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 35441593.
- Also identified by DOI 10.7554/eLife.77558 and PMC identifier 9071269.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Resurgent currents (<i>I</i><sub>NaR</sub>) produced by voltage-gated sodium channels are required for many neurons to maintain high-frequency firing and contribute to neuronal hyperexcitability and disease pathophysiology. Here, we show, for the first time, that <i>I</i><sub>NaR</sub> can be reconstituted in a heterologous system by coexpression of sodium channel α-subunits and A-type fibroblast growth factor homologous factors (FHFs). Specifically, A-type FHFs induces <i>I</i><sub>NaR</sub> from Nav1.8, Nav1.9 tetrodotoxin (TTX)-resistant neuronal channels, and, to a lesser extent, neuronal Nav1.7 and cardiac Nav1.5 channels. Moreover, we identified the N-terminus of FHF as the critical molecule responsible for A-type FHFs-mediated <i>I</i><sub>NaR</sub>. Among the FHFs, FHF4A is the most important isoform for mediating Nav1.8 and Nav1.9 <i>I</i><sub>NaR</sub>. In nociceptive sensory neurons, FHF4A knockdown significantly reduces <i>I</i><sub>NaR</sub> amplitude and the percentage of neurons that generate <i>I</i><sub>NaR</sub>, substantially suppressing excitability. Thus, our work reveals a novel molecular mechanism underlying TTX-resistant <i>I</i><sub>NaR</sub> generation and provides important potential targets for pain treatment.
Medical subject headings
- Sensory Receptor Cells
- Voltage-Gated Sodium Channels