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See related article, pages e65–e72 Marks and colleagues published some influential results in 2000, suggesting that protein kinase A phosphorylation regulates ryanodine receptor (RyR2) open probability ( P oRyR). The authors attributed this to the dissociation of the RyR-associated regulatory protein FKBP12.6.1 They went on to propose that, in failing hearts, RyR2 is hyperphosphorylated, which leads to defective channel function by increasing sensitivity to Ca-induced activation of the molecule. Moreover, these effects were attributable to phosphorylation of a single amino acid, serine 2809 (S2809). There are 4 of these serine molecules at location 2808 in the human RyR2 molecule, 1 on each subunit of the tetramer. Much subsequent work has referred to the 2809 residue, which is found in rabbits. Marks and colleagues further suggested that phosphorylation of S2809 was also responsible for the normal effects of adrenergic stimulation on excitation–contraction coupling (ECC) and that hyperphosphorylation was responsible for abnormal ECC during failure.The RyR is a tetramer that forms the largest membrane ion channel. In muscle, it is found in the sarcoplasmic reticulum (SR), where it functions as the Ca release channel. The heart isoform is designated RyR2. The pore sequences are largely found in membrane spanning domains.2 There is a large cytosolic domain. Although hyperphosphorylation refers, by definition, to the occupation of all the putative phosphorylation sites in a molecule in the context of the work by Marks and colleagues,1 hyperphosphorylation refers to 3 or perhaps 4 of the serine residues. In RyRs, there are a large number of consensus phosphorylation sites.3 RyRs are associated with a number of proteins, and these include anchoring protein phosphatases and kinases, as well as the regulatory protein FKBP12.6. From the standpoint of this editorial, this last protein is perhaps the most interesting, and it is considered …

What Are the Consequences of Phosphorylation and Hyperphosphorylation of Ryanodine Receptors in Normal and Failing Heart?