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From the
We have identified a G-protein-coupled receptor specifically
activated by parathyroid hormone, which we refer to as the PTH2
receptor. Parathyroid hormone (PTH) and parathyroid hormone-related
peptide (PTHrP, hypercalcemia of malignancy factor) activate a
previously identified PTH/PTHrP receptor, which has a widespread tissue
distribution. The PTH2 receptor is much more selective in ligand
recognition and appears to have a more specific tissue distribution. It
is activated by PTH and not by PTHrP and is particularly abundant in
the brain and pancreas.
PTH
The effects
of exogenous PTH and PTHrP are indistinguishable in most tissues (8) and on the cloned PTH/PTHrP receptor expressed in tissue
culture cells(9, 10) . The relative roles of PTH and
PTHrP are not known. Circulating PTHrP is undetectable in the adult
except for malignancies and lactating mothers(11) ; however,
PTHrP mRNA or immunoreactivity has been demonstrated in many of the
tissues that respond to exogenous PTH(12) . It is currently
thought that local PTHrP normally acts on the PTH/PTHrP receptors in
most tissues(14) .
The PTH/PTHrP receptor is a member of a
recently recognized subfamily of G-protein-coupled receptors that
includes the receptors for the glucagon-GHRH-VIP family of peptides
(glucagon, GLP-I, GIP, GHRH, VIP, secretin, PACAP) and for calcitonin
and CRF (see Ref. 15 for references). These receptors have no obvious
sequence homology with the remaining majority of G-protein-coupled
receptors but share 30-60% amino acid identity with each other.
We have now identified a new PTH-recognizing receptor, which we refer
to as the PTH2 receptor. Unlike the PTH/PTHrP receptor the PTH2
receptor recognizes PTH and not PTHrP, and it has a more circumscribed
distribution than the PTH/PTHrP receptor.
PCR using degenerate primers (3S1 and 7S3) was performed
using a rat cerebral cortex cDNA library as the template. Material
between 400 and 600 base pairs was excised from a 2% NuSieve-agarose
gel, amplified again using the same primers, digested with BamHI and EcoRI, for which restriction sites were
present in the PCR primers, and ligated into pUC18 vector. cDNA inserts
in individual bacterial colonies were sequenced, as described
previously(16) . One of these sequences, encoding a potentially
unique receptor, is referred to as CXS1.
A human genomic clone
containing the last 5 exons (to be described separately) was obtained
from a cosmid library (Stratagene) using CXS1 as a probe. PCR using
primers based on sequences within predicted exons in this clone (hCXS1f
and hCXS1g) was used to identify a clone in a human cerebral cortex
cDNA library. This clone did not contain the receptor's full
coding sequence. cDNA was synthesized from human hippocampal RNA using
random hexamer primers. Single-sided anchored PCR (anchored rapid
amplification of cDNA ends(17) ) performed using nested
antisense primers (hCXS1i and hCXS1k) derived from the partial cDNA
clone yielded an additional sequence that included the apparent
translation initiation site. PCR using Pfu polymerase
(Stratagene) with specific primers (hCXS1l and hCXS1k) generated a
fragment overlapping the first partial clone. The two fragments were
ligated at a ScaI site in the region of overlap and subcloned
into the expression vector CMVires (16) to generate hPTH2.ires.
All sequences were obtained as described previously(16) . The
final sequence was obtained from both strands of overlapping
restriction fragments from either the cDNA or genomic clones. Human
PTH/PTHrP receptor cDNA was obtained by PCR with Pfu polymerase (Stratagene) from human liver RNA using primers (PTHRup
and PTHRdn) based on the known receptor sequence (GenBank U17418) and
ligated into the vector CMVires. The human PTH/PTHrP receptor clone
obtained lacks the exon containing the putative signal peptide (bases
172-294 in GenBank U17418) but otherwise contains the published
coding sequence. PCR primers used in this study were: 3S1, 5`-ccc ggat
cc GTI GA(A/G) GGI (C/T)TI TA(C/T) (C/T)TI CA; 7S3, 5`-ccc atc gat ITC
(A/G)TT IA(A/G) (A/G)AA (A/G)CA (A/G)TA (small letters indicate
appended restriction enzyme recognition sequences, bases in parentheses
are degenerate, and I indicates inosine); hCXS1f, 5`-GGA AGC AAT ACA
GGA AA; hCXS1g, 5`-AAA GTC AGC CAC AAA TG; hCXS1i, 5`-GTC TGA AGT AAC
CAA TGA TGA; hCXS1k, 5`-TGC TTT CCT ATG CTG ATA; hCXS1l, 5`-TCC CTG CTT
CTT CCT ACA; PTHRup, 5`-gga att cGC TGC TCA GGG ACT ATC CAT; PTHRdn,
5`-gga att cAT TCA ACC ACC CAT CTT TTG.
