The calcium-sensing receptor (CaSR) regulates organismal Ca?* homeostasis. Dysregulation of CaSR expression or muta- tions in the CASR gene cause disorders of Ca2* homeostasis and contribute to the progression or severity of cancers and cardio- vascular disease. This brief review highlights recent findings that define the CasR life cycle, which controls the cellular abundance of CaSR and CasR signaling. A novel mechanism, termed ago- nist-driven insertional signaling (ADIS), contributes to the unique hallmarks of CaSR signaling, including the high degree of coop- erativity and the lack of functional desensitization. Agonist-me- diated activation of plasma membrane-localized CaSR increases the rate of insertion of CaSR at the plasma membrane without altering the constitutive endocytosis rate, thereby acutely in- creasing the maximum signaling response. Prolonged CasSR sig- naling requires a large intracellular ADIS-mobilizable pool of CaSR, which is maintained by signaling-mediated increases in biosynthesis. This model provides a rational framework for char- acterizing the defects caused by CaSR mutations and the altered functional expression of wild-type CaSR in disease states. Mech- anistic dissection of ADIS of CaSR should lead to optimized phar- macological approaches to normalize CaSR signaling in disorders of Ca?* homeostasis.
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