Luo1994_CardiacVentricularActionPotential
Ontology highlight
ABSTRACT:
SUBMITTER: 
Vijayalakshmi Chelliah
PROVIDER: MODEL0912160003 | BioModels | 2005-01-01
REPOSITORIES: BioModels
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Project description:BACKGROUND: Cardiac hypertrophy compensates for increased biomechanical stress of the heart induced by prevalent cardiovascular pathologies, but can result in cardiac failure if left untreated. We hypothesized that the tail-anchored protein Dysferlin with multiple Ca2+-binding C2-domains is critical for the integrity of the transverse-axial tubule (TAT) network inside cardiomyocytes, and contributes to the proliferation of TAT endomembranes during pressure overload-induced cardiac hypertrophy. OBJECTIVE: To reveal the impact of the membrane fusion and repair protein Dysferlin on TAT network stabilization and proliferation necessary for the hypertrophic growth of cardiomyocytes. METHODS AND RESULTS: Super-resolution light and electron microscopy of mouse cardiomyocytes identified a specific localization of Dysferlin in a vesicular compartment in nanometric proximity to contact sites of the TAT network with the sarcoplasmic reticulum (SR), a.k.a. junctional complexes for Ca2+-induced Ca2+ release. Mass spectrometry was used to characterize the cardiac Dysferlin interactome, thereby identifying a novel protein interaction with the membrane-tethering SR protein Juncophilin-2, a known interactor of L-type Ca2+ channels and Ryanodine Receptor Ca2+ release channels in junctional complexes. While the Dysferlin knockout caused a mild progressive phenotype of dilated cardiomyopathy in the mouse heart, global proteome analysis revealed changes preceding systolic failure. Following transverse aortic constriction (TAC), Dysferlin protein expression was significantly increased in hypertrophied wild-type myocardium, while Dysferlin knockout animals presented markedly reduced left-ventricular hypertrophy. Live-cell membrane imaging demonstrated a profound reorganization of the TAT network in wild-type left-ventricular myocytes post-TAC with robust proliferation of axial tubules, which critically depended on the increased expression of Dysferlin within newly-emerging tubule components. CONCLUSIONS: Dysferlin represents a new molecular target in cardiac disease that protects the integrity of tubule-SR junctional complexes for regulated excitation-contraction coupling, and controls TAT network reorganization and tubular membrane proliferation in cardiomyocyte hypertrophy induced by pressure-overload.
2024-07-15 | PXD053037 | Pride
Project description:BACKGROUND: Cardiac hypertrophy compensates for increased biomechanical stress of the heart induced by prevalent cardiovascular pathologies, but can result in cardiac failure if left untreated. We hypothesized that the tail-anchored protein Dysferlin with multiple Ca2+-binding C2-domains is critical for the integrity of the transverse-axial tubule (TAT) network inside cardiomyocytes, and contributes to the proliferation of TAT endomembranes during pressure overload-induced cardiac hypertrophy. OBJECTIVE: To reveal the impact of the membrane fusion and repair protein Dysferlin on TAT network stabilization and proliferation necessary for the hypertrophic growth of cardiomyocytes. METHODS AND RESULTS: Super-resolution light and electron microscopy of mouse cardiomyocytes identified a specific localization of Dysferlin in a vesicular compartment in nanometric proximity to contact sites of the TAT network with the sarcoplasmic reticulum (SR), a.k.a. junctional complexes for Ca2+-induced Ca2+ release. Mass spectrometry was used to characterize the cardiac Dysferlin interactome, thereby identifying a novel protein interaction with the membrane-tethering SR protein Juncophilin-2, a known interactor of L-type Ca2+ channels and Ryanodine Receptor Ca2+ release channels in junctional complexes. While the Dysferlin knockout caused a mild progressive phenotype of dilated cardiomyopathy in the mouse heart, global proteome analysis revealed changes preceding systolic failure. Following transverse aortic constriction (TAC), Dysferlin protein expression was significantly increased in hypertrophied wild-type myocardium, while Dysferlin knockout animals presented markedly reduced left-ventricular hypertrophy. Live-cell membrane imaging demonstrated a profound reorganization of the TAT network in wild-type left-ventricular myocytes post-TAC with robust proliferation of axial tubules, which critically depended on the increased expression of Dysferlin within newly-emerging tubule components. CONCLUSIONS: Dysferlin represents a new molecular target in cardiac disease that protects the integrity of tubule-SR junctional complexes for regulated excitation-contraction coupling, and controls TAT network reorganization and tubular membrane proliferation in cardiomyocyte hypertrophy induced by pressure-overload.
