This Controversies in Research article discusses the hypothesis that
protein kinase A (PKA)-mediated phosphorylation of the
Ryanodine Receptor (RyR) at a single
serine (RyRS2808) is essential for normal sympathetic regulation of cardiac myocyte contractility and is responsible for the disturbed Ca(2+) regulation that underlies depressed contractility in
heart failure. Studies supporting this hypothesis have associated hyperphosphorylation of RyRS2808 and
heart failure progression in animals and humans and have shown that a phosphorylation defective RyR mutant mouse (RyRS2808A) does not respond normally to sympathetic agonists and does not exhibit
heart failure symptoms after
myocardial infarction. Studies to confirm and extend these ideas have failed to support the original data. Experiments from many different laboratories have convincingly shown that PKA-mediated RyRS2808 phosphorylation does not play any significant role in the normal sympathetic regulation of sarcoplasmic reticulum Ca2+ release or cardiac contractility. Hearts and myocytes from RyRS2808A mice have been shown to respond normally to sympathetic agonists, and to increase Ca(2+) influx, Ca(2+) transients, and Ca(2+) efflux. Although the RyR is involved in
heart failure-related Ca(2+) disturbances, this results from Ca(2+)-
calmodulin kinase II and
reactive oxygen species-mediated regulation rather than by RyR2808 phosphorylation. Also, a new study has shown that RyRS2808A mice are not protected from
myocardial infarction. Collectively, there is now a clear consensus in the published literature showing that dysregulated RyRs contribute to the altered Ca(2+) regulatory phenotype of the failing heart, but PKA-mediated phosphorylation of RyRS2808 has little or no role in these alterations.