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Regulation and Remodeling of Calcium Signaling and Excitation-Contraction Coupling in Cardiac Muscle

English title Regulation and Remodeling of Calcium Signaling and Excitation-Contraction Coupling in Cardiac Muscle
Applicant Niggli Ernst
Number 109693
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 01.10.2005 - 30.09.2010
Approved amount 837'000.00
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All Disciplines (2)

Discipline
Cardiovascular Research
Physiology : other topics

Keywords (5)

Calcium signaling; Excitation-contraction coupling; Cardiac myocytes Confocal microscopy; photolysis of caged compounds; Electrophysiology

Lay Summary (English)

Lead
Lay summary
Goal:
In this research project our team concentrates on the question how the force of the cardiac muscle is regulated to guarantee an adequate blood circulation for the changing needs of everyday life, from rest to work and strenuous exercise. In addition, we try to understand how these regulatory mechanisms can maladapt or fail during cardiac diseases, such as hypertrophy and cardiac failure.

Background:
The discovery of subcellular elementary events of cardiac calcium (Ca) signaling and excitation-contraction (EC) coupling (Ca sparks) has revolutionized the present view of cardiac Ca signaling. The concept of functionally independent Ca sparks allows the cellular Ca signals to be regulated by employing a recruitment scheme, whereby single voltage-dependent L-type Ca channels located in the cell membrane locally control a group of SR Ca release channels (ryanodine receptors or RyRs). Ca sparks not only allow to account for the graded Ca signals observed under experimental conditions, but also provide a means for the cell to regulate Ca signaling by changing the sensitivity of EC-coupling. This can be accomplished by varying the Ca spark trigger probability. Related to this, during pathophysiological conditions the sensitivity of cardiac EC coupling may be altered, which could impair cardiac function significantly, but without catastrophic consequences (i.e. without mechanical arrest).

Working Hypothesis:
From these possibilities and relevant experimental findings in several laboratories (including ours), we propose the working hypothesis that 1). The sensitivity of EC-coupling itself may be modulated by cellular regulatory mechanisms and 2). the sensitivity EC-coupling may adapt (or maladapt) to pathological conditions, by adjustments of the same regulatory mechanisms or by impairment of other cellular processes.

Experimental Design and Methods:
Using a combination biophysical and molecular biology methods such as the voltage-clamp technique with laser-scanning confocal microscopy and simultaneous UV-laser flash and two-photon excitation photolysis of caged compounds, we are able to measure, control and/or eliminate several parameters of the Ca signaling system of single live cardiac myocytes. The simultaneous application of all these techniques together with transgenic animal approaches allows us to obtain detailed and specific information about this complex signaling system.

Expected Value of the Proposed Project:
Obviously, the results obtained will be pertinent for our understanding of cardiac Ca signaling in health and disease. Alterations of Ca signaling have been implied in many cardiac conditions, including hypertrophy and congestive heart failure. More recently, mutations of the RyRs have been identified, which destabilize cardiac Ca signaling leading to arrhythmias and sudden cardiac deaths in young adults. Thus, treatment of Ca signaling disturbances might turn out to be more important and beneficial than previously thought.

More information: http://beam.to/calcium_quark
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Associated projects

Number Title Start Funding scheme
132689 Calcium signaling in the heart: Role of SR Ca2+ release channels (RyRs) in health and disease 01.10.2010 Project funding (Div. I-III)
61344 Efficiency of calcium signaling and excitation-contraction coupling in the heart: modulation by calcium load and beta-adre- nergic stimulation 01.10.2000 Project funding (Div. I-III)
121390 Transmission electron microscope for (cryo-) electron tomography 01.08.2008 R'EQUIP

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