Activation and Propagation of Ca2+ Release during Excitation-Contraction Coupling in Atrial Myocytes

Kockskämper, Jens; Sheehan, Katherine A.; Bare, Dan J.; Lipsius, Stephen L.; Mignery, Gregory A.; Blatter, Lothar A.

doi:10.1016/s0006-3495(01)75903-6

Cited by 112 publications

(189 citation statements)

References 31 publications

(46 reference statements)

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“…This means that action potentials can only trigger Ca 2+ entry and CICR at the outer edge of an atrial myocyte. The distribution of RyRs in adult atrial cells appears to be similar to that in ventricular myocytes [10][11][12]. However, there is an important functional difference.…”

Section: Introductionmentioning

confidence: 75%

Comparison of the T-tubule system in adult rat ventricular and atrial myocytes, and its role in excitation–contraction coupling and inotropic stimulation

et al. 2010

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a b s t r a c t Narrow, tubular, inward projections of the sarcolemma ('T-tubules') are an established feature of adult mammalian ventricular myocytes that enables them to generate the whole-cell Ca 2+ transients and produce coordinated contraction. Loss of T-tubules can occur during ageing and under pathological conditions, leading to altered cardiac excitation-contraction coupling. In contrast to adult ventricular cells, atrial myocytes do not generally express an extensive T-tubule system at any stage of development, and therefore rely on Ca 2+ channels around their periphery for the induction of Ca 2+ signalling and excitation-contraction coupling. Consequently, the characteristics of systolic Ca 2+ signals in adult ventricular and atrial myocytes are temporally and spatially distinct. However, although atrial myocytes do not have the same regularly spaced convoluted T-tubule structures as adult ventricular cells, it has been suggested that a proportion of adult atrial cells have a more rudimentary tubule system. We examined the structure and function of these atrial tubules, and explored their impact on the initiation and recovery of Ca 2+ signalling in electrically paced myocytes. The atrial responses were compared to those in adult ventricular cells that had intact T-tubules, or that had been chemically detubulated. We found that tubular structures were present in a significant minority of adult atrial myocytes, and were unlike the T-tubules in adult ventricular cells. In those cells where they were present, the atrial tubules significantly altered the on-set, amplitude, homogeneity and recovery of Ca 2+ transients. The properties of adult atrial myocyte Ca 2+ signals were different from those in adult ventricular cells, whether intact or detubulated. Excitation-contraction coupling in detubulated adult ventricular myocytes, therefore, does not approximate to atrial signalling, even though Ca 2+ signals are initiated in the periphery of the cells in both of these situations. Furthermore, inotropic responses to endothelin-1 were entirely dependent on T-tubules in adult ventricular myocytes, but not in atrial cells. Our data reveal that that the T-tubules in atrial cells impart significant functional properties, but loss of these tubular membranes does not affect Ca 2+ signalling as dramatically as detubulation in ventricular myocytes.

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Section: Introductionmentioning

confidence: 75%

Comparison of the T-tubule system in adult rat ventricular and atrial myocytes, and its role in excitation–contraction coupling and inotropic stimulation

et al. 2010

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“…2A, the spacing between rings of Ca 2+ release sites is 1 μm inside the cell, with a 2 μm gap to the peripheral junctional ring of Ca 2+ release sites. The 2 μm gap was adopted into the model because studies have shown such a discontinuity in the expression of RyR clusters (10,12,13). The physiological reason for this gap in atrial RyR distribution is not known.…”

Section: Resultsmentioning

confidence: 99%

Subcellular calcium dynamics in a whole-cell model of an atrial myocyte

Thul

Coombes

Roderick

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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In this study, we present an innovative mathematical modeling approach that allows detailed characterization of Ca 2+ movement within the three-dimensional volume of an atrial myocyte. Essential aspects of the model are the geometrically realistic representation of Ca 2+ release sites and physiological Ca 2+ flux parameters, coupled with a computationally inexpensive framework. By translating nonlinear Ca 2+ excitability into threshold dynamics, we avoid the computationally demanding time stepping of the partial differential equations that are often used to model Ca 2+ transport. Our approach successfully reproduces key features of atrial myocyte Ca 2+ signaling observed using confocal imaging. In particular, the model displays the centripetal Ca 2+ waves that occur within atrial myocytes during excitation-contraction coupling, and the effect of positive inotropic stimulation on the spatial profile of the Ca 2+ signals. Beyond this validation of the model, our simulation reveals unexpected observations about the spread of Ca 2+ within an atrial myocyte. In particular, the model describes the movement of Ca 2+ between ryanodine receptor clusters within a specific z disk of an atrial myocyte. Furthermore, we demonstrate that altering the strength of Ca 2+ release, ryanodine receptor refractoriness, the magnitude of initiating stimulus, or the introduction of stochastic Ca 2+ channel activity can cause the nucleation of proarrhythmic traveling Ca 2+ waves. The model provides clinically relevant insights into the initiation and propagation of subcellular Ca 2+ signals that are currently beyond the scope of imaging technology.A human heart beats more than a billion times during the average lifespan, and is required to do so with great fidelity. The ventricular chambers of the heart are responsible for generating the force that propels blood to the lungs and body (1). Under sedentary conditions, the atrial chambers make only a minor contribution to blood pumping. However, during periods of increased hemodynamic demand, such as exercise, atrial contraction increases to enhance the amount of blood within the ventricles before they contract. This "atrial kick" is believed to account for up to 30% extra blood-pumping capacity. Deterioration of atrial myocytes with aging causes the loss of this blood-pumping reserve, thereby increasing frailty in the elderly. Atrial kick is also lost during atrial fibrillation (AF), the most common form of cardiac arrhythmia. The stagnation of blood within the atrial chambers during AF can cause thrombus formation, leading to thromboembolism. Approximately 15% of all strokes occur in people with AF. As shown in numerous reports, the genesis and maintenance of AF is causally linked to the dysregulation of Ca 2+ signaling (2-4). Detailed characterization of Ca 2+ movement within atrial myocytes is therefore necessary to understand changes involved in aging and conditions such as AF.Elevation of the cytosolic Ca 2+ concentration is the trigger for contraction of cardiac myocytes (1). Engageme...

