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Modulation of excitation-contraction coupling in atrial cardiomyocytes: role of inositol(1,4,5)-triphosphate induced calcium release and sodium-calcium exchange

English title Modulation of excitation-contraction coupling in atrial cardiomyocytes: role of inositol(1,4,5)-triphosphate induced calcium release and sodium-calcium exchange
Applicant Egger Marcel
Number 111983
Funding scheme Project funding (Div. I-III)
Research institution Institut für Physiologie Medizinische Fakultät Universität Bern
Institution of higher education University of Berne - BE
Main discipline Cardiovascular Research
Start/End 01.04.2006 - 31.03.2012
Approved amount 260'000.00
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Keywords (6)

excitation-contraction coupling; calcium signaling; cardiac myocytes; InsP3 signaling; Na-Ca exchanger; two-photon excitation

Lay Summary (English)

Lead
Lay summary
Our understanding of cardiac Ca2+ signaling and the molecular mechanisms of excitation-contraction coupling (EC-coupling) has been revolutionized by the visualization of intracellular and subcellular Ca2+ release events (microdomain Ca2) with laser-scanning confocal microscopy and the use of specific fluorescent Ca2+ indicators. In the heart, the leading mechanism of intracellular Ca2+ release is Ca2+-induced Ca2+ release (CICR) via sarcoplasmic reticulum (SR) release channels (ryanodine receptors, RyRs), which is a prerequisite for muscle contraction. A second mechanism, Ca2+ release through channels sensitive to the intracellular second messenger inositol-1,4,5-triphosphate (InsP3) has been described predominantely in artial myocytes. Its contribution and significance in cardiac EC-coupling are still a matter of debate. However, there is preliminary evidence suggesting that this type of Ca2+ signaling plays a role in adaptive and in pathophysiological settings associated with atrial disease and may contribute to the frequent and clinically relevant arrhythmias. It is therefore important to characterize the EC-coupling mechanisms and Ca2+ signaling, specifically their InsP3 dependence, in atrial myocytes. Our working hypothesis predicts a modulatory role of the InsP3 sensitive Ca2+ release channels for cytosolic Ca2+, thereby changing its sensitivity for triggers of Ca2+ release from the SR. Our second hypothesis relates to a central player for cellular Ca2+ homeostasis and SR Ca2+ loading, theNa+-Ca2+ exchanger (NCX) and predicts conformational currents evoked bythe molecular rearrangement of the NCX molecule during the ion translocation cycle. The aims of the project will be addressed with a methodology that simultaneously applies three state-of the-art biophysical techniques in a single experiment: (1) laser-scanning confocal microscopy,(2) UV-flash and/or two-photon excitation photolysis of caged compounds, and (3) whole-cell voltage clamp techniques. The use of all these techniques in cells of genetically modified animals will allow the examination of atrial EC-coupling in conditions, that allow us to obtain detailed new information about the involved mechanisms at the sub-cellular and even molecular level. We expect to obtain new information about the cellular and subcellular mechanisms that explain regulation and/or dysfunction of atrial cardiac contractility and may contribute to the understanding of atrial arrhythmogenesis.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Minimum information about a cardiac electrophysiology experiment (MICEE): Standardised reporting for model reproducibility, interoperability, and data sharing
T.A. Quinn, S. Granite, M.A. Allessie, C. Antzelevitch, C. Bollensdorff, G. Bub, R.A.B. Burton, E. Cerbai, P.S. Chen, M. Delmar, D. DiFrancesco, Y.E. Earm, I.R. Efimov, M. Egger, et.al (2011), Minimum information about a cardiac electrophysiology experiment (MICEE): Standardised reporting for model reproducibility, interoperability, and data sharing, in Progress in Biophysics and Molecular Biology, 107(1), 4-10.
Functional coupling of alpha2-isoform Na+/K+-ATPase and Ca2+ extrusion through the Na+/Ca2+-exchanger in cardiomyocytes
Swift Fredrik, Tovsrud Nils, Sjaastad Ivar, Sejersted Ole M., Niggli Ernst, Egger Marcel (2010), Functional coupling of alpha2-isoform Na+/K+-ATPase and Ca2+ extrusion through the Na+/Ca2+-exchanger in cardiomyocytes, in Cell Calcium, 48(1), 54-60.
Angiotensin II-mediated adaptive and maladaptive remodeling of cardiomyocyte excitation-contraction coupling.
Gusev Konstantin, Domenighetti Andrea A, Delbridge Lea M D, Pedrazzini Thierry, Niggli Ernst, Egger Marcel (2009), Angiotensin II-mediated adaptive and maladaptive remodeling of cardiomyocyte excitation-contraction coupling., in Circulation Research, 105(1), 42-50.
Calcium waves driven by "sensitization" wave-fronts.
Keller Markus, Kao Joseph P Y, Egger Marcel, Niggli Ernst (2007), Calcium waves driven by "sensitization" wave-fronts., in Cardiovasc. Res., 74(1), 39-45.
F90927: a new member in the class of cardioactive steroids.
Keller Markus, Pignier Christophe, Egger Marcel, Niggli Ernst (2007), F90927: a new member in the class of cardioactive steroids., in Cardiovasc Drug Rev, 25(3), 210-220.
Adaptive and maladaptive remodeling of cardiomyocyte excitation-contraction coupling by angiotensin II.
Egger Marcel, Domenighetti Andrea A (2002), Adaptive and maladaptive remodeling of cardiomyocyte excitation-contraction coupling by angiotensin II., in Trends Cardiovas. Med., 20(3), 78-85.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
AGLA & Cardiovascular Biology 08.03.2012 Zürich, Switzerland
Gordon Conference: Excitation/Contraction Coupling 14.06.2009 Waterville Valley, USA
14th Cardiovascular and Clinical Implication Meeting 03.10.2008 Muntelier, Switzerland
CHFS Symposium Oslo 18.09.2008 Oslo, Norway
Annual Meeting of the German Cardiac Society 14.04.2007 Mannheim, Germany


Associated projects

Number Title Start Funding scheme
68056 Regulatory Mechanisms of the Sodium-Calcium Exchanger in Cardiac Muscle: Interactions with intracellular signaling pathways. 01.10.2002 Project funding (Div. I-III)

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