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A computational model of cytosolic and mitochondrial [ca] in paced rat ventricular myocytes.

ABSTRACT: We carried out a series of experiment demonstrating the role of mitochondria in the cytosolic and mitochondrial Ca(2+) transients and compared the results with those from computer simulation. In rat ventricular myocytes, increasing the rate of stimulation (1~3 Hz) made both the diastolic and systolic [Ca(2+)] bigger in mitochondria as well as in cytosol. As L-type Ca(2+) channel has key influence on the amplitude of Ca(2+)-induced Ca(2+) release, the relation between stimulus frequency and the amplitude of Ca(2+) transients was examined under the low density (1/10 of control) of L-type Ca(2+) channel in model simulation, where the relation was reversed. In experiment, block of Ca(2+) uniporter on mitochondrial inner membrane significantly reduced the amplitude of mitochondrial Ca(2+) transients, while it failed to affect the cytosolic Ca(2+) transients. In computer simulation, the amplitude of cytosolic Ca(2+) transients was not affected by removal of Ca(2+) uniporter. The application of carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP) known as a protonophore on mitochondrial membrane to rat ventricular myocytes gradually increased the diastolic [Ca(2+)] in cytosol and eventually abolished the Ca(2+) transients, which was similarly reproduced in computer simulation. The model study suggests that the relative contribution of L-type Ca(2+) channel to total transsarcolemmal Ca(2+) flux could determine whether the cytosolic Ca(2+) transients become bigger or smaller with higher stimulus frequency. The present study also suggests that cytosolic Ca(2+) affects mitochondrial Ca(2+) in a beat-to-beat manner, however, removal of Ca(2+) influx mechanism into mitochondria does not affect the amplitude of cytosolic Ca(2+) transients.

SUBMITTER: Youm JB

PROVIDER: S-EPMC3186923 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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.

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A computational model of cytosolic and mitochondrial [ca] in paced rat ventricular myocytes.

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