PO-675-05 AUTOSOMAL DOMINANT CPVT2 IS CAUSED BY IMPAIRED DYNAMIC CALCIUM BUFFERING IN THE SARCOPLASMIC RETICULUM
0
Citation
0
Reference
10
Related Paper
Keywords:
Calsequestrin
Introduction: Sarcoplasmic reticulum (SR) Ca2+ leak activates the inward Na+-Ca2+ exchange current (INCX) causing delayed afterdepolarsations (DADs) that promote arrhythmias. Whether this mechanism contributes to promotion of atrial fibrillation (AF) is unknown and was the object of this study. Methods: Membrane currents and potentials (patch clamp) and [Ca2+]i (Fluo-3) were measured in right-atrial myocytes from sinus rhythm (Ctl) or chronic AF (cAF) patients. Tetracaine (1 mM) or single-channel recordings were used to quantify SR Ca2+ leak through ryanodine-receptor channels (RyR2). Proteins were measured by immunoblotting. Results: Diastolic [Ca2+]i and SR Ca2+ content (integrated INCX during caffeine-induced [Ca2+]i transient [cCaT]) were unchanged, whereas diastolic SR Ca2+ leak was ∼50% higher in cAF than in Ctl (Figure). Calmodulin expression (+60%), CaMKII autophosphorylation (activation) at Thr287 (+40%) and Ser2808-phosphorylation (PKA/CaMKII-site) of RyR2 (+250%) were higher in cAF than in Ctl....
Afterdepolarization
Cite
Citations (6)
Abnormal intracellular calcium ([Ca2+]i) handling appears to be a major cause of both systolic and diastolic dysfunction in animals and human beings with hypertrophy and/or heart failure. We utilized the bioluminescent calcium indicator aequorin to examine the cyclical variations in intracellular calcium levels during isometric contractions. Studies of ventricular muscle from patients with end-stage heart failure exhibited three physiologic findings not seen in preparations taken from normal hearts including: 1) abnormalities in calcium handling; 2) deficient production of cyclic AMP; and 3) a reversed force-frequency relationship. These observations have important implications with regard to the pathogenesis and therapeutics of heart failure in man.
Aequorin
Calcium in biology
Pathophysiology
Pathogenesis
Cite
Citations (21)
Beta-adrenergic receptors (β-AR) enhance cardiac contractility by increasing cAMP levels and activating PKA. PKA increases Ca2+-induced Ca2+ release (CICR) by phosphorylating L-type Ca2+ channels (...
L-type calcium channel
Cite
Citations (0)
Background: Chronic atrial fibrillation (cAF) is associated with abnormal atrial Ca 2+ signalling, causing remodeling, contractile dysfunction and triggered activity. The poorly understood molecular basis of impaired atrial Ca 2+ signaling in cAF was the object of this study. Methods: Membrane currents (whole-cell voltage clamp) and [Ca 2+ ] i (Fluo-3) were measured in right atrial myocytes from sinus rhythm (Ctl) and cAF patients. Protein expression was quantified by immunoblotting. Results: In cAF L-type Ca 2+ current density and [Ca 2+ ] i transient amplitude were 43% and 46% lower than in Ctl, whereas diastolic [Ca 2+ ] i was unchanged (Figure). Despite reduced protein expression of Serca2a, sarcoplasmic reticulum (SR) Ca 2+ content calculated by integrating Na + -Ca 2+ exchange current (I NCX ) during caffeine-induced Ca 2+ release was preserved in cAF, likely because of attenuated Serca2a inhibition by hyperphoshorylated phospholamban. The phosphorylation of ryanodine receptor channels at Ser2809 was 140% higher in cAF compared to Ctl, without protein changes in the major SR Ca 2+ buffer calsequestrin. The decay of the caffeine-evoked Ca 2+ transient is attributable to Ca 2+ transport by NCX and was 100% faster in cAF, consistent with the greater I NCX amplitude in cAF. In addition, a given Ca 2+ release produced larger INCX current, possibly as a result of NCX protein upregulation. Conclusions: We conclude that reduced SR Ca 2+ release and enhanced NCX activity both contribute to atrial hypocontractility in cAF. The generation of a larger depolarising I NCX for a given SR Ca 2+ release may cause delayed afterdepolarisations and triggered activity, contributing to AF maintenance.
Phospholamban
Calsequestrin
Sodium-calcium exchanger
Cite
Citations (13)