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Parathyroid cells express a cell surface receptor, coupled to
the mobilization of intracellular Ca
Volume 270,
Number 21,
Issue of May 26, pp. 12919-12925, 1995
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
, that is
activated by increases in the concentration of extracellular
Ca
and by a variety of other cations. This
``Ca
receptor'' (CaR) serves as the primary
physiological regulator of parathyroid hormone secretion. Alterations
in the CaR have been proposed to underlie the increases in
Ca
set-point seen in primary hyperparathyroidism due
to parathyroid adenoma. We have isolated human CaR cDNAs from an
adenomatous parathyroid gland. The cloned receptor, expressed in
Xenopus oocytes, responds to extracellular application of
physiologically relevant concentrations of Ca
and
other CaR agonists. The rank order of potency of CaR agonists displayed
by the native receptor (Gd
> neomycin B >
Ca
> Mg
) is maintained by the
expressed receptor. The nucleotide sequence of the human CaR cDNA
predicts a protein of 1078 amino acids with high sequence similarity to
a bovine CaR, and displays seven putative membrane-spanning regions
common to G protein-coupled receptors. The deduced protein sequence
shows potential sites for N-linked glycosylation and
phosphorylation by protein kinase C and has a low level of sequence
similarity to the metabotropic glutamate receptors. Comparison of the
cDNA sequence to that of the normal human CaR gene showed no alteration
in the coding region sequence of the CaR in this particular instance of
parathyroid adenoma. Human cDNA clones with differing 5`-untranslated
regions were isolated, suggesting alternative splicing of the
parathyroid CaR mRNA. A rare variant cDNA clone representing a 10 amino
acid insertion into the extracellular domain was also isolated.
Northern blot analysis of normal and adenomatous parathyroid gland mRNA
identified a predominant transcript of
5.4 kilobases, and less
abundant transcripts of
10, 4.8 and 4.2 kilobases in RNA from the
adenoma. While there is no evidence for alteration of the primary amino
acid sequence of the CaR in this adenoma, modulation of CaR
biosynthesis through alternative RNA processing may play a role in
set-point alterations.
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