This research will be done primarily in Slovak Republic as an extension of NIH grant #HL074045. The overall goal of this proposal is to elucidate the changes of calcium signaling mechanisms in dyads of mammalian cardiac muscle cells during heart failure. These structures contain clusters of L-type calcium channels (DHPRs) in opposition to clusters of ryanodine receptor calcium release channels functionally coupled by calcium ions. Alterations in calcium signaling during excitation-contraction coupling contribute to the decreased performance of failing hearts. The changes in calcium signaling steps during activation of calcium release by DHPRs and their relationship to the ultrastructural organization of dyads and the topology of channels in the excitation-contraction coupling units will be determined. To this end, measurements of the kinetics of whole-cell calcium currents, whole-cell calcium transients, and dyadic calcium release events (calcium spikes) will be carried out. These measurements will be supplemented by morphological analysis of the volume and surface densities of the tubular system and of cisternal and longitudinal sarcoplasmic reticulum, and of colocalization between calcium channels and calcium release channels, using electron microscopy and confocal microscopy. Quantitative analysis of the kinetics of calcium current and calcium release in parallel will be used to estimate parameters of calcium signaling critical for control of gradation and efficiency of excitation-contraction coupling. Computer simulation of experiments will be used to ascertain possible mechanisms and to design experiments with high predictive power. Understanding the abnormalities of cardiac E-C coupling in heart failure is important since it might become a strategic site for therapeutic intervention. Furthermore, defining the relationships between the spatial organization of channel clusters and their calcium signaling has a broader significance for understanding processes such as synaptic transmission, neuroendocrine secretion and regulation of vascular tone.

Agency
National Institute of Health (NIH)
Institute
Fogarty International Center (FIC)
Type
Small Research Grants (R03)
Project #
5R03TW005543-06
Application #
7052035
Study Section
International and Cooperative Projects 1 Study Section (ICP)
Program Officer
Primack, Aron
Project Start
2001-05-20
Project End
2008-04-30
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
6
Fiscal Year
2006
Total Cost
$39,372
Indirect Cost
Name
Ohio State University
Department
Physiology
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
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Valent, Ivan; Zahradnikova, Alexandra; Pavelkova, Jana et al. (2007) Spatial and temporal Ca2+, Mg2+, and ATP2- dynamics in cardiac dyads during calcium release. Biochim Biophys Acta 1768:155-66
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Zahradnikova, A; Dura, M; Gyorke, I et al. (2003) Regulation of dynamic behavior of cardiac ryanodine receptor by Mg2+ under simulated physiological conditions. Am J Physiol Cell Physiol 285:C1059-70
Dura, M; Zahradnik, I; Zahradnikova, A (2003) Kinetics of cardiac RyR channel gating studied at high temporal resolution. Physiol Res 52:571-8