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J. Biol. Chem., Vol. 277, Issue 37, 33736-33741, September 13, 2002
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From the The extracellular calcium
(Ca2+o)-sensing receptor (CaR) can be
potentiated by allosteric activators including calcimimetics and
L-amino acids. In this study, we found that many mutations had differential effects on the functional modulation of the CaR by
these two allosteric activators, supporting the idea that these modulators act through distinct sites. 10 mM
L-phenylalanine and 1 µM NPS R-467,
submaximal doses of the two agents, each elicited similar modulation of
R185Q. However, there are different relative potencies for these two
modulators with some receptors being more responsive to
L-phenylalanine and others being more responsive to NPS
R-467. The responsiveness of the CaR to Ca2+o
appears to be essential to observe the potentiating action of
L-phenylalanine but not of NPS R-467 on the receptor. NPS
R-467 reduces the Hill coefficients of the wild-type as well as mutant
receptors, suggesting that engagement of all Ca2+ binding
sites is not required when the receptor is activated by NPS R-467. In
contrast, L-phenylalanine has little effect on the Hill
coefficients of mutant receptors. The two-site model is further
supported by the observation that these two classes of modulators exert
a synergistic effect on CaRs with inactivating mutations that are
responsive to both modulators.
L-Phenylalanine and NPS R-467 Synergistically
Potentiate the Function of the Extracellular Calcium-sensing Receptor
through Distinct Sites*
,,,¶
Department of Medicine,
Endocrine-Hypertension Division and Membrane Biology Program,
Brigham and Women's Hospital and Harvard Medical School, Boston,
Massachusetts 02115 and § NPS Pharmaceuticals, Inc.,
Salt Lake City, Utah 84108
*
This work was supported National Institutes of Health Grant
DK54934 (to M. B.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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