LVIP reporter cells were
transfected with plasmids as described
previously(15, 16, 18) . COS-7 cells were
transfected using the DEAE-dextran method (19) and transferred
to 24 or 48 well plates the following day. Cells transiently expressing
the receptors were assayed for ligand-stimulated
Northern blots of human RNA (Clontech) were hybridized to random
hexamer-primed
Nucleic acid sequence analysis was performed
using the University of Wisconsin GCG package(20) , DNA
Strider(21) , and Seqman (DNASTAR, Madison WI). Peptides were
obtained from Bachem California. Human osteosarcoma cell lines Saos2
(HTB-85) and G-292 (CRL1423) were obtained from the American Type
Culture Collection (Rockville, MD).
We identified the PTH2 receptor based on its homology to
related receptors. Starting with a PCR product obtained using
degenerate primers derived from common amino acid sequences in the
third and seventh transmembrane domains of the secretin, calcitonin,
and PTH/PTHrP receptors and using a rat cerebral cortex cDNA library as
the template, we obtained human cDNAs (see ``Experimental
Procedures'') encoding a composite 2.64-kb cDNA (GenBank U25128).
It contains 143 bases of 5`-untranslated sequence, 1.65 kb of coding
sequence, and 850 bases of 3`-untranslated sequence ending in an
authentic poly(A) sequence (based on comparison with the gene
sequence). The deduced amino acid sequence is shown in Fig. 1.
The sequence is a member of the subfamily that includes the receptors
for secretin, VIP, GLP-I, PACAP, glucagon, GIP, GHRH, PTH, calcitonin,
and CRF. The similarity of the deduced amino acid sequences of these
receptors ranges from 32% (CRF receptor) to 70% (PTH/PTHrP receptor)
identity. The PTH2 receptor has a number of features that are
characteristic of this receptor subfamily, including a potential signal
sequence (absent in most other G-protein-coupled receptors), a
hydrophilic, predicted extracellular amino terminus of 138 residues
that contains 6 conserved cysteine residues, and several highly
conserved stretches of amino acids within the putative transmembrane
domains. Several recent studies suggest that the amino-terminal domain
contributes significantly to ligand binding
specificity(22, 23, 24, 25, 26) .
The amino terminus of the PTH/PTHrP receptor contains a 45-amino acid
domain encoded by a distinct exon (exon E2) that can be deleted without
apparent effect on function of the receptor(27) . There is no
homologous sequence in the PTH2 receptor and no indication in our PCR
reactions of a larger species, which might contain an additional exon.
Thirty-three of 67 residues in the amino-terminal domains are identical
between the PTH2 receptor and the PTH/PTHrP receptor when the potential
signal sequences and the PTH/PTHrP receptor exon E2 are not considered.
hPTH-(1-34) potently activates the
PTH2 receptor expressed in COS-7 cells (EC
We have identified a novel PTH receptor, which we call the
PTH2 receptor. The most notable difference from the PTH/PTHrP receptor
is that it is recognized by PTH and not by PTHrP. An attractive
possibility would be for the PTH2 receptor to mediate the effects of
circulating PTH, thus providing selectivity. However, our preliminary
investigation suggests that the PTH2 receptor is likely not to mediate
the major effects of PTH on calcium and phosphate metabolism. Messenger
RNA encoding the PTH2 receptor is not abundant in kidney or in the two
bone-derived cell lines that we examined, all of which contain
PTH/PTHrP receptor mRNA. The PTH2 receptor is most likely to function
in the brain and pancreas where its mRNA is particularly abundant, and
possibly in the testis and placenta.
The broad distribution of PTHrP
and the PTH/PTHrP receptor in the brain has lead to the proposal that
PTHrP is a neurotransmitter(29) . While attention is generally
focused on PTH synthesized in the parathyroid gland there is also
evidence for authentic PTH in the brain, particularly in several
hypothalamic nuclei(30, 31) . Intracerebral
administration of PTH affects dopamine metabolism (32) and
prolactin release (33) and has effects on memory,
nociperception, and serum Ca
The extracellular amino-terminal domain of the
PTH/PTHrP receptor appears to be a major determinant of ligand binding
specificity (22) as does the homologous domain of related
receptors(22, 23, 24, 25, 26) .
Considerable insight into the receptor residues involved in ligand
recognition has been gained by studying chimeras between species
homologs of the PTH/PTHrP receptor (22) and by site-directed
mutagenesis(27) . The ability of the PTH2 receptor to
discriminate between PTH and PTHrP peptides and the high degree of
similarity between the PTH2 and PTH/PTHrP receptors should prove useful
in further characterizing the residues within both receptors that are
responsible for ligand specificity.
