title: Molecular determinants of altered Ca2+ handling in human chronic atrial fibrillation.
abstract: 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.
  
  
  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.
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, Medical Center Hamburg-Eppendorf, Germany.
authors.forename: Ali
authors.initials: A
authors.lastname: El-Armouche
authors.forename: Peter
authors.initials: P
authors.lastname: Boknik
authors.forename: Thomas
authors.initials: T
authors.lastname: Eschenhagen
authors.forename: Lucie
authors.initials: L
authors.lastname: Carrier
authors.forename: Michael
authors.initials: M
authors.lastname: Knaut
authors.forename: Ursula
authors.initials: U
authors.lastname: Ravens
authors.forename: Dobromir
authors.initials: D
authors.lastname: Dobrev
mesh_terms: D008841:Actin Cytoskeleton / Q000201:enzymology / Q000502:physiology; D000368:Aged; D001145:Arrhythmias, Cardiac / Q000503:physiopathology; D001281:Atrial Fibrillation / Q000209:etiology* / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000032:analysis / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000032:analysis / Q000378:metabolism; D002352:Carrier Proteins / Q000032:analysis / Q000378:metabolism*; D002908:Chronic Disease; D017868:Cyclic AMP-Dependent Protein Kinases / Q000032:analysis / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D009200:Myocardial Contraction / Q000502:physiology*; D009206:Myocardium / Q000201:enzymology*; D010749:Phosphoprotein Phosphatases / Q000032:analysis / Q000378:metabolism; D010766:Phosphorylation; D019837:Ryanodine Receptor Calcium Release Channel / Q000032:analysis / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000201:enzymology / Q000502:physiology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D019831:Sodium-Calcium Exchanger / Q000032:analysis / Q000378:metabolism; D019210:Troponin I / Q000032:analysis / Q000378:metabolism; D000099211:Phospholamban; D000099163:Myosin Binding Protein C
chemical_list: D002118:Calcium; D002135:Calcium-Binding Proteins; D000252:Calcium-Transporting ATPases; D002352:Carrier Proteins; D017868:Cyclic AMP-Dependent Protein Kinases; D010749:Phosphoprotein Phosphatases; D019837:Ryanodine Receptor Calcium Release Channel; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D019831:Sodium-Calcium Exchanger; D019210:Troponin I; D000099211:Phospholamban; D000099163:Myosin Binding Protein C