Journal article
Conformational photo-trapping in NaV1.5: Inferring local motions at the “inactivation gate”
Biophysical journal, Vol.123(14), pp.2167-2175
07/16/2024
DOI: 10.1016/j.bpj.2024.04.017
PMCID: PMC11309974
PMID: 38664963
Abstract
Rapid and effectual inactivation in voltage-gated sodium channels is required for canonical action-potential firing. This "fast" inactivation arises from swift and reversible protein conformational changes that utilize transmembrane segments and the cytoplasmic linker between channel domains III and IV. Until recently, fast inactivation had been accepted to rely on a "ball and chain" mechanism whereby a hydrophobic triplet of DIII-IV amino acids (IFM) impairs conductance by binding to a site in central pore of the channel made available by channel opening. New structures of sodium channel have upended this model. Specifically, cryo-EM structures of eukaryotic sodium channels depict a peripheral binding site for the IFM motif, outside of the pore, opening the possibility of a yet unidentified allosteric mechanism of fast inactivation gating. We set out to study fast inactivation by photo-trapping human sodium channels in various functional states under voltage control. This was achieved by genetically encoding the cross-linking unnatural amino acid benzophenone-phenylalanine at various sites within the DIII-IV linker in the cardiac sodium channel Na
1.5. These data show dynamic state and positional dependent trapping of the transient conformations associated with fast inactivation, each yielding different phenotypes and rates of trapping. These data reveal distinct conformational changes that underly fast inactivation and point to a dynamic environment around the IFM locus.
Details
- Title: Subtitle
- Conformational photo-trapping in NaV1.5: Inferring local motions at the “inactivation gate”
- Creators
- Samuel J Goodchild - University of British ColumbiaChristopher A Ahern - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Biophysical journal, Vol.123(14), pp.2167-2175
- DOI
- 10.1016/j.bpj.2024.04.017
- PMID
- 38664963
- PMCID
- PMC11309974
- NLM abbreviation
- Biophys J
- ISSN
- 0006-3495
- eISSN
- 1542-0086
- Alternative title
- Photo trapping voltage-gated cardiac sodium channels: inferring local motions at the 'inactivation gate'
- Language
- English
- Electronic publication date
- 04/24/2024
- Date published
- 07/16/2024
- Academic Unit
- Molecular Physiology and Biophysics; Iowa Neuroscience Institute
- Record Identifier
- 9984619998102771
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