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(Received for publication, August 18, 1995; and in revised form, September 5, 1995) From the
The pancreatic polypeptide family includes pancreatic
polypeptide (PP), neuropeptide Y (NPY), and peptide YY (PYY). Members
of the PP family regulate numerous physiological processes, including
appetite, gastrointestinal transit, anxiety, and blood pressure. Of the
multiple Y-type receptors proposed for PP family members, only the Y1
subtype has been cloned previously. We now report the cloning of an
additional Y-type receptor, designated Y4, by homology screening of a
human placental genomic library with transmembrane (TM) probes derived
from the rat Y1 gene. The Y4 genomic clone encodes a predicted protein
of 375 amino acids that is most homologous to Y1 receptors from human,
rat, and mouse (42% overall; 55% in TM).
The pancreatic polypeptide family includes pancreatic
polypeptide (PP), ( At least five
receptor subtypes have been proposed for PP family members(1) :
1) Y1 binds NPY, PYY, and
[Leu
A human genomic placenta library was screened, under reduced
stringency conditions, with oligonucleotide probes directed to the
first, second, third, fifth, and seventh TM regions of the rat Y1
neuropeptide receptor gene. One positive hybridizing phage clone called
hp25a, whose gene product will be referred to in this report as hY4,
was characterized by Southern blot analysis to reveal a 1.3-kb PstI fragment and further analyzed by subcloning and
sequencing. DNA sequence analysis indicated greatest homology to the
rat and human Y1 receptor genes. Since this clone represented a partial
intronless gene fragment, the full-length gene was subcloned as a
2.0-kb BamHI/EcoRI hybridizing fragment into an
expression vector and sequenced. The genomic full-length construct
contains an open reading frame of 1125 bp (intronless), with 680 bp
upstream and 205 bp downstream of the coding region. The gene would be
predicted to encode a protein of 375 amino acids, with a predicted
molecular mass of Initial
sequence analysis revealed that hY4 contained several structural
features/residues (see Fig. 1) found among the members of the
neuropeptide receptor family, including two glycines and an asparagine
in TM1 (positions 55, 58, and 59, respectively), an asparagine,
leucine, and aspartic acid in TM2 (positions 82, 83, and 87,
respectively), a serine and leucine in TM3 (positions 128 and 132,
respectively), a tryptophan and proline in TM4 (positions 164 and 173,
respectively), a tyrosine and proline in TM5 (positions 223 and 226,
respectively), a phenylalanine, tryptophan, and proline in TM6
(positions 274, 278, and 280, respectively), and a serine, threonine,
asparagine, and proline in TM7 (positions 314, 315, 318, and 319,
respectively). Other features of hY4 are the presence of three
potential sites for N-linked glycosylation in the amino
terminus (asparagine residues 2, 19, and 29; Fig. 1) and the
presence of several serines and threonines in the carboxyl terminus and
intracellular loops, which may serve as sites for potential
phosphorylation by protein kinases. It is interesting that the sequence
ERH (Glu-Arg-His), which is immediately downstream of TM3, is also
contained in the hY1 sequence; this is distinct from the DRY
(Asp-Arg-Tyr) sequence which occurs in most members of the
G-protein-coupled receptor superfamily. Additionally, two of the three
potential N-linked glycosylation sites found in hY4 are also
present in the corresponding positions in the hY1 receptor.
Figure 1:
Amino acid sequence alignment of human
Y4 (hp25a clone) with human Y1 and Y2 receptors. The deduced amino acid
sequence of the human Y4 receptor (first line) is aligned with the
human Y1 receptor (12) and the human Y2 receptor clone (see
accompanying paper(36) ). Periods represent added spaces
necessary for proper alignment. Gray shading indicates
residues in receptors which are identical to Y4. Numbers correspond to amino acid positions of Y4 (M). The seven
putative transmembrane domains are boxed and numbered I-VII. Black circles indicate potential N-linked glycosylation sites in the NH
A
comparison of nucleotide and peptide sequences of hY4 with sequences
contained in the GenBank(TM)/EMBL data bases reveals that the clone
is most related to the rat, mouse, Xenopus, and human Y1
receptor genes and proteins. At the nucleotide level there is 58%
identity between hY4 and hY1; at the amino acid level there is 42%
identity overall, 55% in TM domains, with the greatest identity of 71%
in TM7 (Fig. 1). A similar comparison of hY4 with the cloned
human Y2 (hY2) gene (see accompanying paper by Gerald et
al.(36) ) reveals lower homology; hY4 versus hY2
nucleotide identity is 57% and amino acid identity is 34% overall, with
43% in TM domains (see also Fig. 1). Southern blot analysis on
human genomic DNA suggest that the genome contains a single Y4 gene
(data not shown). Human Y4 mRNA was detected by reverse
transcriptase-PCR using specific hY4 primers in a broad range of human
tissues (Fig. 2). Relatively intense hybridization signals were
detected in total brain (including the hypothalamus), coronary artery,
and ileum. Liver failed to express hY4 mRNA, whereas pancreas and
kidney exhibited very low levels of expression. Interestingly, the
endometrium and myometrium of the uterus displayed differential
expression, with the former containing higher levels of Y4 mRNA than
the latter. No signal was observed when either the RNA was absent
(distilled H
Figure 2:
Tissue distribution of Y4 receptor mRNA in
various human tissues. Localization data reflect PCR-based
amplification of human Y4 cDNA derived from RNA extracts of human
tissues. Total RNA (250 ng) was assayed for all tissues except
hippocampus and hypothalamus, where poly(A)
Human Y4 bound human PP family
members in
Incubation of
intact LMTK
Figure 3:
PP-dependent signaling events in intact
LMTK
Intracellular free [Ca We have cloned the gene for a
novel human Y-type receptor, Y4, which is functionally activated by PP.
