The calcium-sensing receptor in chronic kidney disease-mineral and bone disorder: Structural biology, biased signaling, osteoimmune crosstalk, and therapeutic implications.

The calcium-sensing receptor (CaSR) is a Family C G protein-coupled receptor (GPCR) that functions as a principal sensor of extracellular calcium ions ([Ca2+]o) and a broad-spectrum integrator of polyanionic, amino acid, and ionic stimuli. Its structural architecture - encompassing a bilobed Venus flytrap domain (VFT), cysteine-rich domain (CRD), heptahelical transmembrane domain (TMD), and an intrinsically disordered intracellular C-terminal tail - enables a remarkable allosteric landscape that goes far beyond simple on/off switching. CaSR operates as an obligate homodimer stabilized by intermolecular disulfide bonds and is embedded in macromolecular signaling complexes involving Gαq/11, Gαi, Gα12/13, β-arrestins, filamin A, and a growing proteome of scaffold and regulatory proteins. In the context of chronic kidney disease (CKD), CaSR is positioned at the intersection of mineral homeostasis and immune biology - a field increasingly recognized as osteoimmunology - where dysregulated receptor signaling drives secondary hyperparathyroidism, vascular calcification, inflammasome activation in immune cells, and osteoclast-osteoblast coupling defects. This review synthesizes current knowledge of CaSR molecular pharmacology, its structural determinants of ligand recognition, the mechanobiology of transmembrane signal propagation, and its roles in coordinating bone, immune, parathyroid, and renal cell biology within the pathological milieu of CKD. Therapeutic implications, including calcimimetics, calcilytics, and structure-guided drug design, are discussed in the context of restoring CaSR signalome homeostasis.