Hadiatullah Hadiatullah, He Zhao, Yuchi Zhiguang
Tianjin Key Laboratory for Modern Drug Delivery and High-Efficiency, Collaborative Innovation Center of Chemical Science and Engineering, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China.
Department of Molecular Pharmacology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
Front Pharmacol. 2022 May 23;13:897494. doi: 10.3389/fphar.2022.897494. eCollection 2022.
The ryanodine receptors (RyRs) are large cation-selective ligand-gated channels that are expressed in the sarcoplasmic reticulum (SR) membrane. They mediate the controlled release of Ca from SR and play an important role in many cellular processes. The mutations in RyRs are associated with several skeletal muscle and cardiac conditions, including malignant hyperthermia (MH), central core disease (CCD), catecholaminergic polymorphic ventricular tachycardia (CPVT), and arrhythmogenic right ventricular dysplasia (ARVD). Recent breakthroughs in structural biology including cryo-electron microscopy (EM) and X-ray crystallography allowed the determination of a number of near-atomic structures of RyRs, including wildtype and mutant structures as well as the structures in complex with different modulating molecules. This allows us to comprehend the physiological gating and regulatory mechanisms of RyRs and the underlying pathological mechanisms of the disease-causing mutations. In this review, based on the insights gained from the available high-resolution structures of RyRs, we address several questions: 1) what are the gating mechanisms of different RyR isoforms; 2) how RyRs are regulated by multiple channel modulators, including ions, small molecules, and regulatory proteins; 3) how do disease-causing mutations affect the structure and function of RyRs; 4) how can these structural information aid in the diagnosis of the related diseases and the development of pharmacological therapies.
兰尼碱受体（RyRs）是一种在肌浆网（SR）膜中表达的大型阳离子选择性配体门控通道。它们介导Ca从SR的可控释放，并在许多细胞过程中发挥重要作用。RyRs的突变与多种骨骼肌和心脏疾病有关，包括恶性高热（MH）、中央轴空病（CCD）、儿茶酚胺能多形性室性心动过速（CPVT）和致心律失常性右心室发育不良（ARVD）。包括冷冻电子显微镜（EM）和X射线晶体学在内的结构生物学的最新突破，使得能够确定一些RyRs的近原子结构，包括野生型和突变体结构以及与不同调节分子结合的结构。这使我们能够理解RyRs的生理门控和调节机制以及致病突变的潜在病理机制。在这篇综述中，基于从现有的RyRs高分辨率结构中获得的见解，我们回答几个问题：1）不同RyR亚型的门控机制是什么；2）RyRs如何被多种通道调节剂调节，包括离子、小分子和调节蛋白；3）致病突变如何影响RyRs的结构和功能；4）这些结构信息如何有助于相关疾病的诊断和药物治疗的开发。