The human Y4 pharmacological profile is similar to rat PP receptor
binding profiles derived from cell and tissue models. For example, a PP
receptor in rat PC-12 cells was reported to bind PP >
PP The human Y4 could
conceivably be designated a PP receptor. We propose the name Y4,
however, as a direct extension of the Y-type nomenclature previously
established for Y1, Y2, and Y3 receptors. Arguments are as follows: 1)
Y4 was cloned by virtue of its homology with the Y1 receptor and is
most similar in sequence with Y1 receptors from several species. As
such, the Y4 is structurally linked to receptors currently entrenched
in Y-type nomenclature; 2) the human Y4 displayed a narrow range of K The tissue distribution
of the Y4 mRNA is consistent with reports of PP binding and function in
brain and peripheral tissues and further suggests potential Y4
involvement in gastrointestinal, cardiovascular, and central nervous
system function. As there appears to be an inverse correlation between
pancreatic or circulating PP levels and obesity in human, rat, and
mouse (i.e. circulating PP levels are increased in anorexia
nervosa), one may speculate a role for Y4 in appetite and body weight
control(23, 29, 30, 31) .
Circulating PP has access to central sites through penetration of
fenestrated capillaries (8) and through transport past the
blood brain barrier(32) . Additional routes of Y4 receptor
activation may also exist, as PP mRNA has been recently identified by
PCR in rat brain, and in particular, hypothalamus(33) .
Localization of Y4 receptor mRNA in hypothalamus and potential receptor
activation are intriguing in that not only NPY and PYY, but also PP,
can enhance food intake when injected into rat brain
intracerebroventricular(34, 35) . One hypothesis is
that the Y4 receptor is involved in hypothalamic control of feeding.
This and other aspects of Y4 function can be further explored using
techniques based on the Y4 receptor clone, such as expression of
species homologs, selective antagonist design, receptor antisense, and
transgenic animal models.
The nucleotide
sequence(s) reported in this paper has been submitted to the
GenBank(TM)/EMBL Data Bank with accession number(s)
U35232[GenBank].
Volume 270,
Number 45,
Issue of November 10, 1995 pp. 26762-26765
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS AND DISCUSSION
FOOTNOTES
ACKNOWLEDGEMENTS
REFERENCES
I-PYY binding to
transiently expressed Y4 receptors was saturable (pK
= 9.89) and displaceable by human PP family
derivatives: PP (pK
= 10.25)
PP
(pK
=
10.06) > PYY (pK
= 9.06)
[Leu
,Pro
]NPY (pK
= 8.95) > NPY (pK
= 8.68) > PP
(pK
= 7.13) >
PP
(pK
=
6.46) > PP
free acid (pK
< 5). Human PP decreased [cAMP] and increased
intracellular [Ca
] in Y4-transfected
LMTK
cells. Y4 mRNA was detected by reverse
transcriptase-polymerase chain reaction in human brain, coronary
artery, and ileum, suggesting potential roles for Y4 receptors in
central nervous system, cardiovascular, and gastrointestinal function.
