Decoding the Effect of Hydrostatic Pressure on TRPV1 Lower-Gate Conformation by Molecular-Dynamics Simulation

In response to hydrostatic pressure, the cation channel transient receptor potential vanilloid 1 (TRPV1) is essential in signaling pathways linked to glaucoma. When activated, TRPV1 undergoes a gating transition from a closed to an open state that allows the influx of Ca2+ ions. However, the gating...

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Bibliographic Details
Published in:International journal of molecular sciences 2022-07, Vol.23 (13), p.7366
Main Authors: Zamri, Muhammad Harith Bin, Ujihara, Yoshihiro, Nakamura, Masanori, Mofrad, Mohammad R. K., Sugita, Shukei
Format: Article
Language:English
Subjects:
Apoptosis
Calcium influx
Calcium ions
Capsaicin receptors
Cell membranes
Channel gating
Conformation
Glaucoma
Hydrostatic pressure
mechanotransduction
Molecular dynamics
molecular mechanics
Optic nerve
Pressure
Pressure effects
Proteins
Simulation
Transient receptor potential proteins
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Summary:In response to hydrostatic pressure, the cation channel transient receptor potential vanilloid 1 (TRPV1) is essential in signaling pathways linked to glaucoma. When activated, TRPV1 undergoes a gating transition from a closed to an open state that allows the influx of Ca2+ ions. However, the gating mechanism of TRPV1 in response to hydrostatic pressure at the molecular level is still lacking. To understand the effect of hydrostatic pressure on the activation of TRPV1, we conducted molecular-dynamics (MD) simulations on TRPV1 under different hydrostatic pressure configurations, with and without a cell membrane. The TRPV1 membrane-embedded model is more stable than the TPRV1-only model, indicating the importance of including the cell membrane in MD simulation. Under elevated pressure at 27.6 mmHg, we observed a more dynamic and outward motion of the TRPV1 domains in the lower-gate area than in the simulation under normal pressure at 12.6 mmHg. While a complete closed-to-open-gate transition was not evident in the limited course of our MD simulations, an increase in the channel radius at the lower gate was observed at 27.6 mmHg versus that at 12.6 mmHg. These findings provide novel information regarding the effect of hydrostatic pressure on TRPV1 channels.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms23137366