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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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Relationships among the Ca2+ release of the LCR ensemble, LCR period, SR Ca2+ load and AP firing rate.The total LCR Ca2+ ensemble (A) average data and (B) histogram in the presence of Ru360 or CGP-37157. (C) The relationship between caffeine-induced Ca2+ release F/F0 and the total LCR Ca2+ ensemble. Specific inhibition of Ca2+ influx into or efflux from mitochondria in intact SANC shifts the LCR period and AP cycle length. (D) LCR period and (E) AP cycle length in the presence of Ru360 (n = 12; 102 LCRs) or CGP-37157 (n = 12; 92 LCRs). (F) The change in LCR period in response to perturbing mitochondrial Ca2+ flux predicts the concomitant change in AP cycle length. The Ru360-induced decrease in the spontaneous cycle length, and CGP-37157-induced increase in spontaneous cycle length, are both predicted by their effects on the LCR period. The dashed line is the line of identity. *p<0.05 vs. control, **p<0.05 vs. Ru360.
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pone-0037582-g005: Relationships among the Ca2+ release of the LCR ensemble, LCR period, SR Ca2+ load and AP firing rate.The total LCR Ca2+ ensemble (A) average data and (B) histogram in the presence of Ru360 or CGP-37157. (C) The relationship between caffeine-induced Ca2+ release F/F0 and the total LCR Ca2+ ensemble. Specific inhibition of Ca2+ influx into or efflux from mitochondria in intact SANC shifts the LCR period and AP cycle length. (D) LCR period and (E) AP cycle length in the presence of Ru360 (n = 12; 102 LCRs) or CGP-37157 (n = 12; 92 LCRs). (F) The change in LCR period in response to perturbing mitochondrial Ca2+ flux predicts the concomitant change in AP cycle length. The Ru360-induced decrease in the spontaneous cycle length, and CGP-37157-induced increase in spontaneous cycle length, are both predicted by their effects on the LCR period. The dashed line is the line of identity. *p<0.05 vs. control, **p<0.05 vs. Ru360.

Mentions: The total Ca2+ of the LCR ensemble shifted to lower values in response to CGP-37157, and to higher values in response to Ru360 (Fig. 5A–B). Figure 5A shows that, interestingly, Ru360 increased the ensemble LCR Ca2+ from 38±6 to 61±7 ms*µm*F/F0 (p<0.001) and CGP-37157 decreased it from 35±3 to 17±2 ms*µm*F/F0 (p = 0.003). The Ru360-induced increase, and the CGP-37157-induced decrease in the total LCR ensemble Ca2+ paralleled the effects of Ru360 and CGP-37157 on the amplitude of caffeine induced Ca2+ release into the cytosol (Fig. 5C). This suggests that changes in spontaneous LCRs elicited by Ru360 or CGP-37157 are linked to concomitant changes in SR Ca2+ load effected by these drugs.


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)

Relationships among the Ca2+ release of the LCR ensemble, LCR period, SR Ca2+ load and AP firing rate.The total LCR Ca2+ ensemble (A) average data and (B) histogram in the presence of Ru360 or CGP-37157. (C) The relationship between caffeine-induced Ca2+ release F/F0 and the total LCR Ca2+ ensemble. Specific inhibition of Ca2+ influx into or efflux from mitochondria in intact SANC shifts the LCR period and AP cycle length. (D) LCR period and (E) AP cycle length in the presence of Ru360 (n = 12; 102 LCRs) or CGP-37157 (n = 12; 92 LCRs). (F) The change in LCR period in response to perturbing mitochondrial Ca2+ flux predicts the concomitant change in AP cycle length. The Ru360-induced decrease in the spontaneous cycle length, and CGP-37157-induced increase in spontaneous cycle length, are both predicted by their effects on the LCR period. The dashed line is the line of identity. *p<0.05 vs. control, **p<0.05 vs. Ru360.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0037582-g005: Relationships among the Ca2+ release of the LCR ensemble, LCR period, SR Ca2+ load and AP firing rate.The total LCR Ca2+ ensemble (A) average data and (B) histogram in the presence of Ru360 or CGP-37157. (C) The relationship between caffeine-induced Ca2+ release F/F0 and the total LCR Ca2+ ensemble. Specific inhibition of Ca2+ influx into or efflux from mitochondria in intact SANC shifts the LCR period and AP cycle length. (D) LCR period and (E) AP cycle length in the presence of Ru360 (n = 12; 102 LCRs) or CGP-37157 (n = 12; 92 LCRs). (F) The change in LCR period in response to perturbing mitochondrial Ca2+ flux predicts the concomitant change in AP cycle length. The Ru360-induced decrease in the spontaneous cycle length, and CGP-37157-induced increase in spontaneous cycle length, are both predicted by their effects on the LCR period. The dashed line is the line of identity. *p<0.05 vs. control, **p<0.05 vs. Ru360.
Mentions: The total Ca2+ of the LCR ensemble shifted to lower values in response to CGP-37157, and to higher values in response to Ru360 (Fig. 5A–B). Figure 5A shows that, interestingly, Ru360 increased the ensemble LCR Ca2+ from 38±6 to 61±7 ms*µm*F/F0 (p<0.001) and CGP-37157 decreased it from 35±3 to 17±2 ms*µm*F/F0 (p = 0.003). The Ru360-induced increase, and the CGP-37157-induced decrease in the total LCR ensemble Ca2+ paralleled the effects of Ru360 and CGP-37157 on the amplitude of caffeine induced Ca2+ release into the cytosol (Fig. 5C). This suggests that changes in spontaneous LCRs elicited by Ru360 or CGP-37157 are linked to concomitant changes in SR Ca2+ load effected by these drugs.

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