Diao Jiayin, DeBono Aaron, Josephs Tracy M, Bourke Jane E, Capuano Ben, Gregory Karen J, Leach Katie
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
ACS Pharmacol Transl Sci. 2021 Mar 8;4(2):666-679. doi: 10.1021/acsptsci.1c00046. eCollection 2021 Apr 9.
The CaSR is a class C G protein-coupled receptor (GPCR) that acts as a multimodal chemosensor to maintain diverse homeostatic functions. The CaSR is a clinical therapeutic target in hyperparathyroidism and has emerged as a putative target in several other diseases. These include hyper- and hypocalcaemia caused either by mutations in the gene or in genes that regulate CaSR signaling and expression, and more recently in asthma. The development of CaSR-targeting drugs is complicated by the fact that the CaSR possesses many different binding sites for endogenous and exogenous agonists and allosteric modulators. Binding sites for endogenous and exogenous ligands are located throughout the large CaSR protein and are interconnected in ways that we do not yet fully understand. This review summarizes our current understanding of CaSR physiology, signaling, and structure and how the many different binding sites of the CaSR may be targeted to treat disease.
钙敏感受体（CaSR）是一种C类G蛋白偶联受体（GPCR），作为多模式化学传感器维持多种稳态功能。CaSR是甲状旁腺功能亢进症的临床治疗靶点，并已成为其他几种疾病的潜在靶点。这些疾病包括由该基因或调节CaSR信号传导和表达的基因发生突变引起的高钙血症和低钙血症，以及最近发现的哮喘。由于CaSR对内源性和外源性激动剂以及变构调节剂具有许多不同的结合位点，因此开发靶向CaSR的药物变得复杂。内源性和外源性配体的结合位点遍布整个大型CaSR蛋白，并且其相互连接方式我们尚未完全了解。本综述总结了我们目前对CaSR生理学、信号传导和结构的理解，以及如何针对CaSR的许多不同结合位点来治疗疾病。
