Journal Article

FZJ-2018-03541

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png β1 subunit stabilises sodium channel Nav1.7 against mechanical stress

Körner, J. ; Meents, J. ; Machtens, J.-P.FZJ* ; Lampert, A. (Corresponding author)

2018
Wiley-Blackwell Hoboken, NJ

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Please use a persistent id in citations: doi:10.1113/JP275905

Abstract: Voltage‐gated sodium channels are key players in neuronal excitability and pain signalling. Precise gating of these channels is crucial as even small functional alterations can lead to pathological phenotypes such as pain or heart failure. Mechanical stress has been shown to affect sodium channel activation and inactivation. This suggests that stabilising components are necessary to ensure precise channel gating in living organisms. Here, we show that mechanical shear stress affects voltage dependence of activation and fast inactivation of the Nav1.7 channel. Co‐expression of the β1 subunit, however, protects both gating modes of Nav1.7 against mechanical shear stress. Using molecular dynamics simulation, homology modelling and site‐directed mutagenesis, we identify an intramolecular disulfide bond of β1 (Cys21‐Cys43) which is partially involved in this process: the β1‐C43A mutant prevents mechanical modulation of voltage dependence of activation, but not of fast inactivation. Our data emphasise the unique role of segment 6 of domain IV for sodium channel fast inactivation and confirm previous reports that the intracellular process of fast inactivation can be modified by interfering with the extracellular end of segment 6 of domain IV. Thus, our data suggest that physiological gating of Nav1.7 may be protected against mechanical stress in a living organism by assembly with the β1 subunit.

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Contributing Institute(s):

1. Zelluläre Biophysik (ICS-4)
2. JARA - HPC (JARA-HPC)

Research Program(s):

1. 551 - Functional Macromolecules and Complexes (POF3-551) (POF3-551)
2. MOLECULAR MODELLING OF BIFUNCTIONAL MEMBRANE TRANSPORT PROTEINS (jics40_20130501) (jics40_20130501)
3. Mechanisms of Ca2+-activated Cl- channels and lipid scramblases of the TMEM16 family (jics41_20161101) (jics41_20161101)
4. Multiscale simulations of voltage-gated sodium channel complexes and clusters (jics42_20181101) (jics42_20181101)

Appears in the scientific report 2018

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Database coverage:
; BIOSIS Previews ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF < 5 ; JCR ; NCBI Molecular Biology Database ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Thomson Reuters Master Journal List ; Web of Science Core Collection

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