Calmodulin kinase II, sarcoplasmic reticulum Ca2+ leak, and atrial fibrillation

Abstract

Although it is generally accepted that excitation-contraction coupling is defective in patients with atrial fibrillation, the underlying cellular mechanisms remain incompletely understood. Recent studies suggest that abnormal sarcoplasmic reticulum calcium "leak" via ryanodine receptors contributes to atrial arrhythmogenesis. Increased activity of the enzyme calmodulin kinase II (CaMKII) and, specifically, enhanced CaMKII phosphorylation of ryanodine receptors appear to play a critical role in the induction and perhaps maintenance of atrial fibrillation. In this review, we will summarize new insights into the role of enhanced CaMKII in sarcoplasmic reticulum calcium leak and atrial arrhythmogenesis during atrial fibrillation.

Figure 1. Overview of alterations in atrial Ca²⁺ movements in human atrial fibrillation

Atrial remodeling during chronic atrial fibrillation (AF) leads to changes in the expression and phosphorylation level of key Ca²⁺-handling proteins involved in atrial Ca²⁺ signaling. Whereas expression levels of the L-type Ca²⁺ channel (LTCC) typically remain unaffected, phosphorylation of the channel appears reduced leading to decreased I_Ca,L. Hypophosphorylation of this channel might be due to increased activity of protein phosphatases PP1 and PP2A. In contract, the sarcoplasmic reticulum (SR) Ca²⁺ release channel/ryanodine receptor (RyR2) is hyperphosphorylated in AF at both protein kinase A (PKA) and Ca²⁺/calmodulin-kinase II (CaMKII) sites. This might be caused by reduced PP1 activity, as a result of hyperphosphorylation (and thus activation) of inhibitor-1 at Thr35 that reduces SR-related PP1 activity. Similar mechanisms may also contribute to hyperphosphorylation of phospholamban (PLN). Increased cytosolic CaMKII activity also contributes to hyperphosphorylation of RyR2 (at Ser2814) and PLN (at Thr17), which might be promoted by the higher atrial rates during AF. Diastolic SR Ca²⁺ leak via RyR2 can activate the Na⁺/Ca²⁺-exchanger, leading to generation of an inward depolarizing NCX current. This may produce delayed afterdepolarizations and triggered activity that may cause focal activity contributing to AF maintenance.