Mathematical Simulations of the Effects of Altered AMP‐Kinase Activity on INa and the Action Potential in Rat Ventricle
Identifieur interne : 001263 ( Main/Exploration ); précédent : 001262; suivant : 001264Mathematical Simulations of the Effects of Altered AMP‐Kinase Activity on INa and the Action Potential in Rat Ventricle
Auteurs : H. Bazzazi [Canada] ; R. B. Clark [Canada] ; W. R. Giles [États-Unis]Source :
- Journal of Cardiovascular Electrophysiology [ 1045-3873 ] ; 2006-05.
English descriptors
- KwdEn :
Abstract
Introduction: Alterations in the activity of a so‐called “metabolic switch” enzyme, adenosine monophosphate‐activated protein kinase (AMP kinase), in mammalian heart contribute to the conduction abnormalities and rhythm disturbances in the settings of Wolff‐Parkinson‐White syndrome and ventricular pre‐excitation. A recent study by Light et al. has shown that augmented AMP kinase activity can alter the biophysical properties of mammalian cardiac sodium currents. These experiments involved an electrophysiological analysis following heterologous expression of human Nav1.5 in tsA201 cells. Constitutive activation of AMP kinase followed by co‐transfection caused: (i) a hyperpolarizing shift in the activation curve for INa, (ii) a small change in the voltage dependence of steady‐state inactivation, and (iii) a significant slowing in the rate of inactivation of INa. Methods and Results: We have attempted to simulate these results using our mathematical model of the membrane action potential of the adult rat ventricular myocyte. The changes in INa produced by AMP kinase activation and/or overexpression can be reconstructed mathematically by altering two rate constants in a Markovian model that governs the INa kinetics. Simulated macroscopic INa records in which a fraction (10–100%) of the Na+ channels had the appropriate rate constants for two state‐dependent transitions increased by a factor of 100‐fold exhibited: (i) slowed inactivation, (ii) a shift in steady‐state activation to more hyperpolarized membrane potentials, and (iii) a very small change in the voltage dependence of steady‐state inactivation. Summary: Thus, straightforward modifications of a previously published kinetic scheme for the time and voltage dependence of mammalian heart INa, when incorporated into a mathematical model for the rat ventricular action potential can reproduce the main features of these AMP kinase‐induced modifications in INa in mammalian ventricle. Ongoing mathematical simulations are directed toward developing formulations that mimic the molecular mechanisms for the AMP kinase effects, e.g., changes in the kinetics of INa resulting from selective phosphorylation/dephosphorylation of sites on the alpha or beta subunits which comprise human Nav1.5. Thereafter, incorporation of these changes into a mathematical model for the action potential of the human ventricular myocyte is planned.
Url:
DOI: 10.1111/j.1540-8167.2006.00402.x
Affiliations:
Links toward previous steps (curation, corpus...)
Le document en format XML
<record><TEI wicri:istexFullTextTei="biblStruct"><teiHeader><fileDesc><titleStmt><title xml:lang="en">Mathematical Simulations of the Effects of Altered AMP‐Kinase Activity on INa and the Action Potential in Rat Ventricle</title><author><name sortKey="Bazzazi, H" sort="Bazzazi, H" uniqKey="Bazzazi H" first="H." last="Bazzazi">H. Bazzazi</name></author><author><name sortKey="Clark, R B" sort="Clark, R B" uniqKey="Clark R" first="R. B." last="Clark">R. B. Clark</name></author><author><name sortKey="Giles, W R" sort="Giles, W R" uniqKey="Giles W" first="W. R." last="Giles">W. R. Giles</name></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:430B6407B819CF312DD5033C42627247C0F962A0</idno><date when="2006" year="2006">2006</date><idno type="doi">10.1111/j.1540-8167.2006.00402.x</idno><idno type="url">https://api.istex.fr/document/430B6407B819CF312DD5033C42627247C0F962A0/fulltext/pdf</idno><idno type="wicri:Area/Main/Corpus">001669</idno><idno type="wicri:Area/Main/Curation">001434</idno><idno type="wicri:Area/Main/Exploration">001263</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main" xml:lang="en">Mathematical Simulations of the Effects of Altered AMP‐Kinase Activity on INa and the Action Potential in Rat Ventricle</title><author><name sortKey="Bazzazi, H" sort="Bazzazi, H" uniqKey="Bazzazi H" first="H." last="Bazzazi">H. Bazzazi</name><affiliation wicri:level="4"><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta</wicri:regionArea><orgName type="university">Université de Calgary</orgName><placeName><settlement type="city">Calgary</settlement><region type="state">Alberta</region></placeName></affiliation></author><author><name sortKey="Clark, R B" sort="Clark, R B" uniqKey="Clark R" first="R. B." last="Clark">R. B. Clark</name><affiliation wicri:level="4"><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta</wicri:regionArea><orgName type="university">Université de Calgary</orgName><placeName><settlement type="city">Calgary</settlement><region type="state">Alberta</region></placeName></affiliation></author><author><name sortKey="Giles, W R" sort="Giles, W R" uniqKey="Giles W" first="W. R." last="Giles">W. R. Giles</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Departments of Bioengineering and Medicine, University of California, San Diego, La Jolla, California</wicri:regionArea><placeName><region type="state">Californie</region></placeName></affiliation></author></analytic><monogr></monogr><series><title level="j">Journal of Cardiovascular Electrophysiology</title><idno type="ISSN">1045-3873</idno><idno type="eISSN">1540-8167</idno><imprint><publisher>Blackwell Publishing Inc</publisher><pubPlace>350 Main Street , Malden , MA 02148‐5018 , USA , and 9600 Garsington Road , Oxford OX4 2DQ , UK .