)neuropeptide Y (NPY), and peptide YY
(PYY), all of which are 36 amino acid peptides characterized by a
hairpin loop(1) . PP is released from pancreatic endocrine
cells post-prandially(2) . PP receptors have been characterized
by binding or functional assays in liver(3) ,
intestine(4) , vas deferens(5) , spinal
cord(6) , adrenal gland, superior cervical ganglia(7) ,
brainstem nuclei(8) , and PC-12 cells(9) . PP exerts
regulatory effects on pancreatic exocrine secretion, gall bladder
contraction, gastrointestinal motility, gastric acid secretion, and
corticosterone secretion(2, 10, 11) . PYY is
localized primarily in intestinal endocrine cells, whereas NPY is
localized primarily in the nervous system(1) . NPY and PYY act
similarly in a majority of biological models (e.g. to increase
food intake and vasocontraction), but exceptions have been
noted(1) . Within the PP family, NPY is most conserved among
species, whereas PP is least conserved(1) .,Pro
]NPY > PP and
COOH-terminal fragments; 2) Y2 binds NPY, PYY, and COOH-terminal
fragments > PP and [Leu
,Pro
]NPY;
3) Y3 binds NPY > PYY; 4) the PP receptor binds PP > NPY, PYY;
and 5) the putative Y1-like feeding receptor is activated by NPY, PYY,
[Leu
,Pro
]NPY, and
NPY
> COOH-terminal fragments. Only the Y1
subtype has been cloned
previously(12, 13, 14, 15, 16) .
Here we describe homology cloning of an additional human Y-type
receptor, Y4, which is functionally activated by PP.
Cloning and Sequencing
A human placenta genomic
library (Stratagene) was screened using overlapping TM oligonucleotide
probes derived from the rat Y1 neuropeptide receptor gene (17;
GenBank(TM) accession number Z11504). Overlapping oligomers were
labeled with [P]dATP and
[
P]dCTP by synthesis with the large fragment of
DNA polymerase: TM1, nucleotides 198-251; TM2, nucleotides
269-328; TM3, nucleotides 401-478; TM5, nucleotides
716-778; and TM7, nucleotides 971-1045. Hybridization was
performed at low stringency conditions, as described
previously(18) . For subcloning and further Southern blot
analysis, DNA was cloned into pUC18 (Pharmacia Biotech
Inc.)(19, 20) . Nucleotide sequence analysis was
accomplished by the Sanger dideoxy nucleotide chain termination method (21) on denatured double-stranded plasmid templates, using
Sequenase (U. S. Biochemical Corp.) and confirmed on both strands.
Tissue Localization/Expression (Reverse
Transcriptase-PCR)
Human tissues, obtained from National Disease
Research Interchange (Philadelphia, PA), were homogenized and total RNA
extracted using guanidine isothiocyanate/CsCl cushion method. In some
instances, poly(A) mRNA was isolated with oligo(dT)
affinity chromatography, using standard protocols. RNA was treated with
DNase to remove any contaminating genomic DNA. cDNA was prepared from
total RNA with random hexanucleotide primers using reverse
transcriptase (Superscript II; Life Technologies, Inc.). An aliquot of
the first strand cDNA (corresponding to 250 ng of total RNA or 5 ng of
poly(A)
RNA) was amplified using a program consisting
of 30 cycles of 94 °C for 2 min, 68 °C for 2 min, and 72 °C
for 3 min, with a pre- and postincubation of 95 °C for 5 min and 72
°C for 10 min, respectively. PCR primers were designed against the
human Y4 sequence in the third intracellular loop and carboxyl-terminal
regions: Forward, 5`-CGCGTGTTTCACAAGGGCACCTA-3`, and reverse,
5`-TGCCACTTAGCCTCAGGGACCC-3`, respectively. The PCR products were
analyzed by Southern blot techniques using a 5` end-labeled
oligonucleotide (located in the carboxyl terminus: 5`-TCCG
TATGTACTGTGGACAGGGGCAGATGCTCCGACTCCTCCAGG-3`) under high stringency.
Under the above conditions, PCR products were identified on Southern
blots using the subtype-specific probes, and no cross-reactivity was
observed with other NPY receptor subtypes (data not shown). Similar PCR
and Southern blot analysis were conducted with primers and probe
directed to the housekeeping gene, glyceraldehyde-3-phosphate
dehydrogenase (Clontech), except 22 cycles were used. In order to
control for the amplification of contaminating genomic DNA, control PCR
reactions were run in parallel with RNA which had not been converted to
cDNA (i.e. minus reverse transcriptase).
Cell Culture
Stocks of COS-7 (African green monkey
kidney) and LMTK (mouse fibroblast) cells were grown
on 150-mm plates in Dulbecco's modified Eagle's medium with
supplements (10% bovine calf serum, 4 mM glutamine, 100
units/ml penicillin, 100 µg/ml streptomycin) at 37 °C and 5%
CO
.Receptor Expression
The coding region of hp25a
(1127 bp) plus 680 bp upstream and 205 bp downstream was cloned into
the BamHI and EcoRI sites of the polylinker-modified
eukaryotic expression vector pCEXV-3(22) , called EXJ.HR. ()COS-7 cells were transiently transfected with plasmid
hp25a/EXJ (expression vector containing the hp25a gene) or with human
Y1 receptor (hY1) DNA (cloned at Synaptic Pharmaceutical Corp.) by the
DEAE-dextran method (23) or without plasmid for
mock-transfection. For stable expression, plasmid hp25a/EXJ was
co-transfected with a G418-resistant plasmid into LMTK cells by the calcium phosphate method. Stably transfected cells
were selected with G418.
