Published Online
on August 7, 2006

A more recent version of this article appeared on August 15, 2006

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Submitted on February 3, 2006
Revised on June 8, 2006
Accepted on June 20, 2006

Molecular Determinants of Altered Ca²⁺ Handling in Human Chronic Atrial Fibrillation

Ali El-Armouche MD, Peter Boknik PhD, Thomas Eschenhagen MD, Lucie Carrier PhD, Michael Knaut MD, Ursula Ravens MD^*, and Dobromir Dobrev MD

From the Institute of Experimental and Clinical Pharmacology and Toxicology (A.E.-A., L.C., T.E.), Medical Center Hamburg-Eppendorf, Germany; Department of Pharmacology and Toxicology, University of Münster (P.B.), Münster, Germany; INSERM U582, University Pierre et Marie Curie, Paris, France (L.C.); and Cardiovascular Center (M.K.) and Department of Pharmacology and Toxicology (U.R., D.D.), Dresden University of Technology, Dresden, Germany.

^* To whom correspondence should be addressed. E-mail: dobrev{at}rcs.urz.tu-dresden.de.

Background--Abnormal Ca²⁺ handling may contribute to impaired atrial contractility and arrhythmogenesis in human chronic atrial fibrillation (cAF). Here, we assessed the phosphorylation levels of key proteins involved in altered Ca²⁺ handling and contractility in cAF patients.

Methods and Results--Total and phosphorylation levels of Ca²⁺-handling and myofilament proteins were analyzed by Western blotting in right atrial appendages of 49 patients in sinus rhythm and 52 cAF patients. We found a higher total activity of type 1 (PP1) and type 2A phosphatases in cAF, which was associated with inhomogeneous changes of protein phosphorylation in the cellular compartments, ie, lower protein kinase A (PKA) phosphorylation of myosin binding protein-C (Ser-282 site) at the thick myofilaments but preserved PKA phosphorylation of troponin I at the thin myofilaments and enhanced PKA (Ser-16 site) and Ca²⁺-calmodulin protein kinase (Thr-17 site) phosphorylation of phospholamban. PP1 activity at sarcoplasmic reticulum is controlled by inhibitor-1 (I-1), which blocks PP1 in its PKA-phosphorylated form only. In cAF, the ratio of Thr-35-phosphorylated to total I-1 was 10-fold higher, which suggests that the enhanced phosphorylation of phospholamban may result from a stronger PP1 inhibition by PKA-hyperphosphorylated (activated) I-1.

Conclusions--Altered Ca²⁺ handling in cAF is associated with impaired phosphorylation of myosin binding protein-C, which may contribute to the contractile dysfunction after cardioversion. The hyperphosphorylation of phospholamban probably results from enhanced inhibition of sarcoplasmic PP1 by hyperphosphorylated I-1 and may reinforce the leakiness of ryanodine channels in cAF. Restoration of sarcoplasmic reticulum-associated PP1 function may represent a new therapeutic option for treatment of atrial fibrillation.

Key words: atrial fibrillation • calcium • myosin binding protein C, cardiac, human • phospholamban protein, human • protein phosphatase-1 • protein phosphatase-2A

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