Dataset Information

Computational analysis of the regulation of Ca(2+) dynamics in rat ventricular myocytes.

ABSTRACT: Force-frequency relationships of isolated cardiac myocytes show complex behaviors that are thought to be specific to both the species and the conditions associated with the experimental preparation. Ca(2+) signaling plays an important role in shaping the force-frequency relationship, and understanding the properties of the force-frequency relationship in vivo requires an understanding of Ca(2+) dynamics under physiologically relevant conditions. Ca(2+) signaling is itself a complicated process that is best understood on a quantitative level via biophysically based computational simulation. Although a large number of models are available in the literature, the models are often a conglomeration of components parameterized to data of incompatible species and/or experimental conditions. In addition, few models account for modulation of Ca(2+) dynamics via ?-adrenergic and calmodulin-dependent protein kinase II (CaMKII) signaling pathways even though they are hypothesized to play an important regulatory role in vivo. Both protein-kinase-A and CaMKII are known to phosphorylate a variety of targets known to be involved in Ca(2+) signaling, but the effects of these pathways on the frequency- and inotrope-dependence of Ca(2+) dynamics are not currently well understood. In order to better understand Ca(2+) dynamics under physiological conditions relevant to rat, a previous computational model is adapted and re-parameterized to a self-consistent dataset obtained under physiological temperature and pacing frequency and updated to include ?-adrenergic and CaMKII regulatory pathways. The necessity of specific effector mechanisms of these pathways in capturing inotrope- and frequency-dependence of the data is tested by attempting to fit the data while including and/or excluding those effector components. We find that: (1) ?-adrenergic-mediated phosphorylation of the L-type calcium channel (LCC) (and not of phospholamban (PLB)) is sufficient to explain the inotrope-dependence; and (2) that CaMKII-mediated regulation of neither the LCC nor of PLB is required to explain the frequency-dependence of the data.

SUBMITTER: Bugenhagen SM

PROVIDER: S-EPMC4593979 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Computational analysis of the regulation of Ca(2+) dynamics in rat ventricular myocytes.

Bugenhagen Scott M SM Beard Daniel A DA

Physical biology 20150911 5

Force-frequency relationships of isolated cardiac myocytes show complex behaviors that are thought to be specific to both the species and the conditions associated with the experimental preparation. Ca(2+) signaling plays an important role in shaping the force-frequency relationship, and understanding the properties of the force-frequency relationship in vivo requires an understanding of Ca(2+) dynamics under physiologically relevant conditions. Ca(2+) signaling is itself a complicated process t ...[more]

PMID: 26358004

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Project description:We measured intracellular Mg2+ concentration ([Mg2+]i) in rat ventricular myocytes using the fluorescent indicator furaptra (25 degrees C). In normally energized cells loaded with Mg2+, the introduction of extracellular Na+ induced a rapid decrease in [Mg2+]i: the initial rate of decrease in [Mg2+]i (initial Delta[Mg2+]i/Deltat) is thought to represent the rate of Na+-dependent Mg2+ efflux (putative Na+/Mg2+ exchange). To determine whether Mg2+ efflux depends directly on energy derived from cellular metabolism, in addition to the transmembrane Na+ gradient, we estimated the initial Delta[Mg2+]i/Deltat after metabolic inhibition. In the absence of extracellular Na+ and Ca2+, treatment of the cells with 1 microM carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone, an uncoupler of mitochondria, caused a large increase in [Mg2+]i from approximately 0.9 mM to approximately 2.5 mM in a period of 5-8 min (probably because of breakdown of MgATP and release of Mg2+) and cell shortening to approximately 50% of the initial length (probably because of formation of rigor cross-bridges). Similar increases in [Mg2+]i and cell shortening were observed after application of 5 mM potassium cyanide (KCN) (an inhibitor of respiration) for > or = 90 min. The initial Delta[Mg2+]i/Deltat was diminished, on average, by 90% in carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone-treated cells and 92% in KCN-treated cells. When the cells were treated with 5 mM KCN for shorter times (59-85 min), a significant decrease in the initial Delta[Mg2+]i/Deltat (on average by 59%) was observed with only a slight shortening of the cell length. Intracellular Na+ concentration ([Na+]i) estimated with a Na+ indicator sodium-binding benzofuran isophthalate was, on average, 5.0-10.5 mM during the time required for the initial Delta[Mg2+]i/Deltat measurements, which is well below the [Na+]i level for half inhibition of the Mg2+ efflux (approximately 40 mM). Normalization of intracellular pH using 10 microM nigericin, a H+ ionophore, did not reverse the inhibition of the Mg2+ efflux. From these results, it seems likely that a decrease in ATP below the threshold of rigor cross-bridge formation (approximately 0.4 mM estimated indirectly in the this study), rather than elevation of [Na+]i or intracellular acidosis, inhibits the Mg2+ efflux, suggesting the absolute necessity of ATP for the Na+/Mg2+ exchange.

Dataset Information

Computational analysis of the regulation of Ca(2+) dynamics in rat ventricular myocytes.

Publications

Computational analysis of the regulation of Ca(2+) dynamics in rat ventricular myocytes.

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