Abstract
BPS2025 - Sequential conformational changes during fast inactivation in voltage-gated sodium channels
Biophysical journal, Vol.124(3 Suppl 1), pp.122a-122a
02/13/2025
DOI: 10.1016/j.bpj.2024.11.696
Abstract
Voltage-gated sodium (Nav) channels can be found ubiquitously in excitable tissues and function as the main drivers for the depolarization phase of the action potentials. Fast inactivation is a unique feature of Nav channels and serves as a negative feedback switch to attenuate the inward sodium current. Despite the prevalence and pharmaceutical importance of Nav channels, the molecular mechanism of fast inactivation remains elusive. Here, we track the conformational changes during fast inactivation in different locations of the Nav channel molecule by incorporating an environment-sensitive fluorescent unnatural amino acid, ANAP. We found that a sequence of conformational changes occurred during fast inactivation. We first tracked the movement of the DIII_DIV linker, where the IFM motif, the inactivation particle, resides. The fluorescent signal obtained from DIII_DIV linker showed a singular fast component that surprisingly preceded the time course of fast inactivation. On the other hand, when we measured the fluorescent signal at the IFM motif position, in addition to the same fast component signal seen in linker region, a second slow component could be distinguished. The time course of this slow component of the fluorescent signal followed the development of the fast inactivation. When we monitored the movement at the bottom of the pore region during fast inactivation near the inactivation gate, we noticed a significant delay in the onset of the fluorescent signal and only a minimal fast component was detected. We have then identified the key residues that coupled the movements among these regions, and interruption of any of them led to significant removal of fast inactivation. Taking all the results, we propose a molecular sequential model describing the conformational changes during the fast inactivation process. This work is supported by the NIH grant R01GM030376, NSF QuBBE QLCI.
Details
- Title: Subtitle
- BPS2025 - Sequential conformational changes during fast inactivation in voltage-gated sodium channels
- Creators
- Yichen Liu - University of ChicagoJason D. Galpin - University of IowaChristopher A. Ahern - University of IowaFrancisco Bezanilla - University of Chicago
- Resource Type
- Abstract
- Publication Details
- Biophysical journal, Vol.124(3 Suppl 1), pp.122a-122a
- Publisher
- Elsevier Inc
- DOI
- 10.1016/j.bpj.2024.11.696
- ISSN
- 0006-3495
- Language
- English
- Date published
- 02/13/2025
- Academic Unit
- Molecular Physiology and Biophysics; Iowa Neuroscience Institute
- Record Identifier
- 9984792366102771
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