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


CONCLUSIONS
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.
Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States of America.
Yael
Y
Yaniv
Harold A
HA
Spurgeon
Alexey E
AE
Lyashkov
Dongmei
D
Yang
Bruce D
BD
Ziman
Victor A
VA
Maltsev
Edward G
EG
Lakatta
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002998:Clonazepam / Q000031:analogs & derivatives / Q000494:pharmacology; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004553:Electric Conductivity; D006339:Heart Rate / Q000187:drug effects; D006352:Heart Ventricles / Q000166:cytology; D007211:Indoles / Q000378:metabolism; D008274:Magnesium / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010507:Periodicity; D011817:Rabbits; D017975:Ruthenium Compounds / Q000494:pharmacology; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D012849:Sinoatrial Node / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D013841:Thiazepines / Q000494:pharmacology
D007211:Indoles; C112020:Ru 360; D017975:Ruthenium Compounds; D019837:Ryanodine Receptor Calcium Release Channel; D013841:Thiazepines; D002998:Clonazepam; C079032:CGP 37157; D008274:Magnesium; C048960:indo-1; D002118:Calcium