Intra-sarcoplasmic reticulum Ca2+ oscillations are driven by dynamic regulation of ryanodine receptor function by luminal Ca2+ in cardiomyocytes

• Published in: The Journal of physiology 2009-10, Vol.587 (20), p.4863-4872
• Main Authors: Stevens, Sarah C.W., Terentyev, Dmitry, Kalyanasundaram, Anuradha, Periasamy, Muthu, Györke, Sandor
• Format: Article
• Language: English
• Subjects: Animals; Arrhythmias, Cardiac - metabolism; Caffeine - pharmacology; Calcium - metabolism; Calcium Signaling - drug effects; Calpain - metabolism; Calsequestrin - deficiency; Cardiovascular; Central Nervous System Stimulants - pharmacology; Dogs; Humans; Male; Mice; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Ryanodine Receptor Calcium Release Channel - metabolism; Sarcoplasmic Reticulum - drug effects; Sarcoplasmic Reticulum - metabolism
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/jphysiol.2009.175547

During the cardiac cycle, the release of Ca 2+ from the sarcoplasmic reticulum (SR) through the ryanodine receptor (RyR2) channel complex is controlled by the levels of cytosolic and luminal Ca 2+ and alterations in these regulatory processes have been implicated in cardiac disease including arrhythmia. To better understand the mechanisms of regulation of SR Ca 2+ release by Ca 2+ on both sides of the SR membrane, we investigated SR Ca 2+ release in a wide range of cytosolic Ca 2+ concentrations ([Ca 2+ ] cyt ; 1–100 μ m ) in permeabilized canine ventricular myocytes by monitoring [Ca 2+ ] inside the SR ([Ca 2+ ] SR ). Exposing myocytes to activating [Ca 2+ ] cyt resulted in spontaneous oscillations of [Ca 2+ ] SR due to periodic opening and closing of the RyR2s. Elevating [Ca 2+ ] cyt (up to 10 μ m ) increased the frequency of [Ca 2+ ] SR oscillations; however at higher [Ca 2+ ] cyt (>50 μ m ) the oscillations diminished due to RyR2s staying perpetually open, resulting in depleted SR. Ablation of cardiac calsequestrin (CASQ2) altered the [Ca 2+ ] cyt dependence of Ca 2+ release oscillations such that oscillations were highly frequent at low [Ca 2+ ] cyt (100 n m ) but became diminished at moderate [Ca 2+ ] cyt (10 μ m ), as determined in myocytes from calsequestrin-null versus wild-type mice. Our results suggest that under conditions of continuous activation by cytosolic Ca 2+ , RyR2s can periodically cycle between open and deactivated states due to effects of luminal Ca 2+ . Deactivation at reduced [Ca 2+ ]SR appears to involve reduction of sensitivity to cytosolic Ca 2+ and might be mediated by CASQ2. Inactivation by cytosolic Ca 2+ plays no detectable role in controlling SR Ca 2+ release.