The potential role of the PTH2
receptor in disease and its usefulness in drug design are also areas
for future exploration. While the PTH2 receptor does not appear
abundant in kidney or bone where PTH is thought to exert most of its
effects on mineral balance, recent data suggest that PTH also affects
serum calcium through an action in the brain(34) , where the
PTH2 receptor is quite abundant. Thus the PTH2 receptor may play a role
in mineral balance as well as other central nervous system and
pancreatic functions. While the possibility of another endogenous
ligand cannot be excluded, the high affinity and selectivity of the
PTH2 receptor for PTH suggests that PTH is the native ligand.
The nucleotide sequence(s) reported in this paper has been
submitted to the GenBank
Volume 270,
Number 26,
Issue of June 30, pp. 15455-15458, 1995
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
()regulates calcium and phosphate
homeostasis through its action on specific receptors in kidney and
bone. PTHrP was identified as an activity released from tumors that
cause elevated serum calcium and was originally referred to as
hypercalcemia of malignancy factor (for review, see Refs. 1 and 2).
PTHrP and PTH are products of distinct genes but have in common 8 out
of their first 13 amino acids, and both activate a cloned PTH/PTHrP
receptor(3, 4) . PTH has effects in a number of tissues
in addition to bone and kidney, including the heart, brain, liver,
testis, pancreas, uterus, placenta, and blood cells (for references,
see Ref. 5). While mRNA encoding the PTH/PTHrP receptor is particularly
abundant in kidney and bone, the receptor has a very widespread
distribution (5, 6) and has been demonstrated in most of
the tissues with PTH responses (for review, see Ref. 7).
-galactosidase
activity (LVIP cells) or cAMP (COS-7 cells) 72 or 96 h following
transfection, as described previously (15) except that
isobutylmethylxanthine was omitted from the LVIP incubation. LVIP
reporter cells stably expressing the PTH2 receptor were generated
following growth in G418 and selection of individual colonies.
P-labeled probes corresponding to
nucleotides 113-653 of the hPTH2 receptor, nucleotides
536-934 of the PTH/PTHrP receptor (GenBank U17418), or
nucleotides 296-693 of mouse neuron-specific enolase (GenBank
X52380; 91% identity with the human sequence). Hybridization was
performed in 5
SSPE, 10
Denhardt's solution, 50%
formamide, 2% SDS containing 100 µg/ml salmon DNA at 42 °C
overnight, and blots were washed to a final stringency of 0.2
SSPE at 60 °C and exposed to a PhosphorImager plate (Fuji
Biomedical BAS2000).
Figure 1:
Alignment of the deduced
amino acid sequences of the human PTH2 and PTH/PTHrP (GenBank U17418)
receptors. Sequence alignment used the GAP algorithm of the GCG package
(20). Amino acid identities are indicated by verticallines and similar residues by dots; potential
transmembrane domains are shaded, and conserved cysteine
residues in the predicted extracellular regions are enclosed in boxes.
The ligand(s) activating the newly cloned PTH2 receptor was
initially identified by screening LVIP reporter cells transiently
expressing the receptor (LVIP cells are mouse L cells stably expressing
a cAMP-responsive element fused to the bacterial lacZ gene so
that activation of adenylyl cyclase leads to -galactosidase
accumulation(18) ). Of the ligands for the known members of the
receptor subfamily and related peptides screened at 1 µM concentration, only PTH activated the receptor (data not shown).
The response in LVIP cells transiently expressing the receptor is
relatively small. To improve the signal-to-noise ratio, experiments
were performed by transient expression in COS-7 cells with
radioimmunoassay of cAMP, and LVIP cells stably expressing the PTH2
receptor were selected.
0.86 ±
0.031 nM, data from three independent transfections of COS-7
cells, mean ± S.E.) while PTHrP-(1-36) had little or no
effect (Fig. 2). In transfected COS-7 cells, in which
hPTH-(1-34) produces a 5-25-fold increase in cAMP over the
basal level no effect of 1 µM PTHrP-(1-36) was
detected. The PTH/PTHrP receptor does not discriminate between PTH and
PTHrP(3, 4) . To verify that the lack of effect of PTHrP
at the PTH2 receptor was a property of the receptor, and not our
experimental conditions, we obtained a human PTH/PTHrP receptor clone
by PCR. The clone that we obtained lacks the signal peptide encoding
exon present in the previously described sequences and probably uses a
different initiating methionine. However, the predicted amino acid
sequence lacks only the first two residues past the predicted signal
peptide of the previously characterized receptor. When expressed in
COS-7 cells this PTH/PTHrP receptor responds to both hPTH-(1-34)
and PTHrP-(1-36) as expected (Fig. 2) confirming that the
lack of effect of PTHrP on the PTH2 receptor is a property of that
protein. Maximal activation of the PTH/PTHrP receptor consistently led
to less accumulation of cAMP than activation of the PTH2 receptor,
which may be due to less efficient expression of the PTH/PTHrP receptor
clone lacking its signal peptide. LVIP cells provide a less direct but
more sensitive assay of receptor activation. PTHrP-(1-36)
produces a small signal at 1 µM in LVIP cells stably
expressing the PTH2 receptor, equivalent to
50,000-fold less
hPTH-(1-34) (Fig. 3).