2024-07-15 | PXD053051 | Pride
Project description:This a model from the article:
Cardiac Ca2+ dynamics: the roles of ryanodine receptor adaptation and
sarcoplasmic reticulum load.
Jafri MS, Rice JJ, Winslow RL. Biophys J
1998 Mar;74(3):1149-68 9512016
,
Abstract:
We construct a detailed mathematical model for Ca2+ regulation in the
ventricular myocyte that includes novel descriptions of subcellular mechanisms
based on recent experimental findings: 1) the Keizer-Levine model for the
ryanodine receptor (RyR), which displays adaptation at elevated Ca2+; 2) a model
for the L-type Ca2+ channel that inactivates by mode switching; and 3) a
restricted subspace into which the RyRs and L-type Ca2+ channels empty and
interact via Ca2+. We add membrane currents from the Luo-Rudy Phase II
ventricular cell model to our description of Ca2+ handling to formulate a new
model for ventricular action potentials and Ca2+ regulation. The model can
simulate Ca2+ transients during an action potential similar to those seen
experimentally. The subspace [Ca2+] rises more rapidly and reaches a higher
level (10-30 microM) than the bulk myoplasmic Ca2+ (peak [Ca2+]i approximately 1
microM). Termination of sarcoplasmic reticulum (SR) Ca2+ release is
predominately due to emptying of the SR, but is influenced by RyR adaptation.
Because force generation is roughly proportional to peak myoplasmic Ca2+, we use
[Ca2+]i in the model to explore the effects of pacing rate on force generation.
The model reproduces transitions seen in force generation due to changes in
pacing that cannot be simulated by previous models. Simulation of such complex
phenomena requires an interplay of both RyR adaptation and the degree of SR Ca2+
loading. This model, therefore, shows improved behavior over existing models
that lack detailed descriptions of subcellular Ca2+ regulatory mechanisms.
This model was taken from the CellML repository
and automatically converted to SBML.
The original model was:
Jafri MS, Rice JJ, Winslow RL. (1998) - version03
The original CellML model was created by:
Lloyd, Catherine, May
c.lloyd@aukland.ac.nz
The University of Auckland
The Bioengineering Institute
This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team.
To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication
for more information.
In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not..
To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.
2005-01-01 | MODEL0847869198 | BioModels
Project description:This a model from the article:
A mathematical treatment of integrated Ca dynamics within the ventricular myocyte.
Shannon TR, Wang F, Puglisi J, Weber C, Bers DM. Biophys J.
15347581
, doi: 10.1529/biophysj.104.047449
Abstract:
We have developed a detailed mathematical model for Ca2+ handling and ionic currents in the rabbit ventricular myocyte. The objective was to develop a model that: 1), accurately reflects Ca-dependent Ca release; 2), uses realistic parameters, particularly those that concern Ca transport from the cytosol; 3), comes to steady state; 4), simulates basic excitation-contraction coupling phenomena; and 5), runs on a normal desktop computer. The model includes the following novel features: 1), the addition of a subsarcolemmal compartment to the other two commonly formulated cytosolic compartments (junctional and bulk) because ion channels in the membrane sense ion concentrations that differ from bulk; 2), the use of realistic cytosolic Ca buffering parameters; 3), a reversible sarcoplasmic reticulum (SR) Ca pump; 4), a scheme for Na-Ca exchange transport that is [Na]i dependent and allosterically regulated by [Ca]i; and 5), a practical model of SR Ca release including both inactivation/adaptation and SR Ca load dependence. The data describe normal electrical activity and Ca handling characteristics of the cardiac myocyte and the SR Ca load dependence of these processes. The model includes a realistic balance of Ca removal mechanisms (e.g., SR Ca pump versus Na-Ca exchange), and the phenomena of rest decay and frequency-dependent inotropy. A particular emphasis is placed upon reproducing the nonlinear dependence of gain and fractional SR Ca release upon SR Ca load. We conclude that this model is more robust than many previously existing models and reproduces many experimental results using parameters based largely on experimental measurements in myocytes.
