Journal Article

FZJ-2024-05444

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Depletion of membrane cholesterol modifies structure, dynamic and activation of Nav1.7

Albani, S.FZJ* ; Eswaran, V. S. B. ; Piergentili, A.FZJ* ; de Souza, P. C. T. ; Lampert, A. (Corresponding author) ; Rossetti, G. (Corresponding author)FZJ*

2024
Elsevier New York, NY [u.a.]

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Please use a persistent id in citations: doi:10.1016/j.ijbiomac.2024.134219  doi:10.34734/FZJ-2024-05444

Abstract: Cholesterol is a major component of plasma membranes and plays a significant role in actively regulating the functioning of several membrane proteins in humans. In this study, we focus on the role of cholesterol depletion on the voltage-gated sodium channel Nav1.7, which is primarily expressed in the peripheral sensory neurons and linked to various chronic inherited pain syndromes. Coarse-grained molecular dynamics simulations revealed key dynamic changes of Nav1.7 upon membrane cholesterol depletion: A loss of rigidity in the structural motifs linked to activation and fast-inactivation is observed, suggesting an easier transition of the channel between different gating states. In-vitro whole-cell patch clamp experiments on HEK293t cells expressing Nav1.7 validated these predictions at the functional level: Hyperpolarizing shifts in the voltage-dependence of activation and fast-inactivation were observed along with an acceleration of the time to peak and onset kinetics of fast inactivation. These results underline the critical role of membrane composition, and of cholesterol in particular, in influencing Nav1.7 gating characteristics. Furthermore, our results also point to cholesterol-driven changes of the geometry of drug-binding regions, hinting to a key role of the membrane environment in the regulation of drug effects.

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Contributing Institute(s):

1. Computational Biomedicine (INM-9)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2024

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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