Defective Cardiac Ryanodine Receptor Regulation During Atrial Fibrillation

Abstract

Background-Ca2ϩ leak from the sarcoplasmic reticulum (SR) may play an important role in triggering and/or maintaining atrial arrhythmias, including atrial fibrillation (AF). Protein kinase A (PKA) hyperphosphorylation of the cardiac ryanodine receptor (RyR2) resulting in dissociation of the channel-stabilizing subunit calstabin2 (FK506-binding protein or FKBP12.6) causes SR Ca 2ϩ leak in failing hearts and can trigger fatal ventricular arrhythmias. Little is known about the role of RyR2 dysfunction in AF, however. Methods and Results-Left and right atrial tissue was obtained from dogs with AF induced by rapid right atrial pacing (nϭ6 for left atrial, nϭ4 for right atrial) and sham instrumented controls (nϭ6 for left atrial, nϭ4 for right atrial). Right atrial tissue was also collected from humans with AF (nϭ10) and sinus rhythm (nϭ10) and normal cardiac function. PKA phosphorylation of immunoprecipitated RyR2 was determined by back-phosphorylation and by immunoblotting with a phosphospecific antibody. The amount of calstabin2 bound to RyR2 was determined by coimmunoprecipitation. RyR2 channel currents were measured in planar lipid bilayers. Atrial tissue from both the AF dogs and humans with chronic AF showed a significant increase in PKA phosphorylation of RyR2, with a corresponding decrease in calstabin2 binding to the channel. Channels isolated from dogs with AF exhibited increased open probability under conditions simulating diastole compared with channels from control hearts, suggesting that these AF channels could predispose to a diastolic SR Ca 2ϩ leak. Conclusions-SR Ca 2ϩ leak due to RyR2 PKA hyperphosphorylation may play a role in initiation and/or maintenance of

Arrhythmias, elicited by catecholamines and serotonin, vanish in human chronic atrial fibrillation

“…S7B). Increased phosphorylation of RyR2 channels at Ser-2808, catalyzed by PKA (11,12), and Ser-2814, catalyzed by CaMKII, has been implicated in the arrhythmogenic release of Ca 2+ through leaky RyR2 channels (13,20); however, in contrast to previous reports, neither basal phosphorylation (SI Appendix, Figs. S6 and S7) nor phosphorylation stimulated by agonists of RyR2 at Ser-2808 ( Fig.…”

“…Spontaneous impulse generation could be related to increased activity of PKA and/or CaMKII, with subsequent uncoordinated release of Ca 2+ from the sarcoplasmic reticulum. Such a concept is attractive, because Ca 2+ released from the "leaky" sarcoplasmic reticulum would activate the Na + -Ca 2+ exchanger to extrude Ca 2+ and to produce a arrhythmogenic depolarizing current, thereby explaining both the contractile dysfunction and the high recurrence rate (11)(12)(13).…”

Intracellular calcium leak due to FKBP12.6 deficiency in mice facilitates the inducibility of atrial fibrillation

“…The increased frequency of potentially arrhythmogenic Ca 2+ sparks and Ca 2+ waves are most likely caused by defective RyR2 channels 5,8,10 . Consistent with these observations, we previously found defects in RyR2 in atrial biopsies of patients in chronic AF.…”

Targeting ryanodine receptors for anti-arrhythmic therapy

“…RyR2 is also regulated by protein kinase A (PKA) phosphorylation, and increased PKA phosphorylation of RyR2 has been observed in patients with atrial fibrillation [7] . Shan et al [57] demonstrated that mice in which RyR2 was constitutively by PKA (RyR2-S2808D knock-in mice) exhibited an increased open probability, more calcium sparks, and increased SR Ca 2+ leak.…”

“…There is now considerable evidence that abnormal RyR2-mediated Ca 2+ release from the SR can lead to both atrial [6,7] and ventricular arrhythmias associated with sudden cardiac death [8][9][10] . Increased SR Ca 2+ release during diastole can lead to activation of the Na + /Ca 2+ -exchanger [11] , which in turn generates a transient inward current that can cause afterdepolarizations and triggered action potentials.…”