Calcium-sensing receptor signaling - How human disease informs biology

The calcium-sensing receptor (CaSR) is a class C G-protein-coupled receptor (GPCR) that plays a fundamental role in extracellular calcium homeostasis by regulating parathyroid hormone (PTH) release. Although the CaSR was identified over 25 years ago, new mechanistic details of how the CaSR controls PTH secretion have recently been uncovered demonstrating heteromerization and phosphate binding affect CaSR-mediated suppression of PTH release. In addition, understanding of how the CaSR performs diverse functions in different cellular contexts is just beginning to be elucidated, with new evidence of tissue-specific regulation, and endo-somal signaling. Insights into CaSR activation mechanisms and signaling bias have arisen from studies of CaSR mutations, which cause disorders of calcium homeostasis. Functional assessment of these mutations demonstrated the importance of the homodimer interface and transmembrane domain in biased signaling and showed CaSR mutations can facilitate G-protein-independent signaling. Population genetics studies have allowed a greater understanding of the prevalence of calcemic disorders and revealed new pathophysiological roles.