[Nle
,Tyr
]bovine
PTH-(1-34)amide is slightly less potent than hPTH-(1-34).
No increase in cAMP over basal levels was produced by any of these
peptides in COS-7 or LVIP cells that were not transfected with one of
the receptors.
Figure 2:
Stimulation of cAMP accumulation in COS-7
cells transiently expressing the PTH2 ( and
) or PTH/PTHrP
( and
) receptor. Seventy-two hours following transfection
cells were stimulated with the indicated concentrations of
hPTH-(1-34) ( and ) or PTHrP-(1-36) ( and
) for 10 min at room temperature, and cAMP in aliquots of cell
lysate was determined as described previously (15). Data represent the
mean ± S.D. of triplicate wells from one
experiment.
Figure 3:
Stimulation of adenylyl cyclase in LVIP
reporter cells stably expressing the PTH2 receptor. Cells were
incubated with the indicated peptides for 6 h at 37 °C, and then
-galactosidase accumulation was determined. Data represent the
mean ± S.D. of quadruplicate determinations from one
experiment.
A Northern blot containing human mRNA was hybridized
with a probe derived from the PTH2 receptor sequence (Fig. 4, a and b). The strongest signal is a single 3.5-kb
band in brain RNA followed by 3.2- and 1.5-kb bands in the pancreas. We
do not know whether the 1.5-kb band represents a distinct gene product.
Because the blot was washed at high stringency it seems more likely
that it represents an alternatively spliced mRNA. We do not know
whether it codes for a functional protein since it is shorter than the
coding sequence of the cDNA that we obtained. The testis and placenta
samples contain less intense bands of 3.0-3.5 kb (while the lane
containing the placenta sample is adjacent to the brain sample,
hybridization with neuron-specific enolase suggests that the signal is
not due to spillover). The cDNA sequences we obtained account for 2.64
kb. Since the cDNA contains a nonstandard polyadenylation signal
(AATTAAA instead of AATAAA) an alternative polyadenylation site might
account for some of the difference. Hybridization of a PTH/PTHrP
receptor probe to the same Northern blot (Fig. 4, c and d) confirmed that distinct species are detected and emphasized
that the distribution of the PTH/PTHrP receptor is much more widespread
than that of the PTH2 receptor. The PTH/PTHrP receptor is particularly
abundant in kidney, as previously reported(4, 28) ,
while PTH2 receptor mRNA is not detected in the kidney by this
procedure. Using reverse transcription PCR we failed to detect mRNA for
the PTH2 receptor in RNA prepared from human osteosarcoma cell lines
(Saos2 and G-292; data not shown).
Figure 4:
Northern blots of human mRNA hybridized to
probes recognizing the PTH2 receptor (upper panels) or the
PTH/PTHrP receptor (lower panels). Blots were hybridized to
random hexamer-primed P-labeled cDNA probes and exposed
for 72 h (PTH2) or 8 h (PTH/PTHrP) to a PhosphorImager plate (Fuji
Biomedical BAS2000).
(33, 34) .
It is not clear whether PTH or PTHrP normally has these effects or
whether there is a distinction between the actions of endogenous PTH
and PTHrP in the brain. In the areas of the rat brain where PTH mRNA
has been demonstrated most clearly, the paraventricular and supraoptic
nuclei of the hypothalamus(31) , PTH/PTHrP receptor mRNA levels
are relatively low(29) , and both PTHrP and PTH/PTHrP receptor
mRNA are absent from the ventromedial nucleus (29) where PTH effects on
neuronal firing have been demonstrated(34) . PTH effects on the
function of endocrine (35, 36, 37) as well as
exocrine (38) cells in the pancreas have been described. PTH effects on
the placenta have also been described (39) although the role of
PTHrP in placental function is being studied more
actively(40, 41) . Effects of PTH in the testis have not
been described.
/EMBL Data Bank with accession
number(s) U25128.
