Wang2008 - Mimicking the inhibitory effect of riluzole on membrane conductance in skeletal fibres

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Wang2008 - Mimicking the inhibitory effect of riluzole on membrane conductance in skeletal fibres

This model is described in the article:

Wang YJ, Lin MW, Lin AA, Wu SN.
Life Sci. 2008 Jan; 82(1-2): 11-20

Abstract:

Riluzole is known to be of therapeutic use in the management of amyotrophic lateral sclerosis. In this study, we investigated the effects of riluzole on ion currents in cultured differentiated human skeletal muscle cells (dHSkMCs). Western blotting revealed the protein expression of alpha-subunits for both large-conductance Ca2+-activated K+ (BK(Ca)) channel and Na+ channel (Na(v)1.5) in these cells. Riluzole could reduce the frequency of spontaneous beating in dHSkMCs. In whole-cell configuration, riluzole suppressed voltage-gated Na+ current (I(Na)) in a concentration-dependent manner with an IC50 value of 2.3 microM. Riluzole (10 microM) also effectively increased Ca2+-activated K+ current (I(K(Ca))) which could be reversed by iberiotoxin (200 nM) and paxilline (1 microM), but not by apamin (200 nM). In inside-out patches, when applied to the inside of the cell membrane, riluzole (10 microM) increased BK(Ca)-channel activity with a decrease in mean closed time. Simulation studies also unraveled that both decreased conductance of I(Na) and increased conductance of I(K(Ca)) utilized to mimic riluzole actions in skeletal muscle cells could combine to decrease the amplitude of action potentials and increase the repolarization of action potentials. Taken together, inhibition of I(Na) and stimulation of BK(Ca)-channel activity caused by this drug are partly, if not entirely, responsible for its muscle relaxant actions in clinical setting.

This model is hosted on BioModels Database and identified by: BIOMD0000000693.

To cite BioModels Database, please use: Chelliah V et al. BioModels: ten-year anniversary. Nucl. Acids Res. 2015, 43(Database issue):D542-8.

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Format
SBML (L2V4)
Related Publication
  • Riluzole-induced block of voltage-gated Na+ current and activation of BKCa channels in cultured differentiated human skeletal muscle cells.
  • Wang YJ, Lin MW, Lin AA, Wu SN
  • Life sciences , 1/ 2008 , Volume 82 , Issue 1-2 , pages: 11-20
  • Institute of Basic Medical Sciences, National Cheng Kung University Medical College, Tainan, Taiwan.
  • Riluzole is known to be of therapeutic use in the management of amyotrophic lateral sclerosis. In this study, we investigated the effects of riluzole on ion currents in cultured differentiated human skeletal muscle cells (dHSkMCs). Western blotting revealed the protein expression of alpha-subunits for both large-conductance Ca2+-activated K+ (BK(Ca)) channel and Na+ channel (Na(v)1.5) in these cells. Riluzole could reduce the frequency of spontaneous beating in dHSkMCs. In whole-cell configuration, riluzole suppressed voltage-gated Na+ current (I(Na)) in a concentration-dependent manner with an IC50 value of 2.3 microM. Riluzole (10 microM) also effectively increased Ca2+-activated K+ current (I(K(Ca))) which could be reversed by iberiotoxin (200 nM) and paxilline (1 microM), but not by apamin (200 nM). In inside-out patches, when applied to the inside of the cell membrane, riluzole (10 microM) increased BK(Ca)-channel activity with a decrease in mean closed time. Simulation studies also unraveled that both decreased conductance of I(Na) and increased conductance of I(K(Ca)) utilized to mimic riluzole actions in skeletal muscle cells could combine to decrease the amplitude of action potentials and increase the repolarization of action potentials. Taken together, inhibition of I(Na) and stimulation of BK(Ca)-channel activity caused by this drug are partly, if not entirely, responsible for its muscle relaxant actions in clinical setting.
Contributors
Vijayalakshmi Chelliah, administrator

Metadata information

is
isDescribedBy
PubMed 18068197
PubMed 18068197
Gene Ontology action potential
hasTaxon
Taxonomy Homo sapiens
hasInstance
Gene Ontology response to drug
D00775
105528
Taxonomy Homo sapiens
Human Disease Ontology amyotrophic lateral sclerosis
Brenda Tissue Ontology skeletal muscle
GO:0022832
Gene Ontology action potential
BioModels Database MODEL7817907010
hasPart
isVersionOf
GO:0022832
Gene Ontology response to drug
Human Disease Ontology amyotrophic lateral sclerosis
occursIn
Brenda Tissue Ontology skeletal muscle
Curation status
Curated
Name Description Size Actions

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  • Model originally submitted by : Vijayalakshmi Chelliah
  • Submitted: Mar 23, 2009 4:51:45 PM
  • Last Modified: Mar 21, 2018 4:49:54 PM
Revisions
  • Version: 3 public model Download this version
    • Submitted on: Mar 21, 2018 4:49:54 PM
    • Submitted by: administrator
    • With comment: Notes updated using online editor.
  • Version: 2 public model Download this version
    • Submitted on: Mar 23, 2009 4:51:45 PM
    • Submitted by: Vijayalakshmi Chelliah
    • With comment: Current version of Wang2008_Rilusole_SkeletalMuscleCells
  • Version: 1 public model Download this version
    • Submitted on: Mar 23, 2009 4:51:45 PM
    • Submitted by: Vijayalakshmi Chelliah
    • With comment: Original import of Wang2008_Rilusole_SkeletalMuscleCells
Curator's comment:
(added: 21 Mar 2018, 16:51:13, updated: 21 Mar 2018, 16:51:13)
Figure 6 of the publication has been reproduced. Model, initial conditions and parameter values were obtained from ModelDB. Values for d(0) and o(0) could not be found and were set to 0.1. Cm was set to 0.009uF (not 9 nF as in table 1, simulation units are uF). I_Ca equation is supposedly meant to be changed from gca*d^2 to gca*(d^2)*(Vm-ECa) (CellML) however the figure was reproduced using the original equations from ModelDB. The simulations were performed in COPASI 4.22 (Build 170) and the figure was generated with MATLAB R2014b.