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The calcium-sensing receptor (CaSR), a key member of the family C G protein-coupled receptors (GPCRs), plays a crucial role in regulating calcium homeostasis and parathyroid hormone (PTH) secretion. It responds to various physiological ligands, including calcium ions and amino acids, activating multiple signaling pathways through interactions with different G proteins and β-arrestin. This review focuses on the structural features of CaSR, emphasizing recent advances in understanding its activation mechanisms via agonists and allosteric modulators. CaSR holds significant therapeutic potential, particularly in treating calcitropic disorders such as hyperparathyroidism and hypoparathyroidism. Current pharmacological agents, including calcimimetics such as cinacalcet and etelcalcetide, have proven effective in managing secondary hyperparathyroidism (SHPT); however, they are associated with side effects such as hypocalcemia. Emerging investigational drugs, including palopegteriparatide and other small molecules, show promise in addressing various calcium-related conditions. Despite challenges that have led to the discontinuation of some drug developments, ongoing research is focused on refining CaSR-targeted therapies to improve efficacy, reduce adverse effects, and enhance patient outcomes.
Ming Yuan (Wed,) studied this question.