Hyperphosphorylation of the cardiac ryanodine receptor at serine 2808 is not involved in cardiac dysfunction after myocardial infarction.
BACKGROUND
Abnormal behavior of the cardiac ryanodine receptor (RyR2) has been linked to cardiac arrhythmias and heart failure (HF) after myocardial infarction (MI). It has been proposed that protein kinase A (PKA) hyperphosphorylation of the RyR2 at a single residue, Ser-2808, is a critical mediator of RyR dysfunction, depressed cardiac performance, and HF after MI.


OBJECTIVE
We used a mouse model (RyRS2808A) in which PKA hyperphosphorylation of the RyR2 at Ser-2808 is prevented to determine whether loss of PKA phosphorylation at this site averts post MI cardiac pump dysfunction.


RESULTS
MI was induced in wild-type (WT) and S2808A mice. Myocyte and cardiac function were compared in WT and S2808A animals before and after MI. The effects of the PKA activator Isoproterenol (Iso) on L-type Ca(2+) current (I(CaL)), contractions, and [Ca(2+)](I) transients were also measured. Both WT and S2808A mice had depressed pump function after MI, and there were no differences between groups. MI size was also identical in both groups. L type Ca(2+) current, contractions, Ca(2+) transients, and SR Ca(2+) load were also not significantly different in WT versus S2808A myocytes either before or after MI. Iso effects on Ca(2+) current, contraction, Ca(2+) transients, and SR Ca(2+) load were identical in WT and S2808A myocytes before and after MI at both low and high concentrations.


CONCLUSIONS
These results strongly support the idea that PKA phosphorylation of RyR-S2808 is irrelevant to the development of cardiac dysfunction after MI, at least in the mice used in this study.
Temple University School of Medicine, Philadelphia, PA 19140, USA.
Hongyu
H
Zhang
Catherine A
CA
Makarewich
Hajime
H
Kubo
Wei
W
Wang
Jason M
JM
Duran
Ying
Y
Li
Remus M
RM
Berretta
Walter J
WJ
Koch
Xiongwen
X
Chen
Erhe
E
Gao
Héctor H
HH
Valdivia
Steven R
SR
Houser
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005355:Fibrosis / Q000235:genetics / Q000378:metabolism; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D051379:Mice; D008817:Mice, Mutant Strains; D009200:Myocardial Contraction / Q000502:physiology; D009203:Myocardial Infarction / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D010766:Phosphorylation / Q000502:physiology; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics* / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D020257:Ventricular Remodeling / Q000502:physiology
D020746:Calcium Channels, L-Type; D019837:Ryanodine Receptor Calcium Release Channel; D012694:Serine; D017868:Cyclic AMP-Dependent Protein Kinases; D002118:Calcium