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We have applied an optical super-resolution technique based on
single-molecule localization to examine the peripheral distribution
of a cardiac signaling protein, the ryanodine receptor (RyR), in rat
ventricular myocytes. RyRs form clusters with a mean size of
approximately 14 RyRs per cluster, which is almost an order of
magnitude smaller than previously estimated. Clusters were typically
not circular (as previously assumed) but elongated with an
average aspect ratio of 1.9. Edge-to-edge distances between adjacent
RyR clusters were often <50 nm, suggesting that peripheral
RyR clusters may exhibit strong intercluster signaling. The wide
variation of cluster size, which follows a near-exponential distribution,
is compatible with a stochastic cluster assembly process.
We suggest that calcium sparks may be the result of the concerted
activation of several RyR clusters forming a functional ‘‘supercluster’’
whose gating is controlled by both cytosolic and sarcoplasmic
reticulum luminal calcium levels.