Voltage-gated sodium channels (Naᵥ) are membrane proteins which open to facilitate the inward flux of sodium ions into excitable cells. In response to stimuli, Naᵥ channels transition from the resting, closed state to an open, conductive state, before rapidly inactivating. Dysregulation of this functional cycle due to mutations causes diseases including epilepsy, pain conditions, and cardiac disorders, making Naᵥ channels a significant pharmacological target. Phosphoinositides are important lipid cofactors for ion channel function. The phosphoinositide PI(4,5)P decreases Naᵥ1.4 activity by increasing the difficulty of channel opening, accelerating fast inactivation and slowing recovery from fast inactivation. Using multiscale molecular dynamics simulations, we show that PI(4,5)P binds stably to inactivated Naᵥ at a conserved site within the DIV S4-S5 linker, which couples the voltage-sensing domain (VSD) to the pore. As the Naᵥ C-terminal domain is proposed to also bind here during recovery from inactivation, we hypothesize that PI(4,5)P prolongs inactivation by competitively binding to this site. In atomistic simulations, PI(4,5)P reduces the mobility of both the DIV S4-S5 linker and the DIII-IV linker, responsible for fast inactivation, slowing the conformational changes required for the channel to recover to the resting state. We further show that in a resting state Naᵥ model, phosphoinositides bind to VSD gating charges, which may anchor them and impede VSD activation. Our results provide a mechanism by which phosphoinositides alter the voltage dependence of activation and the rate of recovery from inactivation, an important step for the development of novel therapies to treat Naᵥ-related diseases.
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http://dx.doi.org/10.7554/eLife.91218 | DOI Listing |
Int J Biol Macromol
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College of Food and Bioengineering, Zhengzhou University of Light Industry, Zhengzhou 450001, PR China; Key Laboratory of Cold Chain Food Processing and Safety Control (Zhengzhou University of Light Industry), Ministry of Education, Zhengzhou 450001, PR China. Electronic address:
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View Article and Find Full Text PDFSci Total Environ
January 2025
College of Water Resources and Civil Engineering, China Agricultural University, Beijing 100083, China.
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View Article and Find Full Text PDFBiochem Pharmacol
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Institute of Medical Research at the San Carlos Clinic Hospital (IdISSC), Madrid, Spain; Department of Cell Biology, Faculty of Medicine, Complutense University of Madrid, Spain.
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View Article and Find Full Text PDFACS Appl Mater Interfaces
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Instituto de Química, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-909, Brazil.
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