The Ca ²⁺ leak paradox and "rogue ryanodine receptors": SR Ca ²⁺ efflux theory and practice

Ca ²⁺ efflux from the sarcoplasmic reticulum (SR) is routed primarily through SR Ca ²⁺ release channels (ryanodine receptors, RyRs). When clusters of RyRs are activated by trigger Ca ²⁺ influx through L-type Ca ²⁺ channels (dihydropyridine receptors, DHPR), Ca ²⁺ sparks are observed. Close spatial coupling between DHPRs and RyR clusters and the relative insensitivity of RyRs to be triggered by Ca ²⁺ together ensure the stability of this positive-feedback system of Ca ²⁺ amplification. Despite evidence from single channel RyR gating experiments that phosphorylation of RyRs by protein kinase A (PKA) or calcium-calmodulin dependent protein kinase II (CAMK II) causes an increase in the sensitivity of the RyR to be triggered by [Ca ²⁺] _i there is little clear evidence to date showing an increase in Ca ²⁺ spark rate. Indeed, there is some evidence that the SR Ca ²⁺ content may be decreased in hyperadrenergic disease states. The question is whether or not these observations are compatible with each other and with the development of arrhythmogenic extrasystoles that can occur under these conditions. Furthermore, the appearance of an increase in the SR Ca ²⁺ "leak" under these conditions is perplexing. These and related complexities are analyzed and discussed in this report. Using simple mathematical modeling discussed in the context of recent experimental findings, a possible resolution to this paradox is proposed. The resolution depends upon two features of SR function that have not been confirmed directly but are broadly consistent with several lines of indirect evidence: (1) the existence of unclustered or "rogue" RyRs that may respond differently to local [Ca ²⁺] _i in diastole and during the [Ca ²⁺] _i transient; and (2) a decrease in cooperative or coupled gating between clustered RyRs in response to physiologic phosphorylation or hyper-phosphorylation of RyRs in disease states such as heart failure. Taken together, these two features may provide a framework that allows for an improved understanding of cardiac Ca ²⁺ signaling.