CaSR

The extracellular CaSR (calcium-sensing receptor is a unique G protein-coupled receptor (GPCR) activated by extracellular Ca²⁺ and by other physiological cations including Mg²⁺, amino acids, and polyamines. CaSR is the most important master controller of the extracellular Ca²⁺ homeostatic system being expressed at high levels in the parathyroid gland, kidney, gut, and bone, where it regulates parathyroid hormone (PTH) secretion, vitamin D synthesis, and Ca²⁺ absorption and resorption, respectively. Gain and loss of function mutations in the CaSR are responsible for severe disturbances in extracellular Ca²⁺ metabolism.

The CaSR stimulates two major signal transduction cascades. The first is the G_q/11-phospholipase C (PLC)-mediated generation of inositol 1,4,5-trisphosphate (IP3), which induces a rapid rise in intracellular calcium (Ca²⁺_i) concentrations. The second is the mitogen-activated protein kinases (MAPKs), such as extracellular signal-regulated kinases 1 and 2 (ERK1/2), which phosphorylate proteins mediating cytosolic signaling and translocate into the nucleus to activate transcription factors involved in cellular proliferation and differentiation. The CaSR has been shown to activate MAPK signaling in a manner that depends on the G proteins G_q/11, and G_i/o, which inhibits cyclic adenosine monophosphate (cAMP) synthesis, and by a potentially G protein-independent mechanism involving β-arrestin types 1 and 2.