CaSr

Calcium-sensing receptor (CASR) is a class C G-protein-coupled receptor that monitors extracellular calcium concentration and helps maintain systemic calcium homeostasis. The receptor is encoded by the CASR gene, located on chromosome 3 in humans, and is expressed primarily in parathyroid chief cells and renal tubular cells, with additional roles in bone and other tissues. By sensing small changes in Ca2+ levels, CASR modulates parathyroid hormone (PTH) secretion and renal calcium handling.

CASR senses Ca2+ through its large extracellular Venus flytrap domain, binding Ca2+ and allosterically altering receptor activity. Activation signals mainly through Gq/11 and, to a lesser extent, Gi/o pathways, leading to phospholipase C activation, inositol trisphosphate production, intracellular calcium mobilization, and downstream effects on PTH release. In the kidney, CASR activation reduces calcium reabsorption, increasing urinary calcium excretion; in bone and intestine, it influences remodeling and calcium handling. The receptor also responds to other divalent or polyvalent cations and certain amino acids that modulate sensitivity.

Clinical relevance includes disorders caused by CASR mutations. Loss-of-function mutations cause familial hypocalciuric hypercalcemia (FHH), typically autosomal dominant, with mild hypercalcemia and low urinary calcium. Gain-of-function mutations cause autosomal dominant hypocalcemia, which can be associated with symptoms such as neuromuscular excitability. Neonatal severe hyperparathyroidism can occur in offspring of affected parents. Pharmacologically, calcimimetics such as cinacalcet and etelcalcetide activate CASR to suppress PTH in hyperparathyroid states, while calcilytics are experimental antagonists aiming to transiently raise PTH.