Ca²⁺ Release Channels Join the ‘Resolution Revolution’

Ryanodine receptors (RyRs) are calcium release channels expressed in the sarcoendoplasmic reticula of many cell types including cardiac and skeletal muscle cells. In recent years Ca²⁺ leak through RyRs has been implicated as a major contributor to the development of diseases including heart failure, muscle myopathies, Alzheimer's disease, and diabetes, making it an important therapeutic target. Recent mammalian RyR1 cryoelectron microscopy (cryo-EM) structures of multiple functional states have clarified longstanding questions including the architecture of the transmembrane (TM) pore and cytoplasmic domains, the location and architecture of the channel gate, ligand-binding sites, and the gating mechanism. As we advance toward complete models of RyRs this new information enables the determination of domain–domain interfaces and the location and structural effects of disease-causing RyR mutations. Ca²⁺ ions are pivotal to signaling pathways involving extracellular and intracellular Ca²⁺ stores and protein transporters including ion channels and ATP-dependent Ca²⁺ pumps. Recent advances in cryoelectron microscopy detectors, software, and specimen preparation have revolutionized structural biology, allowing the solution of near-atomic-resolution structures of large protein complexes including the ryanodine receptor (RyR) and inositol 1,4,5-trisphosphate receptor Ca²+ release channels. Structures of RyR1 in multiple functional states helped identify ligand-binding sites and unravel the channel's gating mechanism.