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
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G. Mazzocchi, F. Aragona, L. K. Malendowicz, and G. G. Nussdorfer PTH and PTH-related peptide enhance steroid secretion from human adrenocortical cells Am J Physiol Endocrinol Metab, February 1, 2001; 280(2): E209 - E213. [Abstract] [Full Text] [PDF]
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S. R. J. Hoare and T. B. Usdin Tuberoinfundibular Peptide (7-39) [TIP(7-39)], a Novel, Selective, High-Affinity Antagonist for the Parathyroid Hormone-1 Receptor with No Detectable Agonist Activity J. Pharmacol. Exp. Ther., November 1, 2000; 295(2): 761 - 770. [Abstract] [Full Text]
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S. R. J. Hoare, D. A. Rubin, H. Juppner, and T. B. Usdin Evaluating the Ligand Specificity of Zebrafish Parathyroid Hormone (PTH) Receptors: Comparison of PTH, PTH-Related Protein, and Tuberoinfundibular Peptide of 39 Residues Endocrinology, September 1, 2000; 141(9): 3080 - 3086. [Abstract] [Full Text] [PDF]
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C. M. Isales, B. Sumpio, R. J. Bollag, Q. Zhong, K.-H. Ding, W. Du, J. Rodriguez-Commes, R. Lopez, O. R. Rosales, J. Gasalla-Herraiz, et al. Functional parathyroid hormone receptors are present in an umbilical vein endothelial cell line Am J Physiol Endocrinol Metab, September 1, 2000; 279(3): E654 - E662. [Abstract] [Full Text] [PDF]
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 S. M. Jan de Beur, C.-L. Ding, M. C. LaBuda, T. B. Usdin, and M. A. Levine Pseudohypoparathyroidism 1b: Exclusion of Parathyroid Hormone and Its Receptors as Candidate Disease Genes J. Clin. Endocrinol. Metab., June 1, 2000; 85(6): 2239 - 2246. [Abstract] [Full Text]
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 J. Loughlin, Z. Mustafa, A. Smith, C. Irven, A. J. Carr, K. Clipsham, J. Chitnavis, V. A. Bloomfield, M. McCartney, O. Cox, et al. Linkage analysis of chromosome 2q in osteoarthritis Rheumatology, April 1, 2000; 39(4): 377 - 381. [Abstract] [Full Text] [PDF]
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V. Behar, A. Bisello, G. Bitan, M. Rosenblatt, and M. Chorev Photoaffinity Cross-linking Identifies Differences in the Interactions of an Agonist and an Antagonist with the Parathyroid Hormone/Parathyroid Hormone-related Protein Receptor J. Biol. Chem., January 7, 2000; 275(1): 9 - 17. [Abstract] [Full Text] [PDF]
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P. H. Carter, H. Jüppner, and T. J. Gardella Studies of the N-Terminal Region of a Parathyroid Hormone-Related Peptide(1-36) Analog: Receptor Subtype-Selective Agonists, Antagonists, and Photochemical Cross-Linking Agents Endocrinology, November 1, 1999; 140(11): 4972 - 4981. [Abstract] [Full Text]
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 M. Mannstadt, H. Juppner, and T. J. Gardella Receptors for PTH and PTHrP: their biological importance and functional properties Am J Physiol Renal Physiol, November 1, 1999; 277(5): F665 - F675. [Abstract] [Full Text] [PDF]
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S. R. J. Hoare, T. I. Bonner, and T. B. Usdin Comparison of Rat and Human Parathyroid Hormone 2 (PTH2) Receptor Activation: PTH Is a Low Potency Partial Agonist at the Rat PTH2 Receptor Endocrinology, October 1, 1999; 140(10): 4419 - 4425. [Abstract] [Full Text]
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D. A. Rubin and H. Juppner Zebrafish Express the Common Parathyroid Hormone/Parathyroid Hormone-related Peptide Receptor (PTH1R) and a Novel Receptor (PTH3R) That Is Preferentially Activated by Mammalian and Fugufish Parathyroid Hormone-related Peptide J. Biol. Chem., October 1, 1999; 274(40): 28185 - 28190. [Abstract] [Full Text] [PDF]
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V. Behar, A. Bisello, M. Rosenblatt, and M. Chorev Direct Identification of Two Contact Sites for Parathyroid Hormone (PTH) in the Novel PTH-2 Receptor using Photoaffinity Cross-Linking Endocrinology, September 1, 1999; 140(9): 4251 - 4261. [Abstract] [Full Text]
