RT Journal Article
SR Electronic
T1 Effect of the Calcimimetic R-568 [3-(2-Chlorophenyl)-<em>N</em>-((1<em>R</em>)-1-(3-methoxyphenyl)ethyl)-1-propanamine] on Correcting Inactivating Mutations in the Human Calcium-Sensing Receptor
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 775
OP 786
DO 10.1124/jpet.109.159228
VO 331
IS 3
A1 Jenny Ying Lin Lu
A1 Yuhua Yang
A1 Gilles Gnacadja
A1 Arthur Christopoulos
A1 Jeff D. Reagan
YR 2009
UL http://jpet.aspetjournals.org/content/331/3/775.abstract
AB Over 257 mutations in the human calcium-sensing receptor (hCaSR) gene have been reported. Heterozygous inactivating mutations can result in familial hypocalciuric hypercalcemia (FHH), whereas homozygous inactivating mutations can cause life-threatening neonatal severe hyperparathyroidism (NSHPT). Activating mutations in the hCaSR can result in hypercalciuria and hypocalcemia. A recent publication on the successful treatment of a patient suffering from FHH with the hCaSR positive allosteric modulator cinacalcet prompted our interest in exploring the molecular pharmacology of calcimimetics to correct signaling defects associated with inactivating hCaSR mutations. We prepared 11 mutant hCaSRs, previously identified in patients suffering from NSHPT or FHH, and tested their ability to couple to inositol phosphate accumulation and intracellular calcium mobilization in transiently transfected human embryonic kidney 293 and Chines hamster ovary cells using the calcimimetic R-568 [3-(2-chlorophenyl)-N-((1R)-1-(3-methoxyphenyl)ethyl)-1-propanamine]. We found that extracellular Ca2+ was significantly less potent on the mutated receptors compared with wild-type hCaSR. However, R-568 was able to enhance the potency of extracellular Ca2+ toward the mutant hCaSRs. Furthermore, R-568 increased the maximal agonist response on several of the mutant CaSRs. We applied a novel operational model of allosteric modulation/agonism that provided a common mechanism to account for the behavior of the wild-type and mutant hCaSRs. The data provide evidence for the potential use of calcimimetics to treat diseases such as FHH and NSHPT where severe hypercalcemia can be life-threatening.© 2009 by The American Society for Pharmacology and Experimental Therapeutics