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Vol. 55, Issue 6, 1101-1107, June 1999
R.W. Johnson Pharmaceutical Research Institute, San Diego, California
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Summary |
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 Top
 Summary
 Introduction
Experimental Procedures
Results
Discussion
References
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Histamine regulates neurotransmitter release in the central and peripheral nervous systems through H3 presynaptic receptors. The existence of the histamine H3 receptor was demonstrated pharmacologically 15 years ago, yet despite intensive efforts, its molecular identity has remained elusive. As part of a directed effort to discover novel G protein-coupled receptors through homology searching of expressed sequence tag databases, we identified a partial clone (GPCR97) that had significant homology to biogenic amine receptors. The GPCR97 clone was used to probe a human thalamus library, which resulted in the isolation of a full-length clone encoding a putative G protein-coupled receptor. Homology analysis showed the highest similarity to M2 muscarinic acetylcholine receptors and overall low homology to all other biogenic amine receptors. Transfection of GPCR97 into a variety of cell lines conferred an ability to inhibit forskolin-stimulated cAMP formation in response to histamine, but not to acetylcholine or any other biogenic amine. Subsequent analysis revealed a pharmacological profile practically indistinguishable from that for the histamine H3 receptor. In situ hybridization in rat brain revealed high levels of mRNA in all neuronal systems (such as the cerebral cortex, the thalamus, and the caudate nucleus) previously associated with H3 receptor function. Its widespread and abundant neuronal expression in the brain highlights the significance of histamine as a general neurotransmitter modulator. The availability of the human H3 receptor cDNA should greatly aid in the development of chemical and biological reagents, allowing a greater appreciation of the role of histamine in brain function.
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Introduction |
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Summary
Introduction
Experimental Procedures
Results
Discussion
References
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Since its first pharmacological
description as an endogenous substance in 1910 (Barger and Dale, 1910
),
histamine has proven to exert tremendous influence over a variety of
physiological processes. Most notable are its roles in the inflammatory
"triple response" and in gastric acid secretion, which are mediated
by H1 (Ash and Schild, 1966) and
H2 (Black et al., 1972) receptors, respectively.
In the early 1970s emerged an understanding that histamine is a
neurotransmitter in the central nervous system (Schwartz et al., 1970;
Baudry et al., 1975). In 1983, a third subtype of histamine receptor,
H3, was identified as a presynaptic autoreceptor
on histamine neurons in the brain controlling the stimulated release of
histamine (Arrang et al., 1983). Subsequently, the
H3 receptor has been shown to be a presynaptic
heteroreceptor in nonhistamine-containing neurons in both the central
and peripheral nervous systems (for review, see Hill et al., 1997).
Through the molecular cloning of H1 and
H2, these receptors were proven to belong to the
superfamily of G protein-coupled receptors (GPCRs; Gantz et al., 1991;
Yamashita et al., 1991). For the past 10 years, the histamine
H3 receptor has been the target of numerous
cloning and purification attempts, yet its molecular identity has
remained an enigma.
We have initiated an effort to identify and clone orphan GPCRs as a
means to identify novel drug targets and as a way to discover novel
neurotransmitters and peptides. This is an approach used by many
investigators, and it has led to the successful identification of
ligands such as nociceptin (Reinscheid et al., 1995),
prolactin-releasing factor (Hinuma et al., 1998), the orexins (Sakurai
et al., 1998), and, more recently, apelin (Tatemoto et al., 1998).
There are at least 70 orphan GPCRs in the public domain. We have
identified, through searching public and private databases, at least 30 additional putative members of this family via expressed sequence tags
(ESTs). One of these orphan receptors, our designation GPCR97, was
expressed abundantly in the central nervous system, and its 5'-most
sequence shares significant homology with the putative transmembrane
domain VII of several members of the biogenic amine family of
receptors. Therefore, we investigated the possibility that the
GPCR97 cDNA encodes a novel neurotransmitter receptor.
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Experimental Procedures |
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Top
Summary
Introduction
Experimental Procedures
Results
Discussion
References
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Materials. Human mRNA and all Northern blots were purchased from Clontech (Palo Alto, CA). cDNA synthesis kits were purchased from Gibco Life Technologies (Gaithersburg, MD). Gelzyme was obtained from Invitrogen (San Diego, CA), and pCIneo vector was obtained from Promega (Madison, WI). All cell lines were obtained from American Type Culture Collection (Manassas, VA). Cyclic AMP (cAMP) Flashplates were obtained from DuPont/New England Nuclear (Boston, MA). Fluo-3 was purchased from TEF Laboratories (Austin, TX) G418 was purchased from Calbiochem (San Diego, CA). All histamine ligands were purchased from Research Biochemicals, Inc. (Natick, MA). All other reagents were purchased from Sigma Chemical Co. (St. Louis, MO).
