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Dokos1996_SinoatrialNode

ABSTRACT: This a model from the article: Ion currents underlying sinoatrial node pacemaker activity: a new single cell mathematical model. Dokos S, Celler B, Lovell N. J Theor Biol 1996 Aug 7;181(3):245-72 8869126 , Abstract: The ionic currents underlying autorhythmicity of the mammalian sinoatrial node and their wider contribution to each phase of the action potential have been investigated in this study using a new single cell mathematical model. The new model provides a review and update of existing formulations of sinoatrial node membrane currents, derived from a wide range of electrophysiological data available in the literature. Simulations of spontaneous activity suggest that the dominant mechanism underlying pacemaker depolarisation is the inward background Na+ current, ib,Na. In contrast to previous models, the decay of the delayed rectifying K+ current, iK, was insignificant during this phase. Despite the presence of a pseudo-outward background current throughout the pacemaker range of potentials (Na-K pump+leak currents), the hyperpolarisation-activated current i(f) was not essential to pacemaker activity. A closer inspection of the current-voltage characteristics of the model revealed that the "instantaneous" time-independent current was inward for holding potentials in the pacemaker range, which rapidly became outward within 2 ms due to the inactivation of the L-type Ca2+ current, iCa,L. This suggests that reports in the literature in which the net background current is outward throughout the pacemaker range of potentials may be exaggerated. The magnitudes of the action potential overshoot and the maximum diastolic potential were determined largely by the reversal potentials of iCa,L and iK respectively. The action potential was sustained by the incomplete deactivation of iCa,L and the Na-Ca exchanger, iNaCa. Despite the incorporation of "square-root" activation by [K]o of all K+ currents, the model was unable to correctly simulate the response to elevated [K]o. This model was taken from the CellML repository and automatically converted to SBML. The original model was: Dokos S, Celler B, Lovell N. (1996) - version06 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.

SUBMITTER: Vijayalakshmi Chelliah

PROVIDER: MODEL0912503622 | BioModels | 2005-01-01

REPOSITORIES: BioModels

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Publications

Ion currents underlying sinoatrial node pacemaker activity: a new single cell mathematical model.

Dokos S S Celler B B Lovell N N

Journal of theoretical biology 19960801 3

The ionic currents underlying autorhythmicity of the mammalian sinoatrial node and their wider contribution to each phase of the action potential have been investigated in this study using a new single cell mathematical model. The new model provides a review and update of existing formulations of sinoatrial node membrane currents, derived from a wide range of electrophysiological data available in the literature. Simulations of spontaneous activity suggest that the dominant mechanism underlying ...[more]

PMID: 8869126

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Project description:This the model describing the action potentials of the peripheral rabbit sinoatrial node from the article: Mathematical models of action potentials in the periphery and center of the rabbit sinoatrial node. Mathematical models of action potentials in the periphery and center of the rabbit sinoatrial node. Am J Physiol Heart Circ Physiol. 2000 Jul;279(1):H397-421. Pubmed ID: 10899081 , full text at AJP - Heart and Circulatory Physiology. Abstract: Mathematical models of the action potential in the periphery and center of the rabbit sinoatrial (SA) node have been developed on the basis of published experimental data. Simulated action potentials are consistent with those recorded experimentally: the model-generated peripheral action potential has a more negative takeoff potential, faster upstroke, more positive peak value, prominent phase 1 repolarization, greater amplitude, shorter duration, and more negative maximum diastolic potential than the model-generated central action potential. In addition, the model peripheral cell shows faster pacemaking. The models behave qualitatively the same as tissue from the periphery and center of the SA node in response to block of tetrodotoxin-sensitive Na(+) current, L- and T-type Ca(2+) currents, 4-aminopyridine-sensitive transient outward current, rapid and slow delayed rectifying K(+) currents, and hyperpolarization-activated current. A one-dimensional model of a string of SA node tissue, incorporating regional heterogeneity, coupled to a string of atrial tissue has been constructed to simulate the behavior of the intact SA node. In the one-dimensional model, the spontaneous action potential initiated in the center propagates to the periphery at approximately 0.06 m/s and then into the atrial muscle at 0.62 m/s. This model was taken from the CellML repository and automatically converted to SBML. The original model was: Zhang, Holden, Kodama, Honjo, Lei, Varghese, Boyett, 2000, version03 The original CellML model was created and curated by: Garny, Alan alan.garny(at)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.

Project description:This a model from the article: A mathematical model of a rabbit sinoatrial node cell. Demir SS, Clark JW, Murphey CR, Giles WR. Am J Physiol 1994 Mar;266(3 Pt 1):C832-52 8166247 , Abstract: A mathematical model for the electrophysiological responses of a rabbit sinoatrial node cell that is based on whole cell recordings from enzymatically isolated single pacemaker cells at 37 degrees C has been developed. The ion channels, Na(+)-K+ and Ca2+ pumps, and Na(+)-Ca2+ exchanger in the surface membrane (sarcolemma) are described using equations for these known currents in mammalian pacemaker cells. The extracellular environment is treated as a diffusion-limited space, and the myoplasm contains Ca(2+)-binding proteins (calmodulin and troponin). Original features of this model include 1) new equations for the hyperpolarization-activated inward current, 2) assessment of the role of the transient-type Ca2+ current during pacemaker depolarization, 3) inclusion of an Na+ current based on recent experimental data, and 4) demonstration of the possible influence of pump and exchanger currents and background currents on the pacemaker rate. This model provides acceptable fits to voltage-clamp and action potential data and can be used to seek biophysically based explanations of the electrophysiological activity in the rabbit sinoatrial node cell. This model was taken from the CellML repository and automatically converted to SBML. The original model was: Demir SS, Clark JW, Murphey CR, Giles WR. (1994) - version01 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.

