title: Review of RyR1 pathway and associated pathomechanisms.
abstract: Ryanodine receptor isoform-1 (RyR1) is a major calcium channel in skeletal muscle important for excitation-contraction coupling. Mutations in the RYR1 gene yield RyR1 protein dysfunction that manifests clinically as RYR1-related congenital myopathies (RYR1-RM) and/or malignant hyperthermia susceptibility (MHS). Individuals with RYR1-RM and/or MHS exhibit varying symptoms and severity. The symptoms impair quality of life and put patients at risk for early mortality, yet the cause of varying severity is not well understood. Currently, there is no Food and Drug Administration (FDA) approved treatment for RYR1-RM. Discovery of effective treatments is therefore critical, requiring knowledge of the RyR1 pathway. The purpose of this review is to compile work published to date on the RyR1 pathway and to implicate potential regions as targets for treatment. The RyR1 pathway is comprised of protein-protein interactions, protein-ligand interactions, and post-translational modifications, creating an activation/regulatory macromolecular complex. Given the complexity of this pathway, we divided these interactions and modifications into six regulatory groups. Three of several RyR1 interacting proteins, FK506-binding protein 12 (FKBP12), triadin, and calmodulin, were identified as playing important roles across all groups and may serve as promising target sites for treatment. Also, variability in disease severity may be influenced by prolongation or hyperactivity of post-translational modifications resulting from RyR1 dysfunction.
authors.affiliation: National Institute of Nursing Research/Tissue Injury Branch/Neuromuscular Symptoms Unit, National Institutes of Health, Bethesda, MD, 20814, USA. jessica.witherspoon@nih.gov.
authors.forename: Jessica W
authors.initials: JW
authors.lastname: Witherspoon
authors.affiliation: National Institute of Nursing Research/Tissue Injury Branch/Neuromuscular Symptoms Unit, National Institutes of Health, Bethesda, MD, 20814, USA.
authors.forename: Katherine G
authors.initials: KG
authors.lastname: Meilleur
mesh_terms: D000818:Animals; D006801:Humans; D018482:Muscle, Skeletal / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel
keywords: Excitation-contraction; Mitochondria; Muscle; Myopathies; Oxidative; Pathomechanism; Post-translational modifications; RyR1; Skeletal; Stress; Treatment