Abstract
Ryanodine receptors (RyRs) are ubiquitous intracellular calcium (Ca2+) release channels required for the function of many organs including heart and skeletal muscle, synaptic transmission in the brain, pancreatic beta cell function, and vascular tone. In disease, defective function of RyRs due either to stress (hyperadrenergic and/or oxidative overload) or genetic mutations can render the channels leaky to Ca2+ and promote defective disease-causing signals as observed in heat failure, muscular dystrophy, diabetes mellitus, and neurodegerative disease. RyRs are massive structures comprising the largest known ion channel-bearing macromolecular complex and exceeding 3 million Daltons in molecular weight. RyRs mediate the rapid release of Ca2+ from the endoplasmic/sarcoplasmic reticulum (ER/SR) to stimulate cellular functions through Ca2+-dependent processes. Recent advances in single-particle cryogenic electron microscopy (cryo-EM) have enabled the determination of atomic-level structures for RyR for the first time. These structures have illuminated the mechanisms by which these critical ion channels function and interact with regulatory ligands. In the present chapter we discuss the structure, functional elements, gating and activation mechanisms of RyRs in normal and disease states.
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Acknowledgements
This work was supported by HHMI (to J.F.) and grants from the National Institutes of Health (R01AR060037 and R01HL061503 to A.R.M., R01GM29169 to J.F., R00DK107895 to G.S.).
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ARM is a consultant and board member and owns shares in ARMGO Pharma, Inc. a biotech startup targeting RyR channels for therapeutic purposes.
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Santulli, G., Lewis, D., des Georges, A., Marks, A.R., Frank, J. (2018). Ryanodine Receptor Structure and Function in Health and Disease. In: Harris, J., Boekema, E. (eds) Membrane Protein Complexes: Structure and Function. Subcellular Biochemistry, vol 87. Springer, Singapore. https://doi.org/10.1007/978-981-10-7757-9_11
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