Project description:This a model from the article: Reconstruction of sino-atrial node pacemaker potential based on the voltage clamp experiments. Yanagihara K, Noma A, Irisawa H. Jpn J Physiol 1980;30(6):841-57 7265560 , Abstract: The pacemaker activity of the S-A node cell was explained by reconstructing the pacemaker potential using a Hodgkin-Huxley type mathematical model which was based on the reported voltage clamp data. In this model four dynamic currents, the sodium current iNa, the slow inward current, is, the potassium current, iK, and the hyperpolarization-activated current, ih, in addition to a time-dependent leak current, i1 were included. The model simulated the spontaneous action potential the current voltage relationship, and the voltage clamp experiment in normal Tyrode solution of the rabbit S-A node. Furthermore, the changes of activity induced by the potassium current blocker Ba2+, by applying constant current, acetylcholine, and epinephrine were also reconstructed. It was strongly suggested that the pacemaker depolarization in the S-A node cell is mainly due to a gradual increase of iS during diastole, and that the contribution of iK is much less compared to the potassium current iK2 in the Purkinje fiber pacemaker depolarization. The rising phase of the action potential was due to iS and the plateau phase is determined by both the inactivation of iS and activation of iK. This model was taken from the CellML repository and automatically converted to SBML. The original model was: Yanagihara K, Noma A, Irisawa H. (1980) - 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:This a model from the article: Dynamical description of sinoatrial node pacemaking: improved mathematical model for primary pacemaker cell. Kurata Y, Hisatome I, Imanishi S, Shibamoto T. Am J Physiol Heart Circ Physiol 2002 Nov;283(5):H2074-101 12384487 , Abstract: We developed an improved mathematical model for a single primary pacemaker cell of the rabbit sinoatrial node. Original features of our model include 1) incorporation of the sustained inward current (I(st)) recently identified in primary pacemaker cells, 2) reformulation of voltage- and Ca(2+)-dependent inactivation of the L-type Ca(2+) channel current (I(Ca,L)), 3) new expressions for activation kinetics of the rapidly activating delayed rectifier K(+) channel current (I(Kr)), and 4) incorporation of the subsarcolemmal space as a diffusion barrier for Ca(2+). We compared the simulated dynamics of our model with those of previous models, as well as with experimental data, and examined whether the models could accurately simulate the effects of modulating sarcolemmal ionic currents or intracellular Ca(2+) dynamics on pacemaker activity. Our model represents significant improvements over the previous models, because it can 1) simulate whole cell voltage-clamp data for I(Ca,L), I(Kr), and I(st); 2) reproduce the waveshapes of spontaneous action potentials and ionic currents during action potential clamp recordings; and 3) mimic the effects of channel blockers or Ca(2+) buffers on pacemaker activity more accurately than the previous models. This model was taken from the CellML repository and automatically converted to SBML. The original model was: Kurata Y, Hisatome I, Imanishi S, Shibamoto T. (2002) - version05 The original CellML model was created by: Noble, Penny, 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:to study the effect of induced expression of TBX3 within the atrium of the heart Background: Treatment of congenital or acquired disorders of the sinus node or atrioventricular node requires insight into the molecular mechanisms for the development and homeostasis of these pacemaker tissues. In the developing heart, transcription factor TBX3 is required for pacemaker and conduction system development. Here, we explore the role of TBX3 in the adult heart and investigate whether TBX3 is able to reprogram terminally differentiated working cardiomyocytes into pacemaker cells. This would be an attractive approach in biological pacemaker formation. Methods and results: TBX3 expression was ectopically induced in cardiomyocytes of adult transgenic mice. Expression analysis revealed an efficient switch from the working myocardial expression profile to that of the pacemaker myocardium. This included suppression of genes encoding gap junction subunits (Cx40, Cx43), the cardiac Na+ channel (NaV1.5; INa) and inwardly rectifying K+ ion channels (Kir-genes; IK1). Concordantly, we observed conduction slowing in these hearts, and reductions in INa and IK1 in cardiomyocytes isolated from these hearts. The reduction in IK1 resulted in a more depolarized maximum diastolic potential, thus enabling spontaneous diastolic depolarization. Neither ectopic pacemaker activity nor pacemaker current, If, were observed. Lentiviral expression of TBX3 in ventricular cardiomyocytes resulted in conduction slowing and development of heterogeneous phenotypes, including depolarized and spontaneously active cardiomyocytes. Conclusions: TBX3 partially reprograms terminally differentiated working cardiomyocytes into pacemaker-like cells and induces important pacemaker properties. The ability of TBX3 to reduce intercellular coupling to overcome current-to-load mismatch and the ability to reduce IK1 density to enable diastolic depolarization, are very promising TBX3 characteristics for biological pacemaker formation strategies. 5 TBX3 expressing left atrial appendage samples (Tamoxifen-treated Myh6MCM;CTBX3 adult male mice) and 6 controls ((Tamoxifen-treated Myh6MCM adult male mice)

Dataset Information

Dokos1996_SinoatrialNode

Publications

Ion currents underlying sinoatrial node pacemaker activity: a new single cell mathematical model.

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