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Crosstalk between mitochondrial and sarcoplasmic reticulum Ca2+ cycling modulates cardiac pacemaker cell automaticity.

Yaniv Y, Spurgeon HA, Lyashkov AE, Yang D, Ziman BD, Maltsev VA, Lakatta EG - PLoS ONE (2012)

Bottom Line: Concurrent with inhibition of mitochondrial Ca(2+) influx or efflux, the SR Ca(2+) load, and LCR size, duration, amplitude and period (imaged via confocal linescan) significantly increased or decreased, respectively.Changes in total ensemble LCR Ca(2+) signal were highly correlated with the change in the SR Ca(2+) load (r(2) = 0.97).A change in SANC Ca(2+) (m) flux translates into a change in the AP firing rate by effecting changes in Ca(2+) (c) and SR Ca(2+) loading, which affects the characteristics of spontaneous SR Ca(2+) release.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States of America.

ABSTRACT

Background: Mitochondria dynamically buffer cytosolic Ca(2+) in cardiac ventricular cells and this affects the Ca(2+) load of the sarcoplasmic reticulum (SR). In sinoatrial-node cells (SANC) the SR generates periodic local, subsarcolemmal Ca(2+) releases (LCRs) that depend upon the SR load and are involved in SANC automaticity: LCRs activate an inward Na(+)-Ca(2+) exchange current to accelerate the diastolic depolarization, prompting the ensemble of surface membrane ion channels to generate the next action potential (AP).

Objective: To determine if mitochondrial Ca(2+) (Ca(2+) (m)), cytosolic Ca(2+) (Ca(2+) (c))-SR-Ca(2+) crosstalk occurs in single rabbit SANC, and how this may relate to SANC normal automaticity.

Results: Inhibition of mitochondrial Ca(2+) influx into (Ru360) or Ca(2+) efflux from (CGP-37157) decreased [Ca(2+)](m) to 80 ± 8% control or increased [Ca(2+)](m) to 119 ± 7% control, respectively. Concurrent with inhibition of mitochondrial Ca(2+) influx or efflux, the SR Ca(2+) load, and LCR size, duration, amplitude and period (imaged via confocal linescan) significantly increased or decreased, respectively. Changes in total ensemble LCR Ca(2+) signal were highly correlated with the change in the SR Ca(2+) load (r(2) = 0.97). Changes in the spontaneous AP cycle length (Ru360, 111 ± 1% control; CGP-37157, 89 ± 2% control) in response to changes in [Ca(2+)](m) were predicted by concurrent changes in LCR period (r(2) = 0.84).

Conclusion: A change in SANC Ca(2+) (m) flux translates into a change in the AP firing rate by effecting changes in Ca(2+) (c) and SR Ca(2+) loading, which affects the characteristics of spontaneous SR Ca(2+) release.

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Related in: MedlinePlus

The extended coupled clock numerical model simulations of kinetics.The simulation of the change in (A) AP firing rate, (B) peak systolic cytosolic Ca2+, (C) peak systolic mitochondrial Ca2+, and (D) peak Ca2+ in junctional SR in response to specific inhibition of Ca2+ flux into or flux from mitochondria.
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pone-0037582-g008: The extended coupled clock numerical model simulations of kinetics.The simulation of the change in (A) AP firing rate, (B) peak systolic cytosolic Ca2+, (C) peak systolic mitochondrial Ca2+, and (D) peak Ca2+ in junctional SR in response to specific inhibition of Ca2+ flux into or flux from mitochondria.

Mentions: Since it is not possible experimentally to implement long recordings in isolated, single SANC (∼15 min) to measure the kinetics of the changes in intracellular Ca2+ dynamics and AP firing we used a numerical model to predict the inhibition of Ca2+ influx or efflux affects on cytosolic Ca2+, SR Ca2+ load, and AP firing rate. Model simulations predict that inhibition of mitochondrial Ca2+ efflux by CGP-37157 increases peak [Ca2+]m over a 10-min time course and concomitantly decreases peak cytosolic Ca2+, peak jSR Ca2+ and spontaneous AP firing rate (Fig. 8). Simulation of inhibition of mitochondrial Ca2+ influx by Ru360 yielded a mirror image of the effect of CGP-37157. Thus these numerical simulations support the idea that when mitochondrial Ca2+ flux is perturbed, the changes in mitochondrial Ca2+, cytosolic Ca2+, SR Ca2+ loading and AP firing rate occur with the same kinetics.


