Modeling CICR in rat ventricular myocytes: voltage clamp studies
| dc.citation.articleNumber | 43 | |
| dc.citation.journalTitle | Theoretical Biology and Medical Modelling | |
| dc.citation.volumeNumber | 7 | |
| dc.contributor.author | Krishna, Abhilash | |
| dc.contributor.author | Sun, Liang | |
| dc.contributor.author | Valderrábano, Miguel | |
| dc.contributor.author | Palade, Philip T. | |
| dc.contributor.author | Clark, John W. | |
| dc.date.accessioned | 2016-02-03T18:41:24Z | |
| dc.date.available | 2016-02-03T18:41:24Z | |
| dc.date.issued | 2010 | |
| dc.date.updated | 2016-02-03T18:41:23Z | |
| dc.description.abstract | Background: The past thirty-five years have seen an intense search for the molecular mechanisms underlying calcium-induced calcium-release (CICR) in cardiac myocytes, with voltage clamp (VC) studies being the leading tool employed. Several VC protocols including lowering of extracellular calcium to affect Ca2+ loading of the sarcoplasmic reticulum (SR), and administration of blockers caffeine and thapsigargin have been utilized to probe the phenomena surrounding SR Ca2+ release. Here, we develop a deterministic mathematical model of a rat ventricular myocyte under VC conditions, to better understand mechanisms underlying the response of an isolated cell to calcium perturbation. Motivation for the study was to pinpoint key control variables influencing CICR and examine the role of CICR in the context of a physiological control system regulating cytosolic Ca2+ concentration ([Ca2+] myo ). Methods: The cell model consists of an electrical-equivalent model for the cell membrane and a fluid-compartment model describing the flux of ionic species between the extracellular and several intracellular compartments (cell cytosol, SR and the dyadic coupling unit (DCU), in which resides the mechanistic basis of CICR). The DCU is described as a controller-actuator mechanism, internally stabilized by negative feedback control of the unit's two diametrically-opposed Ca2+ channels (trigger-channel and release-channel). It releases Ca2+ flux into the cyto-plasm and is in turn enclosed within a negative feedback loop involving the SERCA pump, regulating[Ca2+] myo . Results: Our model reproduces measured VC data published by several laboratories, and generates graded Ca2+ release at high Ca2+ gain in a homeostatically-controlled environment where [Ca2+] myo is precisely regulated. We elucidate the importance of the DCU elements in this process, particularly the role of the ryanodine receptor in controlling SR Ca2+ release, its activation by trigger Ca2+, and its refractory characteristics mediated by the luminal SR Ca2+ sensor. Proper functioning of the DCU, sodium-calcium exchangers and SERCA pump are important in achieving negative feedback control and hence Ca2+ homeostasis. Conclusions: We examine the role of the above Ca2+ regulating mechanisms in handling various types of induced disturbances in Ca2+ levels by quantifying cellular Ca2+ balance. Our model provides biophysically-based explanations of phenomena associated with CICR generating useful and testable hypotheses. | |
| dc.identifier.citation | Krishna, Abhilash, Sun, Liang, Valderrábano, Miguel, et al.. "Modeling CICR in rat ventricular myocytes: voltage clamp studies." <i>Theoretical Biology and Medical Modelling,</i> 7, (2010) BioMed Central: http://dx.doi.org/10.1186/1742-4682-7-43. | |
| dc.identifier.doi | http://dx.doi.org/10.1186/1742-4682-7-43 | |
| dc.identifier.uri | https://hdl.handle.net/1911/88330 | |
| dc.language.iso | eng | |
| dc.publisher | BioMed Central | |
| dc.rights | This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. | |
| dc.rights.holder | Krishna et al; licensee BioMed Central Ltd. | |
| dc.rights.uri | https://creativecommons.org/licenses/by/2.0/ | |
| dc.title | Modeling CICR in rat ventricular myocytes: voltage clamp studies | |
| dc.type | Journal article | |
| dc.type.dcmi | Text | |
| dc.type.publication | publisher version | |
| local.sword.agent | BioMed Central |