This model was taken from the CellML repository
and automatically converted to SBML.
The original model was:
shannon, wang, puglisi, weber, bers, 2004, version04
The original CellML model was created by:
Fink, Martin,
Oxford University
This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team.
To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication
for more information.
In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not..
To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.
2005-01-01 | MODEL7914464799 | BioModels
Project description:This a model from the article:
Simulation study of cellular electric properties in heart failure
Priebe L, Beuckelmann DJ. Circ Res.
1998; 82(11):1206-23 9633920
,
Abstract:
Patients with severe heart failure are at high risk of sudden cardiac death. In the majority of these patients, sudden cardiac death is thought to be due to ventricular tachyarrhythmias. Alterations of the electric properties of single myocytes in heart failure may favor the occurrence of ventricular arrhythmias in these patients by inducing early or delayed afterdepolarizations. Mathematical models of the cellular action potential and its underlying ionic currents could help to elucidate possible arrhythmogenic mechanisms on a cellular level. In the present study, selected ionic currents based on human data are incorporated into a model of the ventricular action potential for the purpose of studying the cellular electrophysiological consequences of heart failure. Ionic currents that are not yet sufficiently characterized in human ventricular myocytes are adopted from the action potential model developed by Luo and Rudy (LR model). The main results obtained from this model are as follows: The action potential in ventricular myocytes from failing hearts is longer than in nonfailing control hearts. The major underlying mechanisms for this prolongation are the enhanced activity of the Na+-Ca2+ exchanger, the slowed diastolic decay of the [Ca2+]i transient, and the reduction of the inwardly rectifying K+ current and the Na+-K+ pump current in myocytes of failing hearts. Furthermore, the fast and slow components of the delayed rectifier K+ current (I(Kr) and I(Ks), respectively) are of utmost importance in determining repolarization of the human ventricular action potential. In contrast, the influence of the transient outward K+ current on APD is only small in both cell groups. Inhibition of I(Kr) promotes the development of early afterdepolarizations in failing, but not nonfailing, myocytes. Furthermore, spontaneous Ca2+ release from the sarcoplasmic reticulum triggers a premature action potential only in failing myocytes. This model of the ventricular action potential and its alterations in heart failure is intended to serve as a tool for investigating the effects of therapeutic interventions on the electric excitability of the human ventricular myocardium.
This model was taken from the CellML repository
and automatically converted to SBML.
The original model was:
Priebe, Beuckelmann. (1998) - version02
The original CellML model was created by:
Lloyd, Catherine, May
c.lloyd@auckland.ac.nz
The University of Auckland
Auckland Bioengineering Institute
This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team.
To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication
for more information.
In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not..
To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.
2005-01-01 | MODEL8683876463 | BioModels
Project description:This a model from the article:
Action potential and contractility changes in [Na(+)](i) overloaded cardiac
myocytes: a simulation study.