Crosstalk between mitochondrial and sarcoplasmic reticulum Ca2+ cycling modulates cardiac pacemaker cell automaticity.

Yaniv Y, Spurgeon HA, Lyashkov AE, Yang D, Ziman BD, Maltsev VA, Lakatta EG - PLoS ONE (2012)

The extended coupled clock numerical model simulations of kinetics.The simulation of the change in (A) AP firing rate, (B) peak systolic cytosolic Ca2+, (C) peak systolic mitochondrial Ca2+, and (D) peak Ca2+ in junctional SR in response to specific inhibition of Ca2+ flux into or flux from mitochondria.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3362629&req=5

pone-0037582-g008: The extended coupled clock numerical model simulations of kinetics.The simulation of the change in (A) AP firing rate, (B) peak systolic cytosolic Ca2+, (C) peak systolic mitochondrial Ca2+, and (D) peak Ca2+ in junctional SR in response to specific inhibition of Ca2+ flux into or flux from mitochondria.
Mentions: Since it is not possible experimentally to implement long recordings in isolated, single SANC (∼15 min) to measure the kinetics of the changes in intracellular Ca2+ dynamics and AP firing we used a numerical model to predict the inhibition of Ca2+ influx or efflux affects on cytosolic Ca2+, SR Ca2+ load, and AP firing rate. Model simulations predict that inhibition of mitochondrial Ca2+ efflux by CGP-37157 increases peak [Ca2+]m over a 10-min time course and concomitantly decreases peak cytosolic Ca2+, peak jSR Ca2+ and spontaneous AP firing rate (Fig. 8). Simulation of inhibition of mitochondrial Ca2+ influx by Ru360 yielded a mirror image of the effect of CGP-37157. Thus these numerical simulations support the idea that when mitochondrial Ca2+ flux is perturbed, the changes in mitochondrial Ca2+, cytosolic Ca2+, SR Ca2+ loading and AP firing rate occur with the same kinetics.

Bottom Line: Concurrent with inhibition of mitochondrial Ca(2+) influx or efflux, the SR Ca(2+) load, and LCR size, duration, amplitude and period (imaged via confocal linescan) significantly increased or decreased, respectively.Changes in total ensemble LCR Ca(2+) signal were highly correlated with the change in the SR Ca(2+) load (r(2) = 0.97).A change in SANC Ca(2+) (m) flux translates into a change in the AP firing rate by effecting changes in Ca(2+) (c) and SR Ca(2+) loading, which affects the characteristics of spontaneous SR Ca(2+) release.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States of America.

ABSTRACT

Background: Mitochondria dynamically buffer cytosolic Ca(2+) in cardiac ventricular cells and this affects the Ca(2+) load of the sarcoplasmic reticulum (SR). In sinoatrial-node cells (SANC) the SR generates periodic local, subsarcolemmal Ca(2+) releases (LCRs) that depend upon the SR load and are involved in SANC automaticity: LCRs activate an inward Na(+)-Ca(2+) exchange current to accelerate the diastolic depolarization, prompting the ensemble of surface membrane ion channels to generate the next action potential (AP).

Objective: To determine if mitochondrial Ca(2+) (Ca(2+) (m)), cytosolic Ca(2+) (Ca(2+) (c))-SR-Ca(2+) crosstalk occurs in single rabbit SANC, and how this may relate to SANC normal automaticity.

Results: Inhibition of mitochondrial Ca(2+) influx into (Ru360) or Ca(2+) efflux from (CGP-37157) decreased [Ca(2+)](m) to 80 ± 8% control or increased [Ca(2+)](m) to 119 ± 7% control, respectively. Concurrent with inhibition of mitochondrial Ca(2+) influx or efflux, the SR Ca(2+) load, and LCR size, duration, amplitude and period (imaged via confocal linescan) significantly increased or decreased, respectively. Changes in total ensemble LCR Ca(2+) signal were highly correlated with the change in the SR Ca(2+) load (r(2) = 0.97). Changes in the spontaneous AP cycle length (Ru360, 111 ± 1% control; CGP-37157, 89 ± 2% control) in response to changes in [Ca(2+)](m) were predicted by concurrent changes in LCR period (r(2) = 0.84).

Conclusion: A change in SANC Ca(2+) (m) flux translates into a change in the AP firing rate by effecting changes in Ca(2+) (c) and SR Ca(2+) loading, which affects the characteristics of spontaneous SR Ca(2+) release.

Show MeSH
Related in: MedlinePlus