Key result
Application of phosphorylation and 0.1 mmol/L Mg2+ moved RYR2 tetramers into a checkerboard configuration, whereas 4 mmol/L Mg2+ induced a dense side-by-side arrangement within 10 minutes.
Why the study?
RYR2 tetramers within mammalian ventricular dyads may have multiple and complex arrangements influenced by physiological and pathological factors, but their precise organization was unclear.
The arrangement of RYR2 tetramers in mammalian dyads is dynamic and modulated by Mg2+ and phosphorylation, which may regulate their open probabilities.
Rationale : Single-tilt tomograms of the dyads in rat ventricular myocytes indicated that type 2 ryanodine receptors (RYR2s) were not positioned in a well-ordered array. Furthermore, the orientation and packing strategy of purified type 1 ryanodine receptors in lipid bilayers is determined by the free Mg 2+ concentration. These observations led us to test the hypothesis that RYR2s within the mammalian dyad have multiple and complex arrangements. Objectives : To determine the arrangement of RYR2 tetramers in the dyads of mammalian cardiomyocytes and the effects of physiologically and pathologically relevant factors on this arrangement. Methods and Results : We used dual-tilt electron tomography to produce en-face views of dyads, enabling a direct examination of RYR2 distribution and arrangement. Rat hearts fixed in situ; isolated rat cardiomyocytes permeabilized, incubated with 1 mmol/L Mg 2+ , and then fixed; and sections of human ventricle, all showed that the tetramer packing within a dyad was nonuniform containing a mix of checkerboard and side-by-side arrangements, as well as isolated tetramers. Both phosphorylation and 0.1 mmol/L Mg 2+ moved the tetramers into a predominantly checkerboard configuration, whereas the 4 mmol/L Mg 2+ induced a dense side-by-side arrangement. These changes occurred within 10 minutes of application of the stimuli. Conclusions : The arrangement of RYR2 tetramers within the mammalian dyad is neither uniform nor static. We hypothesize that this is characteristic of the dyad in vivo and may provide a mechanism for modulating the open probabilities of the individual tetramers.
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Asghari et al. (2014) studied this question. Phosphorylation and varying Mg2+ concentrations vs. 1 mmol/L Mg2+ was evaluated on Arrangement of RYR2 tetramers. Application of phosphorylation and 0.1 mmol/L Mg2+ moved RYR2 tetramers into a checkerboard configuration, whereas 4 mmol/L Mg2+ induced a dense side-by-side arrangement within 10 minutes.
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