Membrane Preparation
COS-7 cells were washed in
phosphate-buffered saline 48 h after transfection and lysed by
sonication on ice in 20 mM Tris-HCl, 5 mM EDTA, pH
7.7. The supernatant remaining after low speed centrifugation (200
g, 10 min, 4 °C) was subjected to high speed
centrifugation (32,000 g, 18 min, 4 °C), and the
resulting membrane pellet was resuspended by sonication into ice-cold
binding buffer (10 mM NaCl, 20 mM HEPES, 0.22
mM KHPO
, 1.26 mM CaCl, 0.81 mM MgSO, pH 7.4).
Protein was measured by the Bradford method (24) using Bio-Rad
reagent.
Membrane
suspensions, porcine I-PYY Binding
I-[Tyr
]PYY
(specific activity = 2200 Ci/mmol) and peptides were diluted in
binding buffer supplemented with 0.1% bovine serum albumin (Sigma) and
distributed into 96-well polypropylene microtiter plates. Samples were
incubated at 30 °C with shaking for 120 min. Membranes were
collected by filtration over Whatman GF/C filters (precoated with 0.5%
polyethyleneimine and air-dried before use) and counted for
I. Nonspecific binding was defined by 100 nM human PP. Data were analyzed by nonlinear regression.
cAMP Measurements
96-Well microtiter plates were
precoated with poly-D-lysine (0.05 mg/well), dried, and seeded
with stably transfected LMTK cells. Serum,
potentially desensitizing, was reduced to 1.5% 4-16 h before the
assay. Cells were pre-equilibrated in Hanks' buffered saline plus
supplements (HBSP: 150 mM NaCl, 20 mM HEPES, 1
mM CaCl
, 5 mM KCl, 1 mM MgCl, and 10 mM glucose plus 0.1% bovine
serum albumin and 5 mM theophylline) for 20 min at 37 °C
in 5% CO, then stimulated 5 min with 10 µM forskolin and peptides prepared in HBSP. Intracellular cAMP was
extracted with 100 mM HCl at 4 °C for 30 min and
quantified by radioimmunoassay. The final antigen-antibody complex was
collected by filtration through a 96-well Durapore filter plate
(Millipore) and counted for I. Data were analyzed by
nonlinear regression and reported as mean ± S.E.
[Ca
Intracellular free
[Ca] Measurements
] was measured by
microspectrofluorometry (25) . Stably transfected
LMTK
cells were seeded into 35-mm culture dishes with
glass coverslip inserts. Cells were loaded with 10 µM Fura-2/AM in HBS for 20 to 40 min, then equilibrated with HBS
alone for an additional 10 to 20 min. Cells were visualized under a
40 microscope objective, and fluorescence emission was
determined at 510 nM with excitation alternating between
340 and 380 nM. Raw fluorescence data were converted to
[Ca
] using standard
[Ca
] curves and reported as mean ±
S.E.
41 kDa. Hydropathy analysis of the protein is
consistent with a putative topography of seven transmembrane domains,
indicative of the G-protein-coupled receptor family.
-terminal
extracellular part of human Y4; arrows correspond to protein
kinase C consensus sites.
0 control) or reverse transcriptase was omitted
from the first strand cDNA conversion (data not shown); the latter
suggests that the signals observed not due to any genomic DNA
contaminating the RNA. We also demonstrated that equal amounts of cDNA
from the different tissues were assayed for NPY expression by
conducting control reverse transcriptase-PCR with primers for the
moderately high level constitutively expressed gene,
glyceraldehyde-3-phosphate dehydrogenase (Clontech) (Fig. 2).
RNA (5 ng)
was used. Southern blots of the PCR products were prepared and
hybridized with
P-labeled oligonucleotide probes selective
for the Y4 receptor subtype or glyceraldehyde-3-phosphate dehydrogenase (G3PDH).
I-PYY (0.06 nM) bound specifically to
membranes from hY4-transfected COS-7 cells (but not from
mock-transfected cells) with an observed association rate (K
) = 0.12 ± 0.02
min
, t
= 6 min, and
100% complete equilibrium binding within 50 min at 30 °C (n = 3). Human Y1-transfected COS-7 cell membranes, when
studied under the same conditions, yielded a K
= 0.06 ± 0.02 min
, t
= 12 min, and 100% complete equilibrium
binding within 90 min (n = 3). Subsequent
I-PYY binding assays involving both hY1 and hY4 receptors
were conducted for 120 min.