Faber GM, Rudy Y. Biophys J
2000 May;78(5):2392-404 10777735
,
Abstract:
Sodium overload of cardiac cells can accompany various pathologies and induce
fatal cardiac arrhythmias. We investigate effects of elevated intracellular
sodium on the cardiac action potential (AP) and on intracellular calcium using
the Luo-Rudy model of a mammalian ventricular myocyte. The results are: 1)
During rapid pacing, AP duration (APD) shortens in two phases, a rapid phase
without Na(+) accumulation and a slower phase that depends on [Na(+)](i). 2) The
rapid APD shortening is due to incomplete deactivation (accumulation) of I(Ks).
3) The slow phase is due to increased repolarizing currents I(NaK) and
reverse-mode I(NaCa), secondary to elevated [Na(+)](i). 4) Na(+)-overload slows
the rate of AP depolarization, allowing time for greater I(Ca(L)) activation; it
also enhances reverse-mode I(NaCa). The resulting increased Ca(2+) influx
triggers a greater [Ca(2+)](i) transient. 5) Reverse-mode I(NaCa) alone can
trigger Ca(2+) release in a voltage and [Na(+)](i)-dependent manner. 6) During
I(NaK) block, Na(+) and Ca(2+) accumulate and APD shortens due to enhanced
reverse-mode I(NaCa); contribution of I(K(Na)) to APD shortening is negligible.
By slowing AP depolarization (hence velocity) and shortening APD, Na(+)-overload
acts to enhance inducibility of reentrant arrhythmias. Shortened APD with
elevated [Ca(2+)](i) (secondary to Na(+)-overload) also predisposes the
myocardium to arrhythmogenic delayed afterdepolarizations.
This model was taken from the CellML repository
and automatically converted to SBML.
The original model was:
Faber GM, Rudy Y. (2000) - version06
The original CellML model was created by:
Ashton, Jesse,
j.ashton@aukland.ac.nz
The University of Auckland
Auckland Bioengineering Institute
This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team.
To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication
for more information.
In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not..
To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.
2005-01-01 | MODEL0912153452 | BioModels
Project description:This a model from the article:
Rate dependence and regulation of action potential and calcium transient in a
canine cardiac ventricular cell model.
Hund TJ, Rudy Y. Circulation
2004 Nov 16;110(20):3168-74 15505083
,
Abstract:
BACKGROUND: Computational biology is a powerful tool for elucidating
arrhythmogenic mechanisms at the cellular level, where complex interactions
between ionic processes determine behavior. A novel theoretical model of the
canine ventricular epicardial action potential and calcium cycling was developed
and used to investigate ionic mechanisms underlying Ca2+ transient (CaT) and
action potential duration (APD) rate dependence. METHODS AND RESULTS: The
Ca2+/calmodulin-dependent protein kinase (CaMKII) regulatory pathway was
integrated into the model, which included a novel Ca2+-release formulation, Ca2+
subspace, dynamic chloride handling, and formulations for major ion currents
based on canine ventricular data. Decreasing pacing cycle length from 8000 to
300 ms shortened APD primarily because of I(Ca(L)) reduction, with additional
contributions from I(to1), I(NaK), and late I(Na). CaT amplitude increased as
cycle length decreased from 8000 to 500 ms. This positive rate-dependent
property depended on CaMKII activity. CONCLUSIONS: CaMKII is an important
determinant of the rate dependence of CaT but not of APD, which depends on
ion-channel kinetics. The model of CaMKII regulation may serve as a paradigm for
modeling effects of other regulatory pathways on cell function.
This model was taken from the CellML repository
and automatically converted to SBML.
The original model was:
Hund TJ, Rudy Y. (2004) - version03
The original CellML model was created by:
Noble, Penny
penny.noble@dpag.ox.ac.uk
University of Oxford
This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team.
To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication
for more information.
In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not..
To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.
