Abstract 13891: Enhanced Sodium-Calcium Exchanger Current, Prolonged Action Potential Duration, and Early/Delayed-Afterdepolarization in Sorcin Knockout Heart
Sorcin, a penta-EF-hand protein, plays a hypothetical role as a [Ca2+]i “sweeper” in cardiac excitation-contraction coupling based on the observations that sorcin a) decreases the open probability of RyRs, b) stimulates Na+-Ca2+exchanger (NCX) and SERCA2a, and c) accelerates L-type Ca2+ channel (LTCC) inactivation. However sorcin’s role on cardiac performance in health and disease are unknown. Thus, we have generated sorcin knockout (sorcin KO) mice. We show that sorcin KO mice a) have increased spontaneous Ca2+ release events (SCaEs) in cardiomyocytes; b) present ~2 fold expression of NCX and LTCC in heart; and c) are more susceptible to arrhythmia and death under stress. We investigated how SCaEs and increased NCX and LTCC expression in sorcin KO heart led to ventricular arrhythmias. Recording of NCX current showed that with 300nM isoproterenol (Iso), sorcin KO cardiomyocytes had significantly enhanced inward NCX current when clamped at -80 to -120mV (p<0.05, 6-8 cells per group). Simultaneous recording of action potential (AP) and [Ca2+]i transient showed a significant prolongation of AP duration at 90% of repolarization in sorcin KO cells at 1Hz pacing (basal condition: 381±98 vs. 74±14 ms, p<0.01; with Iso: 221±19 vs.179±18ms; 9-10 cells per group). Under Iso stimulation, early afterdepolarizations (EADs) and high incidence of delayed afterdepolarizations (DADs) were observed in sorcin KO cells (80% KO vs. 22.2% WT cells, p<0.05, 9-10 cells per group), accompanied with abnormal Ca2+ release between or after pacing. The percentage of SCaEs that triggered DADs was much higher in KO cells than in WT (89% vs. 21%, p<0.05, 9-10 cells per group). DADs and EADs were fully prevented in KO cells that were dialyzed with 10mM fast Ca2+ chelator BAPTA, while 37.5% of KO cells dialyzed with 10mM slow chelator EGTA still presented coordinated SCaEs with DADs (7-8 cells per group). In conclusion, RyRs are sensitized in sorcin KO cells such that a small elevation in sub-sarcolemmal [Ca2+]i can lead to RyR Ca2+ release that triggers full APs. Meanwhile, the enhanced inward NCX current and possibly enhanced L-type Ca2+ current favor membrane depolarization and prolonged AP duration. These factors work together to trigger arrhythmia when sorcin KO heart is under stress.
Author Disclosures: X. Chen: None. C.R. Valdivia: None. C. Weber: None. G. García-Rivas: None. P.A. Powers: None. H.H. Valdivia: None.
- © 2014 by American Heart Association, Inc.