I-PYY binding to the
transiently expressed hY4 receptor was specific and saturable at
I-PYY concentrations ranging from 0.003 to 2.5
nM. Binding data were fit to a one-site model with an apparent
pK
= 9.89 ± 0.04 (0.13 nM)
and B
= 1.9 ± 0.3 pmol/mg membrane
protein (n = 8). The transiently expressed hY1 receptor
bound I-PYY with an apparent pK
= 10.19 ± 0.04 (0.065 nM) and B = 4.0 ± 0.7 pmol/mg membrane
protein (n = 9).I-PYY membrane binding assays with a
distinctive rank order (Table 1): PP > PYY > NPY > NPY
free acid. Human Y4 also bound PP from bovine, rat, salmon, and frog
with a wide range of K
values consistent with PP
species diversity. PYY and NPY binding to hY4 could be enhanced by
inserting PP residues into positions 31 and 34 to make
[Pro]PYY and
[Leu
,Pro
]NPY. However, the
corresponding modifications of PP to reflect the NPY peptide (e.g. [Ile
,Gln
]PP) had no effect on
binding affinity to hY4 (see Table 1), suggesting that for the
favored ligand PP there are significant contributions to binding
affinity from other peptide regions. Human PP could be truncated to
PP
but further NH
-terminal deletion
was disruptive for hY4 binding. The shortest COOH-terminal fragment
studied (PP) was rendered inactive by hydrolysis
of the carboxyl amide. A comparison of structure/activity profiles for
hY4 and hY1 suggests a common mechanism of peptide interaction
optimized for either PP or NPY/PYY, respectively.
cells with 10 µM forskolin
produced an average 7-fold increase in cAMP over a 5-min period (n = 20). Simultaneous incubation with human PP decreased the
forskolin-stimulated [cAMP] with an E
of 83 ± 2% in LMTK cells stably
transfected with hY4 (Fig. 3A), but not in
untransfected cells. The pEC
for human PP (10.13 ±
0.06) was in close agreement with the pK
(10.25
± 0.06) from I-PYY binding assays. The list of
Y-type receptors negatively coupled to cAMP (previously composed of Y1,
Y2, and Y3) can therefore be extended to include Y4(1) .
cells stably expressing the hY4 receptor. A, inhibition of forskolin-stimulated [cAMP]. Data
shown are representative of 20 independent experiments. B,
stimulation of intracellular free [Ca
].
Human PP (100 nM) was added at the time indicated by the arrow. Data shown are selected from 10 recordings made in four
independent experiments.
] was markedly
increased by 100 nM human PP in LMTK
cells
stably transfected with the hY4
(
[Ca]
= 158
± 32 nM, n = 10) but not in
untransfected cells. The Ca transient could be
detected within 30 s of PP application (Fig. 3B). These
data add complexity to existing notions of PP-dependent Ca
regulation centered around inhibition of voltage-dependent
Ca
channels in rat superior cervical
ganglia(26, 27) .
(7) and also PP >
[Leu
,Pro
]NPY,
[Ile
,Gln
]PP NPY (5) .
Receptors on PC-12 cells bound bovine PP > rat PP(7) ,
although rat hepatocyte receptors bound both with equally high
affinity(3) . A receptor on intact rat cells from liver,
pancreas, and elsewhere was reported to bind all PP family members with
similar K
values(28) . Whether the rat
receptors described in these reports represent the same gene product
analyzed under different assay conditions or multiple subtypes and what
their relationship is to hY4 is not yet clear. values for human PP, PYY, and NPY in I-PYY binding assays (10.25
pK 8.68); 3) The letter ``Y'' encodes the conserved
COOH-terminal Tyr in pancreatic polypeptide family members and is
therefore a unifying symbol for the entire ligand family; and 4) the Y4
designation represents a reasonable nomenclature in the event that
peptide rank order should change with assay conditions or with the
discovery of additional PP family members.
)], calcium concentration; HBS,
Hanks' buffered saline; kb, kilobase pair(s); bp, base pair(s).
)
We thank Dr. Pierre Vaysse for expertise in receptor
expression, Dr. Christophe Gerald for helpful discussions, Nancy
Rogacki, Zoya Shaposhnik, Tracy Johnson-Blake, Xiao-xin Yang, Nancy
Shen, Michelle Smith, and Harvey Lichtblau for outstanding technical
assistance and George Moralishvilli, Ernest Lilley, and Adam Zalensky
for graphics support. M. W. W. is indebted to the late Prof. Howard S.
Tager for guidance in Y-type receptor studies.
