Ryanodine receptors: allosteric ion channel giants.

The endoplasmic reticulum (ER) and sarcoplasmic reticulum (SR) form major intracellular Ca(2+) stores. Ryanodine receptors (RyRs) are large tetrameric ion channels in the SR and ER membranes that can release Ca(2+) upon triggering. With molecular masses exceeding 2.2MDa, they represent the pinnacle of ion channel complexity. RyRs have adopted long-range allosteric mechanisms, with pore opening resulting in conformational changes over 200Å away. Together with tens of protein and small molecule modulators, RyRs have adopted rich and complex regulatory mechanisms. Structurally related to inositol-1,4,5-trisphosphate receptors (IP3Rs), RyRs have been studied extensively using cryo-electron microscopy (cryo-EM). Along with more recent X-ray crystallographic analyses of individual domains, these have resulted in pseudo-atomic models. Over 500 mutations in RyRs have been linked to severe genetic disorders, which underscore their role in the contraction of cardiac and skeletal muscles. Most of these have been linked to gain-of-function phenotypes, resulting in premature or prolonged leak of Ca(2+) in the cytosol. This review outlines our current knowledge on the structure of RyRs at high and low resolutions, their relationship to IP3Rs, an overview of the most commonly studied regulatory mechanisms, and models that relate disease-causing mutations to altered channel function.