ArticleBMC physiology2009
Regulation of excitation-contraction coupling in mouse cardiac myocytes: integrative analysis with mathematical modelling.
Article in BMC physiology, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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15 citing papers in PubMed.
- Complex restitution behavior and reentry in a cardiac tissue model for neonatal mice.Physiological reports · 2017Article
- Vascular Endothelial Growth Factor-B Induces a Distinct Electrophysiological Phenotype in Mouse Heart.Frontiers in physiology · 2017Article
- Ryanodine receptor sensitivity governs the stability and synchrony of local calcium release during cardiac excitation-contraction coupling.Journal of molecular and cellular cardiology · 2016Article
- Role of CaMKII in cardiac arrhythmias.Trends in cardiovascular medicine · 2015Review
- Nuclear calcium in cardiac myocytes.Journal of cardiovascular pharmacology · 2015Review
- A novel computational model of mouse myocyte electrophysiology to assess the synergy between Na+ loading and CaMKII.The Journal of physiology · 2014Article
- Modeling CaMKII-mediated regulation of L-type Ca(2+) channels and ryanodine receptors in the heart.Frontiers in pharmacology · 2014Review
- Modeling CaMKII in cardiac physiology: from molecule to tissue.Frontiers in pharmacology · 2014Review
- Interpreting genetic effects through models of cardiac electromechanics.American journal of physiology. Heart and circulatory physiology · 2012Review
- How the Hodgkin-Huxley equations inspired the Cardiac Physiome Project.The Journal of physiology · 2012Article
- Phospholemman is a negative feed-forward regulator of Ca2+ in β-adrenergic signaling, accelerating β-adrenergic inotropy.Journal of molecular and cellular cardiology · 2012Article
- The role of in vivo Ca²⁺ signals acting on Ca²⁺-calmodulin-dependent proteins for skeletal muscle plasticity.The Journal of physiology · 2011Review
- Ca2+-calmodulin-dependent protein kinase II represses cardiac transcription of the L-type calcium channel alpha(1C)-subunit gene (Cacna1c) by DREAM translocation.The Journal of physiology · 2011Article
- Synergy between CaMKII substrates and β-adrenergic signaling in regulation of cardiac myocyte Ca(2+) handling.Biophysical journal · 2010Article
- Integrative modeling of the cardiac ventricular myocyte.Wiley interdisciplinary reviews. Systems biology and medicineReview
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Authors and funding
5 authors.
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No grant is acknowledged in the PubMed record.
Abstract
backgroundThe cardiomyocyte is a prime example of inherently complex biological system with inter- and cross-connected feedback loops in signalling, forming the basic properties of intracellular homeostasis. Functional properties of cells and tissues have been studied e.g. with powerful tools of genetic engineering, combined with extensive experimentation. While this approach provides accurate information about the physiology at the endpoint, complementary methods, such as mathematical modelling, can provide more detailed information about the processes that have lead to the endpoint phenotype.
resultsIn order to gain novel mechanistic information of the excitation-contraction coupling in normal myocytes and to analyze sophisticated genetically engineered heart models, we have built a mathematical model of a mouse ventricular myocyte. In addition to the fundamental components of membrane excitation, calcium signalling and contraction, our integrated model includes the calcium-calmodulin-dependent enzyme cascade and the regulation it imposes on the proteins involved in excitation-contraction coupling. With the model, we investigate the effects of three genetic modifications that interfere with calcium signalling: 1) ablation of phospholamban, 2) disruption of the regulation of L-type calcium channels by calcium-calmodulin-dependent kinase II (CaMK) and 3) overexpression of CaMK. We show that the key features of the experimental phenotypes involve physiological compensatory and autoregulatory mechanisms that bring the system to a state closer to the original wild-type phenotype in all transgenic models. A drastic phenotype was found when the genetic modification disrupts the regulatory signalling system itself, i.e. the CaMK overexpression model.
conclusionThe novel features of the presented cardiomyocyte model enable accurate description of excitation-contraction coupling. The model is thus an applicable tool for further studies of both normal and defective cellular physiology. We propose that integrative modelling as in the present work is a valuable complement to experiments in understanding the causality within complex biological systems such as cardiac myocytes.
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