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“…In addition, the antibody labeling reports the presence of the RyR epitope (5) and thereby avoids any uncertainty as to the possible identification of electron densities within EM thin sections. Although some previous studies (6,7) have looked at the RyR distribution with fluorescence microscopy in the rat, no comparable data are available for human myocytes to our knowledge. Our data suggest that the reported fluorescencederived intercouplon distances are generally too large and provide 3D data sets of RyR distribution in rat and human ventricular myocytes.…”

mentioning

confidence: 98%

Analysis of ryanodine receptor clusters in rat and human cardiac myocytes

Soeller¹,

Crossman²,

Gilbert

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

143

183

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Single rat ventricular myocytes and human ventricle tissue sections were labeled with antibodies against the ryanodine receptor (RyR) and ␣-actinin to examine the 3D distribution of RyRs with confocal microscopy. Image contrast was maximized by refractive index matching and deconvolution. The RyR label formed discrete puncta representing clusters of RyRs or ''couplons'' around the edges of the myofilaments with a nearest-neighbor spacing of 0.66 ؎ 0.06 m in rat and 0.78 ؎ 0.07 m in human. Each bundle of myofibrils was served by approximately six couplons, which supplied a cross-sectional area of Ϸ0.6 m 2 in rat and Ϸ0.8 m 2 in human. Although the couplons were in reasonable registration with zlines, there were discontinuities in the longitudinal position of sarcomeres so that dislocations in the order of RyR clusters occurred. There was Ϸ53% longitudinal registration of RyR clusters, suggesting a nonrandom placement of couplons around the sarcomere. These data can explain the spherical propagation of Ca 2؉ waves and provide quantitative 3D data sets needed for accurate modeling of cardiac Ca 2؉ -induced Ca 2؉ release. By quantifying labeling intensity in rat ventricular myocytes, a lower limit of 78 RyRs per cluster (on average) was obtained. By modeling the couplon as a disk wrapping around a t-tubule and fitting cluster images, 95% of couplons contained between 120 and 260 RyRs (assuming that RyRs are tight packed with a spacing of 29 nm). Assuming similar labeling efficiency in human, from the fluorescence intensity alone we estimate that human ventricular myocytes contain Ϸ30% fewer RyRs per couplon than rat.calcium-induced calcium release ͉ excitation-contraction coupling ͉ sarcoplasmic reticulum I n cardiac ventricular muscle, excitation-contraction (EC) coupling arises from Ca 2ϩ release via clusters of ryanodine receptors (RyRs) in regions of close apposition between the sarcoplasmic reticulum (SR) and surface membranes in functional units called couplons (1, 2). Current work directed at understanding cardiac EC coupling is hindered by uncertainty in the size and 3D distribution of the couplons. Previous detailed analysis from electron micrographs has shown that typically 30-270 RyRs (depending on species) may be present in a couplon (1), but the thin sectioning associated with EM limits analysis of the spatial relationship between nearby and more distant couplons. Such knowledge is important, not only to make sense of the structures that underlie Ca 2ϩ sparks (3, 4) but also for detailed mathematical modeling of cardiac Ca 2ϩ metabolism.In this study, we have used immunocytochemistry combined with 3D imaging and analysis to both reveal the 3D organization of RyR clusters and estimate the numbers of RyRs within the couplon. Our analyses generally support some detailed quantitative measurements from EM (1), but also provide insight into organization in 3D at spatial scales that would be extremely laborious (if not impossible) to achieve by using conventional thin sectioning. In addition, the antibody labe...

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Activation and Propagation of Ca2+ Release during Excitation-Contraction Coupling in Atrial Myocytes

Cited by 112 publications

References 31 publications

Comparison of the T-tubule system in adult rat ventricular and atrial myocytes, and its role in excitation–contraction coupling and inotropic stimulation

Comparison of the T-tubule system in adult rat ventricular and atrial myocytes, and its role in excitation–contraction coupling and inotropic stimulation

Subcellular calcium dynamics in a whole-cell model of an atrial myocyte

Analysis of ryanodine receptor clusters in rat and human cardiac myocytes

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