Ryanodine Receptor S2808 Phosphorylation in Heart Failure

In this issue of Circulation Research , Zhang et al1 provide direct and clear evidence that phosphorylation of S2808 in the cardiac ryanodine receptors (RyR2) has no impact on either normal cardiac function, sympathetic stimulation of the heart, or progression of heart failure (HF) after myocardial infarction (MI). They used mice in which the S2808 site was rendered nonphosphorylatable in S2808A knock-in mice, and the results directly contradict results published by the group of A.R. Marks.2–4 This has been a highly controversial area. This new study compels me to assess this pathway in a balanced way, but recognizing that my opinions are influenced by work that my group has done in this area. My goal here is not to microdissect each controversial piece of data in dozens of relevant papers (see recent reviews and tables5,6), but rather to provide my informed opinion about key aspects of this issue in a balanced manner. Let us first consider the model that importantly raised the issue of SR Ca leak as a potential pathophysiological cardiac effect in HF. Article, see p 831 In 2000 the Marks group published an exciting and seminal paper that has fueled intensive research over the past 11 years.7 They proposed that in HF, PKA hyperphosphorylates RyR2-S2808, causing FKBP12.6 dissociation from RyR2, which directly enhances SR Ca leak/depletion and systolic dysfunction in HF (Figure). Tenets later added to this core model were a down-regulation of phosphatases associated with the RyR2 in HF (which would facilitate the PKA-dependent RyR2 hyperphosphorylation) and that this diastolic SR Ca leak could also contribute to triggered arrhythmias. An extensive series of papers by the same group since then have provided highly consistent and compelling support for this working hypothesis, extending the impact of this intriguing PKA/RyR-S2808/FKBP12.6/RyR …