| The calcium-sensing receptor (CaSR) is a class C G protein–coupled receptor that functions as an extracellular calcium sensor, translating changes in ionized calcium concentration into coordinated endocrine and renal responses. It contains a large extracellular Venus flytrap domain that binds calcium and other polycations, a cysteine‑rich region, and a seven‑transmembrane domain that couples predominantly to Gq/11 and Gi/o proteins. Activation of Gq/11 triggers phospholipase Cβ, leading to inositol trisphosphate–mediated calcium mobilization and diacylglycerol–dependent activation of protein kinase C, while Gi/o coupling suppresses adenylate cyclase and lowers cAMP levels. In parathyroid chief cells, increased extracellular calcium engages CaSR to inhibit parathyroid hormone (PTH) secretion and promote PTH internalization, establishing a major negative feedback loop for systemic calcium homeostasis. In the kidney, CaSR signaling in the thick ascending limb and collecting duct influences calcium and magnesium reabsorption, phosphate handling, and urine concentration by interacting with transporters such as NKCC2, ROMK, and ENaC, and by intersecting with MAPK and mTOR pathways that modulate cell growth and tubular function. CaSR‑dependent signaling also contributes to regulation of vitamin D metabolism and bone turnover through its effects on PTH and downstream endocrine axes. Germline loss‑of‑function mutations in CaSR cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism, characterized by elevated serum calcium and inappropriately normal or high PTH, whereas gain‑of‑function mutations lead to autosomal dominant hypocalcemia with low calcium and suppressed PTH. |