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D. A. Rubin, P. Hellman, L. I. Zon, C. J. Lobb, C. Bergwitz, and H. Juppner A G Protein-coupled Receptor from Zebrafish Is Activated by Human Parathyroid Hormone and Not by Human or Teleost Parathyroid Hormone-related Peptide. IMPLICATIONS FOR THE EVOLUTIONARY CONSERVATION OF CALCIUM-REGULATING PEPTIDE HORMONES J. Biol. Chem., August 13, 1999; 274(33): 23035 - 23042. [Abstract] [Full Text] [PDF]
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 G. R. Mundy and T. A. Guise Hormonal Control of Calcium Homeostasis Clin. Chem., August 1, 1999; 45(8): 1347 - 1352. [Abstract] [Full Text] [PDF]
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A. J. Koh, C. A. Beecher, T. J. Rosol, and L. K. McCauley 3',5'-Cyclic Adenosine Monophosphate Activation in Osteoblastic Cells: Effects on Parathyroid Hormone-1 Receptors and Osteoblastic Differentiation in Vitro Endocrinology, July 1, 1999; 140(7): 3154 - 3162. [Abstract] [Full Text]
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T. B. Usdin, J. Hilton, T. Vertesi, G. Harta, G. Segre, and E. Mezey Distribution of the Parathyroid Hormone 2 Receptor in Rat: Immunolocalization Reveals Expression by Several Endocrine Cells Endocrinology, July 1, 1999; 140(7): 3363 - 3371. [Abstract] [Full Text]
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R. L. Sutliff, C. S. Weber, J. Qian, M. L. Miller, T. L. Clemens, and R. J. Paul Vasorelaxant Properties of Parathyroid Hormone-Related Protein in the Mouse: Evidence for Endothelium Involvement Independent of Nitric Oxide Formation Endocrinology, May 1, 1999; 140(5): 2077 - 2083. [Abstract] [Full Text]
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J. Qian, J. N. Lorenz, S. Maeda, R. L. Sutliff, C. Weber, T. Nakayama, M. C. Colbert, R. J. Paul, J. A. Fagin, and T. L. Clemens Reduced Blood Pressure and Increased Sensitivity of the Vasculature to Parathyroid Hormone-Related Protein (PTHrP) in Transgenic Mice Overexpressing the PTH/PTHrP Receptor in Vascular Smooth Muscle Endocrinology, April 1, 1999; 140(4): 1826 - 1833. [Abstract] [Full Text]
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M. L. Brines and A. E. Broadus Parathyroid Hormone-Related Protein Markedly Potentiates Depolarization-Induced Catecholamine Release in PC12 Cells via L-Type Voltage-Sensitive Ca2+ Channels Endocrinology, February 1, 1999; 140(2): 646 - 651. [Abstract] [Full Text]
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B. Lanske, P. Divieti, C. S. Kovacs, A. Pirro, W. J. Landis, S. M. Krane, F. R. Bringhurst, and H. M. Kronenberg The Parathyroid Hormone (PTH)/PTH-Related Peptide Receptor Mediates Actions of Both Ligands in Murine Bone Endocrinology, December 1, 1998; 139(12): 5194 - 5204. [Abstract] [Full Text] [PDF]
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A. Bisello, A. E. Adams, D. F. Mierke, M. Pellegrini, M. Rosenblatt, L. J. Suva, and M. Chorev Parathyroid Hormone-Receptor Interactions Identified Directly by Photocross-linking and Molecular Modeling Studies J. Biol. Chem., August 28, 1998; 273(35): 22498 - 22505. [Abstract] [Full Text] [PDF]
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M. Mannstadt, M. D. Luck, T. J. Gardella, and H. Juppner Evidence for a Ligand Interaction Site at the Amino-Terminus of the Parathyroid Hormone (PTH)/PTH-related Protein Receptor from Cross-linking and Mutational Studies J. Biol. Chem., July 3, 1998; 273(27): 16890 - 16896. [Abstract] [Full Text] [PDF]
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M. Eggenberger, R. A. McKinney, J. A. Fischer, and R. Muff Differential Expression of Calcitonin and Parathyroid Hormone/Parathyroid Hormone-Related Protein Receptors in P19 Embryonic Carcinoma Cells Treated with Retinoic Acid Endocrinology, March 1, 1998; 139(3): 1023 - 1030. [Abstract] [Full Text] [PDF]
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P. R. Turner, S. Mefford, T. Bambino, and R. A. Nissenson Transmembrane Residues Together with the Amino Terminus Limit the Response of the Parathyroid Hormone (PTH) 2 Receptor to PTH-related Peptide J. Biol. Chem., February 13, 1998; 273(7): 3830 - 3837. [Abstract] [Full Text] [PDF]
