Immunophilins and Coupled Gating of Ryanodine Receptors

The ryanodine receptor (RyR) is the major calcium (Ca2+) release channel in the sarcoplasmic reticulum (SR) of skeletal and cardiac muscle and is required for excitation-contraction (EC) coupling. The 565 kDa RyR protein forms a tetrameric channel that is part of a macromolecular signaling complex that also includes four FK506 binding proteins (FKBPs). The RyR channel complex is localized on specialized regions of the SR, such that the large RyR cytoplasmic domain is closely opposed to the transverse tubule (T-tubule) of the plasma membrane. RyR channel complexes are organized in regular arrays such that neighboring RyRs are in physical contact with each other. We have shown that physical and functional association between RyR1 or RyR2 channels results in coordinated gating behavior termed coupled gating. Coupled gating requires FKBP12 or FKBP12.6 in the RyR1 or RyR2 macromolecular complexes, respectively. FKBPs are known to stabilize single RyR channel function. Coupled gating describes an additional role for FKBPs in the functional coordination of RyR channel complexes that allows clusters of channels to function as “Ca2+release units” (CRU). In addition, the FKBP-RyR interaction is regulated by PKA phosphorylation. In failing hearts PKA hyperphosphorylation of RyR2 causes depletion of FKBP12.6 from the channel macromolecular complex and may contribute to contractile dysfunction by impairing EC coupling. As FKBPs are potent modulators of RyR channel function, the FKBP-RyR interaction is a focus for determining molecular mechanisms of coupled gating and presents an exciting pharmacologic target for restoration of RyR complex function in diseased states.