</pubPlace><date type="published" when="2006-05">2006-05</date><biblScope unit="volume">17</biblScope><biblScope unit="supplement">s1</biblScope><biblScope unit="page" from="S162">S162</biblScope><biblScope unit="page" to="S168">S168</biblScope></imprint><idno type="ISSN">1045-3873</idno></series><idno type="istex">430B6407B819CF312DD5033C42627247C0F962A0</idno><idno type="DOI">10.1111/j.1540-8167.2006.00402.x</idno><idno type="ArticleID">JCE402</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">1045-3873</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>AMP kinase</term><term>Na+ current</term><term>arrhythmia</term><term>mathematical simulations</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Introduction: Alterations in the activity of a so‐called “metabolic switch” enzyme, adenosine monophosphate‐activated protein kinase (AMP kinase), in mammalian heart contribute to the conduction abnormalities and rhythm disturbances in the settings of Wolff‐Parkinson‐White syndrome and ventricular pre‐excitation. A recent study by Light et al. has shown that augmented AMP kinase activity can alter the biophysical properties of mammalian cardiac sodium currents. These experiments involved an electrophysiological analysis following heterologous expression of human Nav1.5 in tsA201 cells. Constitutive activation of AMP kinase followed by co‐transfection caused: (i) a hyperpolarizing shift in the activation curve for INa, (ii) a small change in the voltage dependence of steady‐state inactivation, and (iii) a significant slowing in the rate of inactivation of INa. Methods and Results: We have attempted to simulate these results using our mathematical model of the membrane action potential of the adult rat ventricular myocyte. The changes in INa produced by AMP kinase activation and/or overexpression can be reconstructed mathematically by altering two rate constants in a Markovian model that governs the INa kinetics. Simulated macroscopic INa records in which a fraction (10–100%) of the Na+ channels had the appropriate rate constants for two state‐dependent transitions increased by a factor of 100‐fold exhibited: (i) slowed inactivation, (ii) a shift in steady‐state activation to more hyperpolarized membrane potentials, and (iii) a very small change in the voltage dependence of steady‐state inactivation. Summary: Thus, straightforward modifications of a previously published kinetic scheme for the time and voltage dependence of mammalian heart INa, when incorporated into a mathematical model for the rat ventricular action potential can reproduce the main features of these AMP kinase‐induced modifications in INa in mammalian ventricle. Ongoing mathematical simulations are directed toward developing formulations that mimic the molecular mechanisms for the AMP kinase effects, e.g., changes in the kinetics of INa resulting from selective phosphorylation/dephosphorylation of sites on the alpha or beta subunits which comprise human Nav1.5. Thereafter, incorporation of these changes into a mathematical model for the action potential of the human ventricular myocyte is planned.</div></front></TEI><affiliations><list><country><li>Canada</li><li>États-Unis</li></country><region><li>Alberta</li><li>Californie</li></region><settlement><li>Calgary</li></settlement><orgName><li>Université de Calgary</li></orgName></list><tree><country name="Canada"><region name="Alberta"><name sortKey="Bazzazi, H" sort="Bazzazi, H" uniqKey="Bazzazi H" first="H." last="Bazzazi">H. Bazzazi</name></region><name sortKey="Clark, R B" sort="Clark, R B" uniqKey="Clark R" first="R. B." last="Clark">R. B. Clark</name></country><country name="États-Unis"><region name="Californie"><name sortKey="Giles, W R" sort="Giles, W R" uniqKey="Giles W" first="W. R." last="Giles">W. R. Giles</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Wicri/Sante/explor/ParkinsonV1/Data/Main/Exploration
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 001263 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd -nk 001263 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Wicri/Sante
|area= ParkinsonV1
|flux= Main
|étape= Exploration
|type= RBID
|clé= ISTEX:430B6407B819CF312DD5033C42627247C0F962A0
|texte= Mathematical Simulations of the Effects of Altered AMP‐Kinase Activity on INa and the Action Potential in Rat Ventricle
}}
| This area was generated with Dilib version V0.6.23. |  |