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Numerical analysis of Ca2+ signaling in rat ventricular myocytes with realistic transverse-axial tubular geometry and inhibited sarcoplasmic reticulum.

ABSTRACT: The t-tubules of mammalian ventricular myocytes are invaginations of the cell membrane that occur at each Z-line. These invaginations branch within the cell to form a complex network that allows rapid propagation of the electrical signal, and hence synchronous rise of intracellular calcium (Ca(2+)). To investigate how the t-tubule microanatomy and the distribution of membrane Ca(2+) flux affect cardiac excitation-contraction coupling we developed a 3-D continuum model of Ca(2+) signaling, buffering and diffusion in rat ventricular myocytes. The transverse-axial t-tubule geometry was derived from light microscopy structural data. To solve the nonlinear reaction-diffusion system we extended SMOL software tool (http://mccammon.ucsd.edu/smol/). The analysis suggests that the quantitative understanding of the Ca(2+) signaling requires more accurate knowledge of the t-tubule ultra-structure and Ca(2+) flux distribution along the sarcolemma. The results reveal the important role for mobile and stationary Ca(2+) buffers, including the Ca(2+) indicator dye. In agreement with experiment, in the presence of fluorescence dye and inhibited sarcoplasmic reticulum, the lack of detectible differences in the depolarization-evoked Ca(2+) transients was found when the Ca(2+) flux was heterogeneously distributed along the sarcolemma. In the absence of fluorescence dye, strongly non-uniform Ca(2+) signals are predicted. Even at modest elevation of Ca(2+), reached during Ca(2+) influx, large and steep Ca(2+) gradients are found in the narrow sub-sarcolemmal space. The model predicts that the branched t-tubule structure and changes in the normal Ca(2+) flux density along the cell membrane support initiation and propagation of Ca(2+) waves in rat myocytes.

SUBMITTER: Cheng Y

PROVIDER: S-EPMC2965743 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Numerical analysis of Ca2+ signaling in rat ventricular myocytes with realistic transverse-axial tubular geometry and inhibited sarcoplasmic reticulum.

Cheng Yuhui Y Yu Zeyun Z Hoshijima Masahiko M Holst Michael J MJ McCulloch Andrew D AD McCammon J Andrew JA Michailova Anushka P AP

PLoS computational biology 20101028 10

The t-tubules of mammalian ventricular myocytes are invaginations of the cell membrane that occur at each Z-line. These invaginations branch within the cell to form a complex network that allows rapid propagation of the electrical signal, and hence synchronous rise of intracellular calcium (Ca(2+)). To investigate how the t-tubule microanatomy and the distribution of membrane Ca(2+) flux affect cardiac excitation-contraction coupling we developed a 3-D continuum model of Ca(2+) signaling, buffer ...[more]

PMID: 21060856

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Project description:Basal phosphorylation of sarcoplasmic reticulum (SR) Ca(2+) proteins is high in sinoatrial nodal cells (SANC), which generate partially synchronized, spontaneous, rhythmic, diastolic local Ca(2+) releases (LCRs), but low in ventricular myocytes (VM), which exhibit rare diastolic, stochastic SR-generated Ca(2+) sparks. We tested the hypothesis that in a physiologic Ca(2+) milieu, and independent of increased Ca(2+) influx, an increase in basal phosphorylation of SR Ca(2+) cycling proteins will convert stochastic Ca(2+) sparks into periodic, high-power Ca(2+) signals of the type that drives SANC normal automaticity. We measured phosphorylation of SR-associated proteins, phospholamban (PLB) and ryanodine receptors (RyR), and spontaneous local Ca(2+) release characteristics (LCR) in permeabilized single, rabbit VM in physiologic [Ca(2+)], prior to and during inhibition of protein phosphatase (PP) and phosphodiesterase (PDE), or addition of exogenous cAMP, or in the presence of an antibody (2D12), that specifically inhibits binding of the PLB to SERCA-2. In the absence of the aforementioned perturbations, VM could only generate stochastic local Ca(2+) releases of low power and low amplitude, as assessed by confocal Ca(2+) imaging and spectral analysis. When the kinetics of Ca(2+) pumping into the SR were increased by an increase in PLB phosphorylation (via PDE and PP inhibition or addition of cAMP) or by 2D12, self-organized, "clock-like" local Ca(2+) releases, partially synchronized in space and time (Ca(2+) wavelets), emerged, and the ensemble of these rhythmic local Ca(2+) wavelets generated a periodic high-amplitude Ca(2+) signal. Thus, a Ca(2+) clock is not specific to pacemaker cells, but can also be unleashed in VM when SR Ca(2+) cycling increases and spontaneous local Ca(2+) release becomes partially synchronized. This unleashed Ca(2+) clock that emerges in a physiological Ca(2+) milieu in VM has two faces, however: it can provoke ventricular arrhythmias; or if harnessed, can be an important feature of novel bio-pacemaker designs.

Dataset Information

Numerical analysis of Ca2+ signaling in rat ventricular myocytes with realistic transverse-axial tubular geometry and inhibited sarcoplasmic reticulum.

Publications

Numerical analysis of Ca2+ signaling in rat ventricular myocytes with realistic transverse-axial tubular geometry and inhibited sarcoplasmic reticulum.

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