Review of RyR1 pathway and associated pathomechanisms.
Review of RyR1 pathway and associated pathomechanisms.
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DOI：
10.1186/s40478-016-0392-6
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发表时间：
2016-11-17
影响因子：
7.1
通讯作者：
Meilleur KG
中科院分区：
文献类型：
--
作者：
Witherspoon JW;Meilleur KG
Ryanodine receptor isoform-1（RyR 1）是骨骼肌中的一种主要钙通道，在兴奋-收缩偶联中起重要作用。RYR 1基因突变导致RyR 1蛋白功能障碍，临床表现为RYR 1相关先天性肌病（RYR 1-RM）和/或恶性高热易感性（MHS）。患有RYR 1-RM和/或MHS的个体表现出不同的症状和严重程度。这些症状损害生活质量，使患者面临早期死亡的风险，但不同严重程度的原因尚不清楚。目前，没有食品和药物管理局（FDA）批准的RYR 1-RM治疗。因此，发现有效的治疗方法至关重要，需要了解RyR 1途径。本次审查的目的是汇编工作发表的RyR 1途径，并牵连潜在的区域作为治疗的目标。RyR 1通路由蛋白质-蛋白质相互作用、蛋白质-配体相互作用和翻译后修饰组成，产生激活/调节大分子复合物。鉴于这一途径的复杂性，我们将这些相互作用和修饰分为六个调节组。几个RyR 1相互作用的蛋白，FK 506结合蛋白12（FKBP 12），三聚体，钙调蛋白，被确定为在所有群体中发挥重要作用，并可能作为有前途的治疗靶点。此外，疾病严重程度的变化可能受到RyR 1功能障碍导致的翻译后修饰延长或过度活跃的影响。
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.
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