Send to

Choose Destination
See comment in PubMed Commons below
J Physiol. 2010 Dec 1;588(Pt 23):4743-57. doi: 10.1113/jphysiol.2010.197913. Epub 2010 Oct 20.

Ca²+ spark-dependent and -independent sarcoplasmic reticulum Ca²+ leak in normal and failing rabbit ventricular myocytes.

Author information

  • 1Department of Cell and Molecular Physiology, Loyola University Chicago, Stritch School of Medicine, Maywood, IL 60153, USA.


Sarcoplasmic reticulum (SR) Ca²(+) leak is an important component of cardiac Ca²(+) signalling. Together with the SR Ca²(+)-ATPase (SERCA)-mediated Ca²(+) uptake, diastolic Ca²(+) leak determines SR Ca²(+) load and, therefore, the amplitude of Ca²(+) transients that initiate contraction. Spontaneous Ca²(+) sparks are thought to play a major role in SR Ca²(+) leak. In this study, we determined the quantitative contribution of sparks to SR Ca²(+) leak and tested the hypothesis that non-spark mediated Ca²(+) release also contributes to SR Ca²(+) leak. We simultaneously measured spark properties and intra-SR free Ca²(+) ([Ca²(+)](SR)) after complete inhibition of SERCA with thapsigargin in permeabilized rabbit ventricular myocytes. When [Ca²(+)](SR) declined to 279 ± 10 μm, spark activity ceased completely; however SR Ca²(+) leak continued, albeit at a slower rate. Analysis of sparks and [Ca²(+)](SR) revealed, that SR Ca²(+) leak increased as a function of [Ca²(+)](SR), with a particularly steep increase at higher [Ca²(+)](SR) ( >600 μm) where sparks become a major pathway of SR Ca²(+) leak. At low [Ca²(+)](SR) (< 300 μm), however, Ca²(+) leak occurred mostly as non-spark-mediated leak. Sensitization of ryanodine receptors (RyRs) with low doses of caffeine increased spark frequency and SR Ca²(+) leak. Complete inhibition of RyR abolished sparks and significantly decreased SR Ca²(+) leak, but did not prevent it entirely, suggesting the existence of RyR-independent Ca²(+) leak. Finally, we found that RyR-mediated Ca²(+) leak was enhanced in myocytes from failing rabbit hearts. These results show that RyRs are the main, but not sole contributor to SR Ca²(+) leak. RyR-mediated leak occurs in part as Ca²(+) sparks, but there is clearly RyR-mediated but Ca²(+) sparks independent leak.

[PubMed - indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Wiley Icon for PubMed Central
    Loading ...
    Write to the Help Desk