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
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S. Furtinger, S. Pirker, T. Czech, C. Baumgartner, G. Ransmayr, and G. Sperk Plasticity of Y1 and Y2 Receptors and Neuropeptide Y Fibers in Patients with Temporal Lobe Epilepsy J. Neurosci., August 1, 2001; 21(15): 5804 - 5812. [Abstract] [Full Text] [PDF]
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M. Goumain, T. Voisin, A.-M. Lorinet, R. Ducroc, A. Tsocas, C. Roze, P. Rouet-Benzineb, H. Herzog, A. Balasubramaniam, and M. Laburthe The Peptide YY-Preferring Receptor Mediating Inhibition of Small Intestinal Secretion Is a Peripheral Y2 Receptor: Pharmacological Evidence and Molecular Cloning Mol. Pharmacol., July 1, 2001; 60(1): 124 - 134. [Abstract] [Full Text]
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D. A. Schober, S. L. Gackenheimer, M. L. Heiman, and D. R. Gehlert Pharmacological Characterization of 125I-1229U91 Binding to Y1 and Y4 Neuropeptide Y/Peptide YY Receptors J. Pharmacol. Exp. Ther., April 1, 2000; 293(1): 275 - 280. [Abstract] [Full Text]
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 T. L. nbecher, C. B. Foster, S. Zhu, D. Venzon, S. M. Steinberg, K. Wyvill, J. A. Metcalf, S. S. Cohen, J. Kovacs, R. Yarchoan, et al. Variant genotypes of Fcgamma RIIIA influence the development of Kaposi's sarcoma in HIV-infected men Blood, April 1, 2000; 95(7): 2386 - 2390. [Abstract] [Full Text] [PDF]
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A. Kanatani, S. Mashiko, N. Murai, N. Sugimoto, J. Ito, T. Fukuroda, T. Fukami, N. Morin, D. J. MacNeil, L. H. T. Van der Ploeg, et al. Role of the Y1 Receptor in the Regulation of Neuropeptide Y-Mediated Feeding: Comparison of Wild-Type, Y1 Receptor-Deficient, and Y5 Receptor-Deficient Mice Endocrinology, March 1, 2000; 141(3): 1011 - 1016. [Abstract] [Full Text] [PDF]
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 M. W. Y. Ho, A. G. Beck-Sickinger, and W. F. Colmers Neuropeptide Y5 Receptors Reduce Synaptic Excitation in Proximal Subiculum, But Not Epileptiform Activity in Rat Hippocampal Slices J Neurophysiol, February 1, 2000; 83(2): 723 - 734. [Abstract] [Full Text] [PDF]
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T. Voisin, M. Goumain, A.-M. Lorinet, J.-J. Maoret, and M. Laburthe Functional and Molecular Properties of the Human Recombinant Y4 Receptor: Resistance to Agonist-Promoted Desensitization J. Pharmacol. Exp. Ther., February 1, 2000; 292(2): 638 - 646. [Abstract] [Full Text]
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T. Lehrnbecher, C. B. Foster, S. Zhu, S. F. Leitman, L. R. Goldin, K. Huppi, and S. J. Chanock Variant Genotypes of the Low-Affinity Fcgamma Receptors in Two Control Populations and a Review of Low-Affinity Fcgamma Receptor Polymorphisms in Control and Disease Populations Blood, December 15, 1999; 94(12): 4220 - 4232. [Abstract] [Full Text] [PDF]
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M. R. Jain, S. Pu, P. S. Kalra, and S. P. Kalra Evidence that Stimulation of Two Modalities of Pituitary Luteinizing Hormone Release in Ovarian Steroid-Primed Ovariectomized Rats May Involve Neuropeptide Y Y1 and Y4 Receptors Endocrinology, November 1, 1999; 140(11): 5171 - 5177. [Abstract] [Full Text]
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 A. J. Morris and C. C. Malbon Physiological Regulation of G Protein-Linked Signaling Physiol Rev, October 1, 1999; 79(4): 1373 - 1430. [Abstract] [Full Text] [PDF]
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P. D. Raposinho, P. Broqua, D. D. Pierroz, A. Hayward, Y. Dumont, R. Quirion, J.-L. Junien, and M. L. Aubert Evidence That the Inhibition of Luteinizing Hormone Secretion Exerted by Central Administration of Neuropeptide Y (NPY) in the Rat Is Predominantly Mediated by the NPY-Y5 Receptor Subtype Endocrinology, September 1, 1999; 140(9): 4046 - 4055. [Abstract] [Full Text]
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D. Engler, E. Redei, and I. Kola The Corticotropin-Release Inhibitory Factor Hypothesis: A Review of the Evidence for the Existence of Inhibitory as Well as Stimulatory Hypophysiotropic Regulation of Adrenocorticotropin Secretion and Biosynthesis Endocr. Rev., August 1, 1999; 20(4): 460 - 500. [Abstract] [Full Text] [PDF]
