John Curtin School of Medical Research, Australian National University, PO Box 334, ACT 2601, Australia.
Curr Drug Targets. 2011 May;12(5):709-23. doi: 10.2174/138945011795378595.
The ryanodine receptor (RyR) calcium release channel is an essential intracellular ion channel that is central to Ca(2+) signaling and contraction in the heart and skeletal muscle. The rapid release of Ca(2+) from the internal sarcoplasmic reticulum Ca(2+) stores through the RyR during excitation-contraction coupling is facilitated by the unique arrangement of the surface and sarcoplasmic reticulum membrane systems. Debilitating and sometimes fatal skeletal and cardiomyopathies result from changes in RyR activity that disrupt normal Ca(2+) signaling. Such changes can be caused by point mutations in many different regions of the RyR protein or acquired as a result of stress associated with exercise, heart failure, age or drugs. In general, both inherited and acquired changes include an increase in RyR channel activity. Because of its central function, the RyR is a potential therapeutic target for the inherited disorders and many of the acquired disorders. The RyR is currently used as a therapeutic target in malignant hyperthermia where dantrolene is effective and to relieve ventricular arrhythmia, with the use of JTV519 and flecainide. These drugs show that the RyR is a valid therapeutic target, but have side effects that prevent their chronic use. Thus there is an urgent need for the development of skeletal and cardiac specific drugs to treat these diverse muscle disorders. In this review, we discuss the mutations that cause skeletal myopathies and cardiac arrhythmias and how these mutations pinpoint residues within the RyR protein that are functionally significant and might be developed as targets for therapeutic drugs.
兰尼碱受体（RyR）钙释放通道是一种重要的细胞内离子通道，对心脏和骨骼肌中的 Ca(2+)信号转导和收缩至关重要。兴奋-收缩偶联过程中，RyR 通过将内部肌浆网 Ca(2+)库中的 Ca(2+)快速释放到细胞外，这一过程得益于 RyR 表面和肌浆网膜系统的独特排列。RyR 活性的改变会破坏正常的 Ca(2+)信号转导，从而导致骨骼和心肌病变，这些病变有时是致命的。RyR 蛋白的许多不同区域的点突变或与运动、心力衰竭、年龄或药物相关的应激引起的获得性改变，均可导致 RyR 活性的改变。一般来说，遗传和获得性的改变都包括 RyR 通道活性的增加。由于 RyR 具有核心功能，因此它是遗传性疾病和许多获得性疾病的潜在治疗靶点。目前，RyR 被用作恶性高热的治疗靶点，达那唑在其中有效；也被用于缓解室性心律失常，使用 JTV519 和氟卡尼。这些药物表明 RyR 是一个有效的治疗靶点，但它们都有副作用，这阻止了它们的长期使用。因此，迫切需要开发针对骨骼和心脏的特异性药物来治疗这些不同的肌肉疾病。在这篇综述中，我们讨论了导致骨骼肌病和心律失常的突变，以及这些突变如何确定 RyR 蛋白中功能重要的残基，这些残基可能被开发为治疗药物的靶点。
