Physical Coupling between Ryanodine Receptor–Calcium Release Channels

Ryanodine receptor–calcium release channels play a pivotal role in the calcium signaling that mediates muscle excitation–contraction coupling. Their membrane organization into regular patterns, functional gating studies and theoretical analysis of receptor clustering have led to models that invoke allosteric interaction between individual channel oligomers as a critical mechanism for control of calcium release. Here we show that in reconstituted “checkerboard-like” lattices that mimic in situ membrane channel arrays, each oligomer is interlocked physically with four adjacent oligomers via a specific domain–domain interaction. Direct physical coupling between ryanodine receptors provides structural evidence for an inter-oligomer allosteric mechanism in channel regulation. Therefore, in addition to established cytosolic and luminal regulation of function, these observations indicate that channel–channel communication through physical coupling provides a novel mode of regulation of intracellular calcium release channels.