Recent advances in calcium-sensing receptor structures and signaling pathways

The calcium-sensing receptor (CaSR) is a class C GPCR that has a fundamental role in extracellular calcium homeostasis by regulating parathyroid hormone release and urinary calcium excretion. Germline mutations in the receptor cause disorders of calcium homeostasis and studies of the functional effects of these mutations has facilitated understanding of CaSR signaling and how allosteric modulators affect these responses. In the past year, five cryo-EM structures of the near full-length CaSR have been published, demonstrating how agonist-binding transmits changes in the CaSR extracellular domain to the transmembrane region to activate G proteins, and how allosteric modulators affect these structural dynamics. Additionally, several recent studies have identified CaSR interacting proteins that regulate CaSR signaling and trafficking and contribute to understanding how the receptor achieves rapid and diverse physiological responses.