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Fig. 7. Model for the generation of Ca²⁺ sparks by RyR isoforms and the regulation by FKBP12. The first line shows a schematic representation of ^wtRyR1, ^wtRyR3 and ^V2322DRyR3 tetramers with their putative degree of FKBP12 saturation. At resting Ca²⁺ levels, the affinity of FKBP12 for ^wtRyR1 is high (4 FKBPs/RyR), for ^wtRyR3 is intermediate (2 FKBPs/RyR) and for ^V2322DRyR3 is low (0 FKBPs/RyR). In this model, we propose that the relative FKBP12 saturation degree determines the stability of the closed state of the RyR channel and the sensitivity to channel activators, such as caffeine. This model explains the absence of spontaneous Ca²⁺ sparks in ^wtRyR1-(FKBP12)₄-expressing cells and the increased occurrence of Ca²⁺ sparks in ^V2322DRyR3-expressing cells (68% of cells) as compared to ^wtRyR3-(FKBP12)₂ expressing cells (44% of cells).

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