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S. Iyengar, D. L. Li, and R. M. A. Simmons Characterization of Neuropeptide Y-Induced Feeding in Mice: Do Y1-Y6 Receptor Subtypes Mediate Feeding? J. Pharmacol. Exp. Ther., May 1, 1999; 289(2): 1031 - 1040. [Abstract] [Full Text]
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L. Sun and R. J. Miller Multiple Neuropeptide Y Receptors Regulate K+ and Ca2+ Channels in Acutely Isolated Neurons From the Rat Arcuate Nucleus J Neurophysiol, March 1, 1999; 81(3): 1391 - 1403. [Abstract] [Full Text] [PDF]
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K. E. Smith, M. W. Walker, R. Artymyshyn, J. Bard, B. Borowsky, J. A. Tamm, W.-J. Yao, P. J.-J. Vaysse, T. A. Branchek, C. Gerald, et al. Cloned Human and Rat Galanin GALR3 Receptors. PHARMACOLOGY AND ACTIVATION OF G-PROTEIN INWARDLY RECTIFYING K+ CHANNELS J. Biol. Chem., September 4, 1998; 273(36): 23321 - 23326. [Abstract] [Full Text] [PDF]
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Y. Dumont, A. Fournier, and R. Quirion Expression and Characterization of the Neuropeptide Y Y5 Receptor Subtype in the Rat Brain J. Neurosci., August 1, 1998; 18(15): 5565 - 5574. [Abstract] [Full Text] [PDF]
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 Z. Zukowska-Grojec, E. Karwatowska-Prokopczuk, W. Rose, J. Rone, S. Movafagh, H. Ji, Y. Yeh, W.-T. Chen, H. K. Kleinman, E. Grouzmann, et al. Neuropeptide Y : A Novel Angiogenic Factor From the Sympathetic Nerves and Endothelium Circ. Res., July 27, 1998; 83(2): 187 - 195. [Abstract] [Full Text] [PDF]
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 M. C. Michel, A. Beck-Sickinger, H. Cox, H. N. Doods, H. Herzog, D. Larhammar, R. Quirion, T. Schwartz, and T. Westfall XVI. International Union of Pharmacology Recommendations for the Nomenclature of Neuropeptide Y, Peptide YY, and Pancreatic Polypeptide Receptors Pharmacol. Rev., March 1, 1998; 50(1): 143 - 150. [Abstract] [Full Text] [PDF]
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 J. Robidoux, L. Simoneau, S. St-Pierre, H. Ech-Chadli, and J. Lafond Human syncytiotrophoblast NPY receptors are located on BBM and activate PLC-to-PKC axis Am J Physiol Endocrinol Metab, March 1, 1998; 274(3): E502 - E509. [Abstract] [Full Text] [PDF]
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D. T. Ault, J. M. Radeff, and L. L. Werling Modulation of [3H]Dopamine Release from Rat Nucleus Accumbens by Neuropeptide Y May Involve a Sigma1-like Receptor J. Pharmacol. Exp. Ther., February 1, 1998; 284(2): 553 - 560. [Abstract] [Full Text]
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L. Sun, L. H. Philipson, and R. J. Miller Regulation of K+ and Ca++ Channels by a Family of Neuropeptide Y Receptors J. Pharmacol. Exp. Ther., February 1, 1998; 284(2): 625 - 632. [Abstract] [Full Text]
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C. Schwarzer, N. Kofler, and G. Sperk Up-Regulation of Neuropeptide Y-Y2 Receptors in an Animal Model of Temporal Lobe Epilepsy Mol. Pharmacol., January 1, 1998; 53(1): 6 - 13. [Abstract] [Full Text]
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 M. Jackerott and L.-I. Larsson Immunocytochemical Localization of the NPY/PYY Y1 Receptor in Enteric Neurons, Endothelial Cells, and Endocrine-like Cells of the Rat Intestinal Tract J. Histochem. Cytochem., December 1, 1997; 45(12): 1643 - 1650. [Abstract] [Full Text] [PDF]
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J. Zheng, P. Zhang, and T. D. Hexum Neuropeptide Y Inhibits Chromaffin Cell Nicotinic Receptor-Stimulated Tyrosine Hydroxylase Activity through a Receptor-Linked G Protein-Mediated Process Mol. Pharmacol., December 1, 1997; 52(6): 1027 - 1033. [Abstract] [Full Text]
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M. Jackerott and L.-I. Larsson Immunocytochemical Localization of the NPY/PYY Y1 Receptor in the Developing Pancreas Endocrinology, November 1, 1997; 138(11): 5013 - 5018. [Abstract] [Full Text] [PDF]
