Cardiac ryanodine receptor phosphorylation: target sites and functional consequences.
A study by Xiao and co-workers in this issue of the Biochemical Journal demonstrates PKA (protein kinase A)-dependent phosphorylation of Ser-2030 on the cardiac ryanodine receptor (RyR2) that is activated by beta-adrenergic agonists. They show that RyR2 phosphorylation at this site is not appreciably altered in heart failure samples, but retains PKA-dependence of phosphorylation. They contrast this with RyR2 phosphorylation at Ser-2808, a site previously reported to be the key and only PKA target site on RyR2. Here Ser-2808 phosphorylation was found to be relatively insensitive to either PKA activation or inhibition. These results add important new information to a highly controversial field. This issue is important because it is increasingly clear that altered regulation of the gating of the RyR2 sarcoplasmic reticulum Ca2+-release channel (e.g. by phosphorylation) is critically important in mediating altered diastolic sarcoplasmic reticulum Ca2+ release. This may contribute to both reduced cardiac function and arrhythmogenesis in humans carrying mutations in the RyR2 gene and with acquired heart failure of varied aetiology. This study brings some new answers, but also raises additional new questions that will require further investigation.
Bers
Donald M
DM
Department of Physiology, Loyola University Chicago, 2160 South First Avenue, Maywood, IL 60153, USA. dbers@lumc.edu
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D006333:Heart Failure / Q000378:metabolism; D006801:Humans; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D010768:Phosphoserine / Q000737:chemistry; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D011817:Rabbits; D051381:Rats; D019837:Ryanodine Receptor Calcium Release Channel / Q000737:chemistry* / Q000235:genetics / Q000502:physiology; D012508:Sarcolemma / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D019311:Staurosporine / Q000494:pharmacology
D000318:Adrenergic beta-Agonists; D019837:Ryanodine Receptor Calcium Release Channel; D019831:Sodium-Calcium Exchanger; D010768:Phosphoserine; D017346:Protein Serine-Threonine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019311:Staurosporine; D002118:Calcium