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2012 ; 26
(9
): 1482-95
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Minireview: the intimate link between calcium sensing receptor trafficking and
signaling: implications for disorders of calcium homeostasis
#MMPMID22745192
Breitwieser GE
Mol Endocrinol
2012[Sep]; 26
(9
): 1482-95
PMID22745192
show ga
The calcium-sensing receptor (CaSR) regulates organismal Ca(2+) homeostasis.
Dysregulation of CaSR expression or mutations in the CASR gene cause disorders of
Ca(2+) homeostasis and contribute to the progression or severity of cancers and
cardiovascular 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 agonist-driven insertional signaling (ADIS),
contributes to the unique hallmarks of CaSR signaling, including the high degree
of cooperativity and the lack of functional desensitization. Agonist-mediated
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 increasing the maximum signaling response. Prolonged CaSR
signaling 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 characterizing the defects caused by CaSR mutations and
the altered functional expression of wild-type CaSR in disease states.
Mechanistic dissection of ADIS of CaSR should lead to optimized pharmacological
approaches to normalize CaSR signaling in disorders of Ca(2+) homeostasis.