钙敏感受体(CaSR),C家族G蛋白偶联受体,通过感知细胞外Ca2+的微小浓度变化,在调节钙稳态中起着至关重要的作用,Mg2+,氨基酸(例如,L-Trp和L-Phe),小肽,阴离子(例如,HCO3-和PO43-),和pH。CaSR介导的细胞内Ca2+信号调节一系列不同的细胞过程,包括基因转录,细胞增殖,分化,凋亡,肌肉收缩,和神经元传递。伴随突变的CaSR功能障碍导致常染色体显性低钙血症等疾病,家族性低钙尿性高钙血症,和新生儿严重的甲状旁腺功能亢进。CaSR还影响钙化性疾病,比如骨质疏松症,和非钙性疾病,比如癌症,老年痴呆症,肺动脉高压.本研究首先回顾了CaSR框架及其与天然配体相互作用位点的生化和结构测定的最新进展,以及外源性正变构调节剂和负变构调节剂。第一个CaSR蛋白质-蛋白质相互作用组网络的建立揭示了94个参与内质网蛋白质加工的新参与者,贩运,细胞表面表达,内吞作用,降解,和信号通路。这些蛋白质在Ca2依赖性细胞生理过程和CaSR依赖性细胞信号传导中的作用提供了对由CaSR突变和由其蛋白质相互作用物引起的CaSR活性失调引起的疾病的分子基础的新见解,并促进了靶向CaSR和其他家族CG蛋白偶联受体的治疗剂的设计。
Calcium-sensing receptor (CaSR), a family C G-protein-coupled receptor, plays a crucial role in regulating calcium homeostasis by sensing small concentration changes of extracellular Ca2+, Mg2+, amino acids (e.g., L-Trp and L-Phe), small peptides, anions (e.g., HCO3 - and PO4 3-), and pH. CaSR-mediated intracellular Ca2+ signaling regulates a diverse set of cellular processes including gene transcription, cell proliferation, differentiation, apoptosis, muscle contraction, and neuronal transmission. Dysfunction of CaSR with mutations results in diseases such as autosomal dominant hypocalcemia, familial hypocalciuric hypercalcemia, and neonatal severe hyperparathyroidism. CaSR also influences calciotropic disorders, such as osteoporosis, and noncalciotropic disorders, such as cancer, Alzheimer\'s disease, and pulmonary arterial hypertension. This study first reviews recent advances in biochemical and structural determination of the framework of CaSR and its interaction sites with natural ligands, as well as exogenous positive allosteric modulators and negative allosteric modulators. The establishment of the first CaSR protein-protein interactome network revealed 94 novel players involved in protein processing in endoplasmic reticulum,
trafficking, cell surface expression, endocytosis, degradation, and signaling pathways. The roles of these proteins in Ca2+-dependent cellular physiological processes and in CaSR-dependent cellular signaling provide new insights into the molecular basis of diseases caused by CaSR mutations and dysregulated CaSR activity caused by its protein interactors and facilitate the design of therapeutic agents that target CaSR and other family C G-protein-coupled receptors.