2005-01-01 | MODEL0848116681 | BioModels
Project description:Inflammation and infection can trigger local tissue Na+-accumulation. This Na+-rich environment boosts pro-inflammatory activation of monocyte/macrophage-like cells (MΦ) and their antimicrobial activity. Enhanced Na+-driven MΦ-function requires the osmoprotective transcription factor nuclear factor of activated T cells 5 (NFAT5), which augments NO production and contributes to increased autophagy. However, the mechanism of Na+-sensing in MΦ remained unclear. High extracellular Na+ levels (HS) trigger a substantial Na+-influx and Ca2+ loss. Here, we show that the Na+/ Ca2+-exchanger 1 (NCX1/ solute carrier family 8 member A1 (SLC8A1)) plays a critical role in HS-triggered Na+-influx, concomitant Ca2+ efflux and subsequent NFAT5 accumulation. Moreover, interfering with NCX1-activity impairs HS-boosted inflammatory signaling, infection-triggered autolysosome formation and subsequent antibacterial activity. Taken together, this demonstrates that NCX1 is able to sense Na+ and is required for amplifying inflammatory and antimicrobial MΦ responses upon HS exposure. Manipulating NCX1 offers a new strategy to regulate MΦ function.
2020-06-29 | GSE136662 | GEO
Project description:NCX proteins (Na+/Ca2+ exchangers) are allosterically regulated by cytosolic Ca2+ and Na+ to feedback ion signaling in diverse cell types. The recently discovered cryo-EM structure of the cardiac NCX1.1 provided breakthrough information on the mammalian NCX structure, although the structure-dynamic basis of allosteric regulation remains unresolved. Here, we analyzed the apo, Ca2+-, and Na+ -bound species of the brain NCX1.4 variant using hydrogen-deuterium exchange mass spectrometry (HDX-MS) in conjunction with molecular dynamics (MD) simulations. We show that Ca2+ binding to the regulatory CBD domains dramatically rigidifies the intracellular regulatory loop (5L6) and promotes its interaction with the membrane. Either Na+ or Ca2+ stabilizes the intracellular portions of TM3, TM4, TM9, TM10, and their connecting loops (3L4 and 9L10), exposing a putative cation binding site for allosteric regulation. Either Ca2+ or Na+ rigidifies TMH2, encompassing the palmitoylation domain, and the neighboring two-helix TM1/TM6 bundle(governing the alternating access transitions) to control the ion transport rates. Collectively, our results uncovered important details of allosteric regulation in mammalian NCX, while highlighting structure-dynamic features of functional regions not resolved in the cryo-EM structure. The present outcomes provide useful clues toward resolving the structure-dynamic determinants of regulatory diversity in NCX isoform/splice variants.
2024-04-17 | PXD047098 | Pride
Project description:Rhabdomyolysis is a clinical emergency characterized by severe muscle damage, resulting in the release of intracellular muscle components which leads to myoglobinuria and in severe cases, acute kidney failure. Rhabdomyolysis is caused by genetic factors that are linked to increased disease susceptibility in response to extrinsic triggers. Recessive mutations in TANGO2 result in episodic rhabdomyolysis, metabolic crises, encephalopathy, and cardiac arrhythmia. The underlying mechanism contributing to disease onset in response to specific triggers remains unclear. To address these challenges, we created a zebrafish model of Tango2 deficiency. Here we demonstrate that the loss of Tango2 in zebrafish results in growth defects, early lethality, and increased susceptibility of muscle defects similar to TANGO2 patients. Detailed analyses of skeletal muscle revealed defects in the sarcoplasmic reticulum and mitochondria at the onset of disease development. The sarcoplasmic reticulum (SR) constitutes the primary lipid biosynthesis site and regulates calcium handling in skeletal muscle to control excitation-contraction coupling. Tango2 deficient SR exhibits increased sensitivity to calcium release that was partly restored by inhibition of Ryr1-mediated Ca2+ release in skeletal muscle. Using lipidomics, we identified alterations in the glycerolipid state of tango2 mutants which is critical for membrane stability and energy balance. Therefore, these studies provide insight into key disease processes in Tango2 deficiency and have increased our understanding of the impacts of specific defects on predisposition to environmental triggers in TANGO2-related disorders.
2022-12-07 | ST002398 | MetabolomicsWorkbench