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 C. J. Small, D. G. A. Morgan, K. Meeran, M. M. Heath, I. Gunn, C. M. B. Edwards, J. Gardiner, G. M. Taylor, J. D. Hurley, M. Rossi, et al. Peptide analogue studies of the hypothalamic neuropeptide Y receptor mediating pituitary adrenocorticotrophic hormone release PNAS, October 14, 1997; 94(21): 11686 - 11691. [Abstract] [Full Text] [PDF]
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S. M. Leupen, L. M. Besecke, and J. E. Levine Neuropeptide Y Y1-Receptor Stimulation Is Required for Physiological Amplification of Preovulatory Luteinizing Hormone Surges Endocrinology, July 1, 1997; 138(7): 2735 - 2739. [Abstract] [Full Text] [PDF]
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H. Rhim, G. A. Kinney, P. J. Emmerson, and R. J. Miller Regulation of Neurotransmission in the Arcuate Nucleus of the Rat by Different Neuropeptide Y Receptors J. Neurosci., May 1, 1997; 17(9): 2980 - 2989. [Abstract] [Full Text] [PDF]
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S. Sheriff, William. T. Chance, Josef. E. Fischer, and A. Balasubramaniam Neuropeptide Y Treatment and Food Deprivation Increase Cyclic AMP Response Element-Binding in Rat Hypothalamus Mol. Pharmacol., April 1, 1997; 51(4): 597 - 604. [Abstract] [Full Text]
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P. M. Rose, J. S. Lynch, S. T. Frazier, S. M. Fisher, W. Chung, P. Battaglino, Z. Fathi, R. Leibel, and P. Fernandes Molecular Genetic Analysis of a Human Neuropeptide Y Receptor. THE HUMAN HOMOLOG OF THE MURINE "Y5" RECEPTOR MAY BE A PSEUDOGENE J. Biol. Chem., February 7, 1997; 272(6): 3622 - 3627. [Abstract] [Full Text] [PDF]
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D. O'Shea, D. G. A. Morgan, K. Meeran, C. M. B. Edwards, M. D. Turton, S. J. Choi, M. M. Heath, I. Gunn, G. M. Taylor, J. K. Howard, et al. Neuropeptide Y Induced Feeding in the Rat Is Mediated by a Novel Receptor Endocrinology, January 1, 1997; 138(1): 196 - 202. [Abstract] [Full Text] [PDF]
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G. Chen and A. N. van den Pol Multiple NPY Receptors Coexist in Pre- and Postsynaptic Sites: Inhibition of GABA Release in Isolated Self-Innervating SCN Neurons J. Neurosci., December 1, 1996; 16(23): 7711 - 7724. [Abstract] [Full Text] [PDF]
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M. Matsumoto, T. Nomura, K. Momose, Y. Ikeda, Y. Kondou, H. Akiho, J. Togami, Y. Kimura, M. Okada, and T. Yamaguchi Inactivation of a Novel Neuropeptide Y/Peptide YY Receptor Gene in Primate Species J. Biol. Chem., November 1, 1996; 271(44): 27217 - 27220. [Abstract] [Full Text] [PDF]
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P. Gregor, Y. Feng, L. B. DeCarr, L. J. Cornfield, and M. L. McCaleb Molecular Characterization of a Second Mouse Pancreatic Polypeptide Receptor and Its Inactivated Human Homologue J. Biol. Chem., November 1, 1996; 271(44): 27776 - 27781. [Abstract] [Full Text] [PDF]
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Y. Hu, B. T. Bloomquist, L. J. Cornfield, L. B. DeCarr, J. R. Flores-Riveros, L. Friedman, P. Jiang, L. Lewis-Higgins, Y. Sadlowski, J. Schaefer, et al. Identification of a Novel Hypothalamic Neuropeptide Y Receptor Associated with Feeding Behavior J. Biol. Chem., October 18, 1996; 271(42): 26315 - 26319. [Abstract] [Full Text] [PDF]
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A. N. van den Pol, K. Obrietan, G. Chen, and A. B. Belousov Neuropeptide Y-Mediated Long-Term Depression of Excitatory Activity in Suprachiasmatic Nucleus Neurons J. Neurosci., September 15, 1996; 16(18): 5883 - 5895. [Abstract] [Full Text] [PDF]
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D. H. Weinberg, D. J.S. Sirinathsinghji, C. P. Tan, L.-L. Shiao, N. Morin, M. R. Rigby, R. H. Heavens, D. R. Rapoport, M. L. Bayne, M. A. Cascieri, et al. Cloning and Expression of a Novel Neuropeptide Y Receptor J. Biol. Chem., July 12, 1996; 271(28): 16435 - 16438. [Abstract] [Full Text] [PDF]
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C. Gerald, M. W. Walker, P. J.-J. Vaysse, C. He, T. A. Branchek, and R. L. Weinshank Expression Cloning and Pharmacological Characterization of a Human Hippocampal Neuropeptide Y/Peptide YY Y2 Receptor Subtype J. Biol. Chem., November 10, 1995; 270(45): 26758 - 26761. [Abstract] [Full Text] [PDF]
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