Targeting ryanodine receptors to treat human diseases
Andrew R. Marks
Andrew R. Marks
Published January 17, 2023
Citation Information: J Clin Invest. 2023;133(2):e162891. https://doi.org/10.1172/JCI162891.
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Targeting ryanodine receptors to treat human diseases

Abstract

This Review provides an update on ryanodine receptors (RyRs) and their role in human diseases of heart, muscle, and brain. Calcium (Ca2+) is a requisite second messenger in all living organisms. From C. elegans to mammals, Ca2+ is necessary for locomotion, bodily functions, and neural activity. However, too much of a good thing can be bad. Intracellular Ca2+ overload can result in loss of function and death. Intracellular Ca2+ release channels evolved to safely provide large, rapid Ca2+ signals without exposure to toxic extracellular Ca2+. RyRs are intracellular Ca2+ release channels present throughout the zoosphere. Over the past 35 years, our knowledge of RyRs has advanced to the level of atomic-resolution structures revealing their role in the mechanisms underlying the pathogenesis of human disorders of heart, muscle, and brain. Stress-induced RyR-mediated intracellular Ca2+ leak in the heart can promote heart failure and cardiac arrhythmias. In skeletal muscle, RyR1 leak contributes to muscle weakness in inherited myopathies, to age-related loss of muscle function and cancer-associated muscle weakness, and to impaired muscle function in muscular dystrophies, including Duchenne. In the brain, leaky RyR channels contribute to cognitive dysfunction in Alzheimer’s disease, posttraumatic stress disorder, and Huntington’s disease. Novel therapeutics targeting dysfunctional RyRs are showing promise.

Authors

Andrew R. Marks

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Figure 2

Cryo-EM reconstructions of human RyR2.

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Cryo-EM reconstructions of human RyR2. The reconstructions show that the...
The reconstructions show that the CPVT mutant RyR2-R2474S puts the channel into a primed state partway between closed and open, and treatment with the Rycal ARM210 or calmodulin puts the channel back toward the closed state, preventing leak. (A) Models of open PKA-phosphorylated RyR2 (Protein Data Bank [PDB; https://www.rcsb.org/]: 7U9R; yellow) and closed PKA-phosphorylated RyR2 (PDB: 7U9Q; gray). Arrows show the cytosolic shell of the PKA-phosphorylated RyR2 shifting downward and outward when the channel goes from the closed to the open state. Only the front protomer is colored. The sarcoplasmic reticular membranes are black discs. Conditions include 10 mM ATP, 150 nM free Ca2+, and 500 mM xanthine. (B) Models of closed PKA-phosphorylated RyR2 (PDB: 7U9Q; gray) and primed PKA-phosphorylated RyR2-R2474S (PDB: 7U9X; magenta), with arrows showing the cytosolic shell of RyR2-R2474S shifting downward and outward compared with closed PKA-phosphorylated RyR2, similar to the structural changes observed for PKA-phosphorylated RyR2 when the channel goes from closed to open. We define this state between closed and open as the primed state. (C) Models of primed PKA-phosphorylated RyR2-R2474S (PDB: 7U9X; magenta) and closed PKA-phosphorylated RyR2-R2474S + ARM210 (PDB: 7UA1; cyan). Arrows show the cytosolic shell of PKA-phosphorylated RyR2-R2474S + ARM210 shifting upward and inward compared with RyR2-R2474S, reversing the primed state closer to the closed state. (D) Models of primed PKA-phosphorylated RyR2-R2474S (PDB: 7U9X; magenta) and closed PKA-phosphorylated RyR2-R2474S + calmodulin (CaM) (PDB: 7UA3; cyan). Similarly to the Rycal ARM210, CaM reverses the primed state back to the closed state. Reconstructions were adapted with permission from Structure (74).