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Monitoring ER/SR Calcium Release with the Targeted Ca2+ Sensor CatchER+
Published on: May 19, 2017
Ca(2+) wave probability is determined by the balance between SERCA2-dependent Ca(2+) reuptake and threshold SR Ca(2+)
Mathis K Stokke1, Sarah J Briston, Guro F Jølle
1Institute for Experimental Medical Research, Oslo University Hospital, Ullevål, N-0407 Oslo, Norway. m.k.stokke@medisin.uio.no
Cardiovascular Research
|January 19, 2011
Summary
Reduced sarcoendoplasmic reticulum Ca(2+) ATPase 2 (SERCA2) potentiates Ca(2+) wave development during beta-adrenergic stimulation. This occurs due to a Ca(2+)/calmodulin-dependent kinase II (CaMKII)-dependent shift in calcium handling, increasing ryanodine receptor (RyR) activity.
Area of Science:
- Cardiovascular Physiology
- Molecular Cardiology
- Calcium Signaling
Background:
- Beta-adrenergic stimulation plays a critical role in regulating cardiac contractility.
- Calcium (Ca2+) handling by the sarcoendoplasmic reticulum (SR) is essential for cardiomyocyte function.
- The sarcoendoplasmic reticulum Ca(2+) ATPase 2 (SERCA2) and ryanodine receptor (RyR) are key regulators of SR Ca(2+) content and release.
Purpose of the Study:
- To investigate the roles of SERCA2 and RyR in Ca(2+) wave development during beta-adrenergic stimulation.
- To elucidate the mechanisms underlying altered Ca(2+) wave dynamics in the absence of sufficient SERCA2 function.
Main Methods:
- Utilized SERCA2 knockout (KO) mice with cardio-specific gene deletion.
- Measured Ca(2+) waves in isolated ventricular myocytes from KO and control (FF) mice.
- Assessed SERCA2 abundance, Ca(2+) reuptake rates, and threshold SR Ca(2+) content.
- Investigated Ca(2+)/calmodulin-dependent kinase II (CaMKII) phosphorylation of RyR and SR Ca(2+) leak.
- Employed mathematical modeling to predict Ca(2+) wave probability.
Main Results:
- Reduced SERCA2 abundance (54%) in KO mice led to fewer spontaneous Ca(2+) waves.
- Isoproterenol (ISO) stimulation induced Ca(2+) waves in similar percentages of KO and FF myocytes.
- SERCA2-dependent Ca(2+) reuptake was slower in KO myocytes, but comparable during ISO.
- Threshold SR Ca(2+) content for wave development was lower in KO and increased by ISO only in FF.
- CaMKII-dependent RyR phosphorylation and SR Ca(2+) leak were higher in KO during ISO, indicating increased RyR open probability.
Conclusions:
- Reduced SERCA2 abundance potentiates Ca(2+) wave development during beta-adrenergic stimulation in ventricular cardiomyocytes.
- This potentiation is attributed to a CaMKII-dependent shift in the balance between SERCA2-dependent Ca(2+) reuptake and threshold SR Ca(2+) content.
- Increased Ca(2+) sensitivity of RyR in KO myocytes contributes to enhanced Ca(2+) wave probability during beta-adrenergic stimulation.
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