دورية أكاديمية
Modeling CICR in rat ventricular myocytes: voltage clamp studies.
العنوان: | Modeling CICR in rat ventricular myocytes: voltage clamp studies. |
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المؤلفون: | Krishna A; Department of Electrical and Computer Engineering, Rice University, Houston, TX 77005, USA. jwc@rice.edu, Sun L, Valderrábano M, Palade PT, Clark JW Jr |
المصدر: | Theoretical biology & medical modelling [Theor Biol Med Model] 2010 Nov 10; Vol. 7, pp. 43. Date of Electronic Publication: 2010 Nov 10. |
نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
اللغة: | English |
بيانات الدورية: | Publisher: BioMed Central Country of Publication: England NLM ID: 101224383 Publication Model: Electronic Cited Medium: Internet ISSN: 1742-4682 (Electronic) Linking ISSN: 17424682 NLM ISO Abbreviation: Theor Biol Med Model Subsets: MEDLINE |
أسماء مطبوعة: | Original Publication: [London] : BioMed Central, 2004-2021 |
مواضيع طبية MeSH: | Models, Biological*, Calcium/*metabolism , Heart Ventricles/*cytology , Myocytes, Cardiac/*metabolism, Animals ; Caffeine/pharmacology ; Calcineurin/metabolism ; Calcium Channels/metabolism ; Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism ; Calmodulin/metabolism ; Cell Compartmentation/drug effects ; Cell Membrane/drug effects ; Cell Membrane/metabolism ; Cytosol/drug effects ; Cytosol/metabolism ; Ion Channel Gating/drug effects ; Ion Transport/drug effects ; Kinetics ; Male ; Myocytes, Cardiac/cytology ; Myocytes, Cardiac/drug effects ; Patch-Clamp Techniques ; Protein Binding/drug effects ; Rats ; Rats, Sprague-Dawley ; Ryanodine Receptor Calcium Release Channel/metabolism ; Sarcoplasmic Reticulum/drug effects ; Sarcoplasmic Reticulum/metabolism ; Thapsigargin/pharmacology |
مستخلص: | 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. |
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المشرفين على المادة: | 0 (Calcium Channels) 0 (Calmodulin) 0 (Ryanodine Receptor Calcium Release Channel) 3G6A5W338E (Caffeine) 67526-95-8 (Thapsigargin) EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 2) EC 3.1.3.16 (Calcineurin) SY7Q814VUP (Calcium) |
تواريخ الأحداث: | Date Created: 20101111 Date Completed: 20110610 Latest Revision: 20211020 |
رمز التحديث: | 20221213 |
مُعرف محوري في PubMed: | PMC3245510 |
DOI: | 10.1186/1742-4682-7-43 |
PMID: | 21062495 |
قاعدة البيانات: | MEDLINE |
تدمد: | 1742-4682 |
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DOI: | 10.1186/1742-4682-7-43 |