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Review
. 2011 Mar 1;89(4):734-43.
doi: 10.1093/cvr/cvq324. Epub 2010 Oct 12.

The Ryanodine Receptor Channel as a Molecular Motif in Atrial Fibrillation: Pathophysiological and Therapeutic Implications

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Free PMC article
Review

The Ryanodine Receptor Channel as a Molecular Motif in Atrial Fibrillation: Pathophysiological and Therapeutic Implications

Dobromir Dobrev et al. Cardiovasc Res. .
Free PMC article

Abstract

Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with substantial morbidity and mortality. It causes profound changes in sarcoplasmic reticulum (SR) Ca(2+) homeostasis, including ryanodine receptor channel dysfunction and diastolic SR Ca(2+) leak, which might contribute to both decreased contractile function and increased propensity to atrial arrhythmias. In this review, we will focus on the molecular basis of ryanodine receptor channel dysfunction and enhanced diastolic SR Ca(2+) leak in AF. The potential relevance of increased incidence of spontaneous SR Ca(2+) release for both AF induction and/or maintenance and the development of novel mechanism-based therapeutic approaches will be discussed.

Figures

Figure 1
Figure 1
Fundamental mechanisms of AF induction and persistence. AF is maintained by either reentry or ectopic activity. Reentry formation requires a trigger that acts on an arrhythmogenic substrate. Atrial remodelling creates a substrate for reentrant AF and can eventually promote ectopic activity. Risk factors and clinical disease conditions contribute to reentry by causing atrial remodelling that creates a vulnerable substrate and can participate in AF induction by promoting the triggers of AF. RyR2 dysfunction is suggested to contribute to both the arrhythmogenic substrate and ectopic activity. DAD, delayed afterdepolarization.
Figure 2
Figure 2
Composition of the atrial RyR2 macromolecular complex and Ca2+ spark incidence in AF. (A) Schematic representation of one out of four RyR2 monomers of the RyR2 macromolecular complex, each associating with various subunits indicated. PKA, protein kinase A; PP1, protein phosphatase 1; PP2A, protein phosphatase 2A; TRD, triadin; JNC, junctin; CSQ, calsequestrin. (B) Representative line-scan images in myocytes from patients in sinus rhythm (SR) or AF, in the presence of CaMKII-inhibitor KN-93 or its inactive control (KN-92). The frequency and size of Ca2+ sparks were increased in AF. As known from single-channel recordings of RyR2 reconstituted in lipid bilayers, channel-subunit phosphorylation enhances the open probability of RyR2 at a given [Ca2+]i, without changes in current amplitude or mean open time. This might explain why the CaMKII-inhibitor KN-93 reduces the probability of Ca2+ sparks to occur, but has no effect on Ca2+-spark size. The KN-93-induced reduction of Ca2+-spark frequency is expected to decrease the probability of saltatory Ca2+-wave propagations with accompanying delayed afterdepolarizations/triggered activity, potentially halting AF progression. See text for further details. Reproduced with permission from Neef et al.
Figure 3
Figure 3
Increased phosphorylation and open probability of RyR2 in AF patients. (A) Compared with sinus rhythm (SR) patients, AF patients show increased Ser2809 phosphorylation of RyR2. Calstabin2 (FKBP12.6) levels bound to RyR2 are decreased in AF. Reproduced with permission from Vest et al. (B) AF patients also have enhanced RyR2 phosphorylation by CaMKII at Ser2814 (left), likely due to activation of the cytosolic CaMKII-δc isoform (right). Reproduced with permission from Chelu et al. (C) Left, single-channel tracings of Ser2809-hyperphosphorylated RyR2 channels of dogs with cAF show increased open probability (Po) in AF. Right, corresponding current amplitude histograms. To, average open time; Tc, average closed time. Reproduced with permission from Vest et al.
Figure 4
Figure 4
Increased NCX function in patients with cAF. (A) Representative examples of caffeine-evoked Ca2+ transients (CaT) in voltage-clamped (at –80 mV) atrial myocytes from patients in sinus rhythm (SR) or cAF. (B) Bar graphs showing no significant differences in sarcoplasmic reticulum Ca2+ content evidenced by caffeine-evoked CaT amplitude and integrated Na2+/Ca2+-exchange current (INCX). The non-significantly smaller caffeine-evoked CaT amplitude, but unaltered integrated INCX current in cAF points to a potentially higher Ca2+-buffering capacity in cAF vs. SR patients, but this requires further validation in subsequent work (see text for further details). (C) Western blots showing increased NCX1 expression levels in cAF. (D) INCX evoked by caffeine application reveals a greater INCX for a given [Ca2+]i in AF vs. SR patients. (E) Bar graphs showing an increased slope of the INCX and faster decay of caffeine-evoked CaT in cAF as indices of increased functional NCX. (F) Trend toward increased INCX peak current in cAF. Numbers within parentheses indicate myocytes/patients. Reproduced with permission from Voigt et al.
Figure 5
Figure 5
Reduced L-type Ca2+ current (ICa,L) triggers smaller [Ca2+]i transients in patients with cAF. (Left) Representative recordings of ICa,L on depolarization from the prepulse potential of −40 to +10 mV for 100 ms and corresponding triggering of [Ca2+]i transients in myocytes from sinus rhythm (Ctl) and cAF, respectively. (Right) Mean values of ICa,L, diastolic and systolic [Ca2+]i transient, and [Ca2+]i transient amplitude in Ctl and cAF. Numbers within parentheses indicate myocytes/patients. Reproduced with permission from Voigt et al.
Figure 6
Figure 6
Increased RyR2 Ca2+ leak and enhanced functional NCX might produce DADs and triggered activity during AF. During AF, faster atrial rates, increased oxidative stress, and enhanced sympathetic drive can strongly activate CaMKII, thereby increasing phosphorylation of RyR2, and enhancing SR Ca2+ load due to increased SERCA2a function. Due to the increase in coupling gain, the increased SR Ca2+ leak during diastole can produce a sufficiently large NCX current to induce DADs and triggered APs. The higher incidence of diastolic SR Ca2+ release events can increase the dispersion of atrial refractoriness and can cause dyssynchrony of myocyte contraction, thereby contributing to atrial hypocontractility. Po, open probability; ▵[Ca2+]i, change in [Ca2+]i; ▵Vm, change in membrane voltage in response to a given alteration of [Ca2+]i. See text for further details.

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