Structural Basis for the Modulation of Ryanodine Receptors

Historically, ryanodine receptors (RyRs) have presented unique challenges for high-resolution structural determination despite long-standing interest in their role in excitation–contraction coupling. Owing to their large size (nearly 2.2 MDa), high-resolution structures remained elusive until the advent of cryogenic electron microscopy (cryo-EM) techniques. In recent years, structures for both RyR1 and RyR2 have been solved at near-atomic resolution. Furthermore, recent reports have delved into their more complex structural associations with key modulators – proteins such as the dihydropyridine receptor (DHPR), FKBP12/12.6, and calmodulin (CaM), as well as ions and small molecules including Ca²⁺, ATP, caffeine, and PCB95. This review addresses the modulation of RyR1 and RyR2, in addition to the impact of such discoveries on intracellular Ca²⁺ dynamics and biophysical properties.