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Vol. 55, Issue 4, 642-648, April 1999
NPS Pharmaceuticals, Inc., Salt Lake City, Utah
The Ca2+ receptor is a G protein-coupled receptor that
enables parathyroid cells and certain other cells in the body to
respond to changes in the level of extracellular Ca2+. The
Ca2+ receptor is a member of a family of G protein-coupled
receptors that includes metabotropic glutamate receptors (mGluRs),
-aminobutyric acidB receptors, and putative pheromone
receptors. As a family, these receptors are characterized by limited
sequence homology and an unusually large putative extracellular domain
(ECD). The ECD of the mGluRs is believed to determine agonist
selectivity, but the functions of the structural domains of the
Ca2+ receptor are not known. To identify structural
determinants for cation recognition and activation of the
Ca2+ receptor (and to further study the mGluRs), two
chimeric receptors were constructed in which the large ECD of the
Ca2+ receptor and the mGluR1 were interchanged. When
expressed in Xenopus laevis oocytes, one of these
chimeras, named CaR/mGluR1 [ECD of the Ca2+ receptor and
transmembrane domain (TMD) of the mGluR1], responded to cation
agonists (Gd3+, Ca2+, neomycin) of the
Ca2+ receptor at concentrations similar to those necessary
for activation of the native Ca2+ receptor. A reciprocal
construct, named mGluR1/CaR (ECD of the mGluR1 and TMD of the
Ca2+ receptor), was responsive to mGluR agonists but was
much less sensitive to two of three cation agonists known to activate
the Ca2+ receptor. A deletion construct of the
Ca2+ receptor (
ntCaR), which lacked virtually the entire
ECD, was only activated by one of three agonists tested. These results suggest that the primary determinants for agonist activation of both
the Ca2+ receptor and the mGluRs are found in the large ECD
and that the Ca2+ receptor is possibly distinguished from
the mGluRs in that it may contain sites in the TMD that permit
activation by certain cation agonists.
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