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T. A. Guise and G. R. Mundy Cancer and Bone Endocr. Rev., February 1, 1998; 19(1): 18 - 54. [Abstract] [Full Text]
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J. A. Clark, T. I. Bonner, A. S. Kim, and T. B. Usdin Multiple Regions of Ligand Discrimination Revealed by Analysis of Chimeric Parathyroid Hormone 2 (PTH2) and PTH/PTH-Related Peptide (PTHrP) Receptors Mol. Endocrinol., February 1, 1998; 12(2): 193 - 206. [Abstract] [Full Text]
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C. Bergwitz, P. Klein, H. Kohno, S. A. Forman, K. Lee, D. Rubin, and H. Juppner Identification, Functional Characterization, and Developmental Expression of Two Nonallelic Parathyroid Hormone (PTH)/PTH-Related Peptide Receptor Isoforms in Xenopus laevis (Daudin) Endocrinology, February 1, 1998; 139(2): 723 - 732. [Abstract] [Full Text] [PDF]
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S. Fukayama, M. Royo, M. Sugita, A. Imrich, M. Chorev, L. J. Suva, M. Rosenblatt, and A. H. Tashjian Jr. New insights into interactions between the human PTH/PTHrP receptor and agonist/antagonist binding Am J Physiol Endocrinol Metab, February 1, 1998; 274(2): E297 - E303. [Abstract] [Full Text] [PDF]
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S. Yamamoto, I. Morimoto, K. Zeki, Y. Ueta, H. Yamashita, H. Kannan, and S. Eto Centrally Administered Parathyroid Hormone (PTH)-Related Protein(1-34) But Not PTH(1-34) Stimulates Arginine-Vasopressin Secretion and Its Messenger Ribonucleic Acid Expression in Supraoptic Nucleus of the Conscious Rats Endocrinology, January 1, 1998; 139(1): 383 - 388. [Abstract] [Full Text] [PDF]
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A.-S. Jobert, C. Leroy, D. Butlen, and C. Silve Parathyroid Hormone-Induced Calcium Release from Intracellular Stores in a Human Kidney Cell Line in the Absence of Stimulation of Cyclic Adenosine 3',5'-Monophosphate Production Endocrinology, December 1, 1997; 138(12): 5282 - 5292. [Abstract] [Full Text] [PDF]
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C. Bergwitz, S. A. Jusseaume, M. D. Luck, H. Juppner, and T. J. Gardella Residues in the Membrane-spanning and Extracellular Loop Regions of the Parathyroid Hormone (PTH)-2 Receptor Determine Signaling Selectivity for PTH and PTH-related Peptide J. Biol. Chem., November 14, 1997; 272(46): 28861 - 28868. [Abstract] [Full Text] [PDF]
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L. J. Suva, M. S. Flannery, M. P. Caulfield, D. M. Findlay, H. Jüppner, S. R. Goldring, M. Rosenblatt, and M. Chorev Design, Synthesis and Utility of Novel Benzophenone-Containing Calcitonin Analogs for Photoaffinity Labeling the Calcitonin Receptor J. Pharmacol. Exp. Ther., November 1, 1997; 283(2): 876 - 884. [Abstract] [Full Text]
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E. Schipani, G. S. Jensen, J. Pincus, R. A. Nissenson, T. J. Gardella, and H. Jüppner Constitutive Activation of the Cyclic Adenosine 3',5'-Monophosphate Signaling Pathway by Parathyroid Hormone (PTH)/PTH-Related Peptide Receptors Mutated at the Two Loci for Jansen's Metaphyseal Chondrodysplasia Mol. Endocrinol., June 1, 1997; 11(7): 851 - 858. [Abstract] [Full Text]
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S. Yamamoto, I. Morimoto, N. Yanagihara, K. Zeki, T. Fujihira, F. Izumi, H. Yamashita, and S. Eto Parathyroid Hormone-Related Peptide-(1-34) [PTHrP- (1-34)] Induces Vasopressin Release from the Rat Supraoptic Nucleus in Vitro through a Novel Receptor Distinct from a Type I or Type II PTH/PTHrP Receptor Endocrinology, May 1, 1997; 138(5): 2066 - 2072. [Abstract] [Full Text] [PDF]
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J. D. Bettoun, M. Minagawa, M. Y. Kwan, H. S. Lee, T. Yasuda, G. N. Hendy, D. Goltzman, and J. H. White Cloning and Characterization of the Promoter Regions of the Human Parathyroid Hormone (PTH)/PTH-Related Peptide Receptor Gene: Analysis of Deoxyribonucleic Acid from Normal Subjects and Patients with Pseudohypoparathyroidism Type 1b J. Clin. Endocrinol. Metab., April 1, 1997; 82(4): 1031 - 1040. [Abstract] [Full Text] [PDF]
