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Physiology and pathophysiology of the extracellular calcium-sensing receptor

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The calcium sensing receptor (CaSR) is a class C G protein-coupled receptor that plays a pivotal role in systemic calcium metabolism by regulating parathyroid hormone secretion and urinary calcium excretion. Abnormal CaSR function is implicated in calciotropic disorders such as hyperparathyroidism, and in ...

The calcium sensing receptor (CaSR) is a class C G protein-coupled receptor that plays a pivotal role in systemic calcium metabolism by regulating parathyroid hormone secretion and urinary calcium excretion. Abnormal CaSR function is implicated in calciotropic disorders such as hyperparathyroidism, and in non-calciotropic disorders including cancer, cardiovascular disease, respiratory disease, sarcopenia and Alzheimer’s disease, which account for >25% of the global disease burden. CaSR is a unique GPCR whose principal physiological agonist is the calcium ion. CaSR is expressed almost ubiquitously. CaSR interacts with multiple heterotrimeric G protein subtypes thereby regulating highly divergent downstream signaling pathways, depending upon cellular context. Near ubiquitous expression and lack of CaSR isoforms presents challenges in development of disease-specific treatments without concomitant on-target side effects. Current approaches include development of biased agonists and/or targeting disease-specific epigenetic changes or regulation of subcellular localization. A broad understanding of the genetic, molecular, and cellular regulation of CaSR expression and signaling is crucial to understanding both its importance in normal physiology and devising unique, targeted treatments to treat disease.


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