Dataset Information

Maleckar2008_AtrialMyocyte

ABSTRACT: This a model from the article: Mathematical simulations of ligand-gated and cell-type specific effects on the action potential of human atrium. Maleckar MM, Greenstein JL, Trayanova NA, Giles WR. Prog Biophys Mol Biol. 2008; 98(2-3):161-70 19186188 , Abstract: In the mammalian heart, myocytes and fibroblasts can communicate via gap junction, or connexin-mediated current flow. Some of the effects of this electroto nic coupling on the action potential waveform of the human ventricular myocyte have been analyzed in detail. The present study employs a recently developed mathematical model of the human atrial myocyte to investigate the consequences of this heterogeneous cell-cell interaction on the action potential of the human atrium. Two independent physiological processes which alter the physiology of the human atrium have been studied. i) The effects of the autonomic tra nsmitter acetylcholine on the atrial action potential have been investigated by inclusion of a time-independent, acetylcholine-activated K(+) current in th is mathematical model of the atrial myocyte. ii) A non-selective cation current which is activated by natriuretic peptides has been incorporated into a pre viously published mathematical model of the cardiac fibroblast. These results identify subtle effects of acetylcholine, which arise from the nonlinear inte ractions between ionic currents in the human atrial myocyte. They also illustrate marked alterations in the action potential waveform arising from fibrobla st-myocyte source-sink principles when the natriuretic peptide-mediated cation conductance is activated. Additional calculations also illustrate the effect s of simultaneous activation of both of these cell-type specific conductances within the atrial myocardium. This study provides a basis for beginning to as sess the utility of mathematical modeling in understanding detailed cell-cell interactions within the complex paracrine environment of the human atrial myo cardium. This model was taken from the CellML repository and automatically converted to SBML. The original model was: Maleckar MM, Greenstein JL, Trayanova NA, Giles WR. (2009) - version01 The original CellML model was created by: Fink, Martin, martin.fink@dpag.ox.ac.uk The University of Oxford Department of Physiology, Anatomy & Genetics 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.

SUBMITTER: Vijayalakshmi Chelliah

PROVIDER: MODEL9810152478 | BioModels | 2005-01-01

REPOSITORIES: BioModels

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	MODEL9810152478?filename=MODEL9810152478-biopax2.owl	Owl
	MODEL9810152478?filename=MODEL9810152478-biopax3.owl	Owl
	MODEL9810152478?filename=MODEL9810152478.m	Other
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Publications

Mathematical simulations of ligand-gated and cell-type specific effects on the action potential of human atrium.

Maleckar Mary M MM Greenstein Joseph L JL Trayanova Natalia A NA Giles Wayne R WR

Progress in biophysics and molecular biology 20081001 2-3

In the mammalian heart, myocytes and fibroblasts can communicate via gap junction, or connexin-mediated current flow. Some of the effects of this electrotonic coupling on the action potential waveform of the human ventricular myocyte have been analyzed in detail. The present study employs a recently developed mathematical model of the human atrial myocyte to investigate the consequences of this heterogeneous cell-cell interaction on the action potential of the human atrium. Two independent physi ...[more]

PMID: 19186188

Similar Datasets

Project description:This a model from the article: A model of the action potential and underlying membrane currents in a rabbit atrial cell. Lindblad DS, Murphey CR, Clark JW, Giles WR. Am J Physiol 1996 Oct;271(4 Pt 2):H1666-96 8897964 , Abstract: We have developed a mathematical model of the rabbit atrial myocyte and have used it in an examination of the ionic basis of the atrial action potential. Available biophysical data have been incorporated into the model to quantify the specific ultrastructural morphology, intracellular ion buffering, and time- and voltage-dependent currents and transport mechanisms of the rabbit atrial cell. When possible, mathematical expressions describing ionic currents identified in rabbit atrium are based on whole cell voltage-clamp data from enzymatically isolated rabbit atrial myocytes. This membrane model is coupled to equations describing Na+, K+, and Ca2+ homeostasis, including the uptake and release of Ca2+ by the sarcoplasmic reticulum and Ca2+ buffering. The resulting formulation can accurately simulate the whole cell voltage-clamp data on which it is based and provides fits to a family of rabbit atrial cell action potentials obtained at 35 degrees C over a range of stimulus rates (0.2-3.0 Hz). The model is utilized to provide a qualitative prediction of the intracellular Ca2+ concentration transient during the action potential and to illustrate the interactions between membrane currents that underlie repolarization in the rabbit atrial myocyte. This model was taken from the CellML repository and automatically converted to SBML. The original model was: Lindblad DS, Murphey CR, Clark JW, Giles WR. (1996) - version=1.0 The original CellML model was created by: Penny Noble penny.noble@dpag.ox.ac.uk The 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.

Project description:Introduction: Atrial fibrillation (AF) is the most common arrhythmia and affects around 1% of the population with increasing incidence and substantial morbidity. Functional effects of genetic variants associated with AF should help to identify targets involved in AF initiation and/or subsequent remodeling. Gene variants next to the gene of the transcription factor PITX2 (paired-like homeodomain transcription factor 2) showed the strongest association with AF. A significant number of AF patients showed reduced PITX2 levels in the left atrium. Mouse models have been used to study functional aspects of PITX2 gene deletion (“knock out”), but there are substantial differences in atrial electrophysiology between mouse and human . HiPSC-CM should be able to bridge the gap, provided the cells reproduce typical characteristics of human atrium. Methods: PITX2 knock out samples from a control cell line of human induced pluripotent stem cells (hiPSC) were obtained. Differentiation and generation of Atrial-like engineered heart tissue (aEHT) was performed. RNA-sequencing (RNA-Seq), Quantitative Real-time PCR (RT-qPCR), Protein analysis by Western Blot, Contraction and force analysis, action potential measurements, Calcium current measurements and differential gene expression analysis were run on the samples. Results: Effective knock out of PITX2 was confirmed by mRNA sequencing and WB. It was shown that PITX2 deficiency reduces contraction force. PITX2 deficiency induces action potential triangulation with more negative maximum diastolic potential. Activation of muscarinic receptors shortens APD in both PITX2 knockout and controls but hyperpolarization is lost in PITX2 knock out. It was shown that Ca2+ current density is smaller in PITX2 knock out than controls. We found that more negative MDP in PITX2 knock out is not associated with higher IK1. Conclusion: We improved atrial differentiation, coming very close to human atrial electrophysiology. We demonstrate that PITX2 deficiency induces key characteristics known from persistent AF.