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H. Joun, B. Lanske, M. Karperien, F. Qian, L. Defize, and A. Abou-Samra Tissue-Specific Transcription Start Sites and Alternative Splicing of the Parathyroid Hormone (PTH)/PTH-Related Peptide (PTHrP) Receptor Gene: A New PTH/PTHrP Receptor Splice Variant that Lacks the Signal Peptide Endocrinology, April 1, 1997; 138(4): 1742 - 1749. [Abstract] [Full Text] [PDF]
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A. Iida-Klein, J. Guo, M. Takemura, M. T. Drake, J. T. Potts Jr., A. Abou-Samra, F. R. Bringhurst, and G. V. Segre Mutations in the Second Cytoplasmic Loop of the Rat Parathyroid Hormone (PTH)/PTH-related Protein Receptor Result in Selective Loss of PTH-stimulated Phospholipase C Activity J. Biol. Chem., March 14, 1997; 272(11): 6882 - 6889. [Abstract] [Full Text] [PDF]
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N. Amizuka, H. S. Lee, M. Y. Kwan, A. Arazani, H. Warshawsky, G. N. Hendy, H. Ozawa, J. H. White, and D. Goltzman Cell-Specific Expression of the Parathyroid Hormone (PTH)/PTH-Related Peptide Receptor Gene in Kidney from Kidney-Specific and Ubiquitous Promoters Endocrinology, January 1, 1997; 138(1): 469 - 481. [Abstract] [Full Text] [PDF]
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C. S. Kovacs, B. Lanske, J. L. Hunzelman, J. Guo, A. C. Karaplis, and H. M. Kronenberg Parathyroid hormone-related peptide (PTHrP) regulates fetal-placental calcium transport through a receptor distinct from the PTH/PTHrP receptor PNAS, December 24, 1996; 93(26): 15233 - 15238. [Abstract] [Full Text] [PDF]
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E. H. Holt, A. E. Broadus, and M. L. Brines Parathyroid Hormone-related Peptide Is Produced by Cultured Cerebellar Granule Cells in Response to L-type Voltage-sensitive Ca2+ Channel Flux via a Ca2+/Calmodulin-dependent Kinase Pathway J. Biol. Chem., November 8, 1996; 271(45): 28105 - 28111. [Abstract] [Full Text] [PDF]
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T. J. Gardella, M. D. Luck, G. S. Jensen, T. B. Usdin, and H. Juppner Converting Parathyroid Hormone-related Peptide (PTHrP) into a Potent PTH-2 Receptor Agonist J. Biol. Chem., August 16, 1996; 271(33): 19888 - 19893. [Abstract] [Full Text] [PDF]
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A. Azarani, D. Goltzman, and J. Orlowski Structurally Diverse N-terminal Peptides of Parathyroid Hormone (PTH) and PTH-related Peptide (PTHRP) Inhibit the Na+/H+ Exchanger NHE3 Isoform by Binding to the PTH/PTHRP Receptor Type I and Activating Distinct Signaling Pathways J. Biol. Chem., June 21, 1996; 271(25): 14931 - 14936. [Abstract] [Full Text] [PDF]
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A. Piserchio, T. Usdin, and D. F. Mierke Structure of Tuberoinfundibular Peptide of 39 Residues J. Biol. Chem., August 25, 2000; 275(35): 27284 - 27290. [Abstract] [Full Text] [PDF]
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S. R. J. Hoare, J. A. Clark, and T. B. Usdin Molecular Determinants of Tuberoinfundibular Peptide of 39 Residues (TIP39) Selectivity for the Parathyroid Hormone-2 (PTH2) Receptor. N-TERMINAL TRUNCATION OF TIP39 REVERSES PTH2 RECEPTOR/PTH1 RECEPTOR BINDING SELECTIVITY J. Biol. Chem., August 25, 2000; 275(35): 27274 - 27283. [Abstract] [Full Text] [PDF]
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J. T. Swarthout, T. A. Doggett, J. L. Lemker, and N. C. Partridge Stimulation of Extracellular Signal-regulated Kinases and Proliferation in Rat Osteoblastic Cells by Parathyroid Hormone Is Protein Kinase C-dependent J. Biol. Chem., March 2, 2001; 276(10): 7586 - 7592. [Abstract] [Full Text] [PDF]
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A. Dobolyi, H. Ueda, H. Uchida, M. Palkovits, and T. B. Usdin Anatomical and physiological evidence for involvement of tuberoinfundibular peptide of 39 residues in nociception PNAS, February 5, 2002; 99(3): 1651 - 1656. [Abstract] [Full Text] [PDF]
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