Cloning of GPCR97 cDNA. A human thalamus cDNA library was constructed from poly(A)+-selected RNA as described by the manufacturer (Gibco Life Technologies). Double-stranded DNA was digested with NotI and then run on a 0.8% low-melting agarose gel, and cDNA in the range of 2.5 to 5 kilobases (kb) was excised, purified with Gelzyme, and subsequently was subcloned into pSport vector. The size-selected human thalamus cDNA library was screened with a radiolabeled fragment of the GPCR97 EST clone. A full-length GPCR97 was obtained and, subsequently, cloned into the mammalian expression vector pCIneo (Promega) and transfected into human embryonic kidney 293 cells, rat C6 glioma cells, and human SK-N-MC neuroblastoma cells.
Transfection of Cells with GPCR97 cDNA.
Cells were grown to
about 70% to 80% confluence and then removed from the plate with
trypsin and pelleted in a clinical centrifuge. The pellet was then
resuspended in 400 µl of complete media and transferred to an
electroporation cuvette with a 0.4-cm gap between the electrodes (no.
165-2088; Bio-Rad Laboratories, Hercules, CA). One microgram of
supercoiled DNA was added to the cells and mixed. The voltage
for the electroporation was set at 0.25 kV and the capacitance was set
at 960 µF. After electroporation, the cells were diluted into
10 ml of complete media and were plated onto four 10-cm dishes at the
following ratios: 1:20, 1:10, 1:5, and the remaining cells. The cells
were allowed to recover for 24 h before the addition of G-418.
Colonies that survived selection were grown and tested. Several
different cell lines were used for transfection, which served two
purposes. First, because single-cell cloning can often uncover
endogenously expressed receptors (unpublished observations), it
is imperative to see the desired function in multiple transfections in
different cell lines. Second, each cell line has a unique
characteristic that can be used to enhance different aspects of the
study. For example, C6 cells grow very fast and are easy to culture
and, thus, are good for generating lots of membranes for binding.
SK-N-MC cells give robust cAMP accumulation and give efficient coupling
for inhibition of adenylate cyclase. L cells consistently transfect
well and have few endogenous receptors, and, thus, are good for
reliable initial characterization of recombinant receptors. It should
be noted that inhibition of adenylate cyclase and
[3H]R-
-methylhistamine binding
were observed in all of the GPCR97-transfected cells. Only the best
responding cell lines were used for further study.
cAMP Accumulation. Transfected cells were plated on 96-well plates. Overnight cultures were then incubated with Dulbecco's modified Eagle's medium-F12 media containing isobutylmethylxanthine (2 mM) for 20 min, treated with agonists, antagonists, or both for 5 min, and then treated with forskolin (10 µM) for 20 min. The reaction was stopped with 1/5 volume 0.5 N HCl. Cell media were then tested for cAMP concentration by radioimmunoassay with cAMP Flashplates.
Calcium Mobilization. Transfected cells were plated on black 96-well plates with clear bottoms. Overnight cultures were then incubated with Dulbecco's modified Eagle's medium-F12 media containing the fluorescent calcium indicator fluo-3 (4 µM) and probenicid (2 mM) for 60 min. Ligand-induced fluorescence was then measured on a Fluorometric Imaging Plate Reader (FLIPR; Molecular Devices, Sunnyvale, CA).
R--Methyl[3H]histamine Binding.
Cell pellets from GPCR97-expressing C6 cells were homogenized in 20 mM
Tris-HCl/0.5 mM EDTA. Supernatants from a 800g spin were
collected and recentrifuged at 30,000g for 30 min. Pellets were rehomogenized in 50 mM Tris/5 mM EDTA (pH 7.4). Membranes were
incubated with 0.4 nM
R--methyl[3H]histamine plus/minus
test compounds for 45 min at 25°C and harvested by rapid filtration
over GF/C glass fiber filters (pretreated with 0.3% polyethylenimine),
followed by four washes with ice-cold buffer. Nonspecific binding was
defined with 10 µM histamine. pKI values were
calculated based on a Kd of 150 pM and a
ligand concentration of 400 pM (Cheng and Prusoff, 1973).
In Situ Hybridization.
Three adult male Sprague-Dawley rats
were perfused with 4% paraformaldehyde in 0.1 M borate buffer
fixative, and their brain tissues were postfixed overnight in fixative
with 10% sucrose and frozen in dry ice. Five 1-in-5 series of
30-µm-thick coronal sections of the whole brain were cut on a sliding
microtome and mounted onto glass slides. In situ hybridization
was performed with 35S-riboprobes on this tissue
by an adapted protocol (Simmons et al., 1989). Then the tissue samples
were put on X-ray film for 1 day, after which they were dipped in NBT2
nuclear emulsion (Eastman Kodak Co., Rochester, NY), and kept
desiccated in the dark at 4°C for 6 days. Slides were developed, were
Nissl stained, and were studied under the microscope to identify
structures labeled with the GPCR97 cRNA probe.
RNA Probes. The cRNA probe was constructed from a partial rat GPCR97 cDNA clone originally identified by polymerase chain reaction (PCR) amplification from rat brain cDNA with primers designed against the human receptor (5' primer, 5'-AGTCGGATCCAGCTACGACCGCTTCCTGTC-3'; 3' primer, 5'-AGTCAAGCTTGGAGCCCCTCTTGAGTGAGC-3'). The resulting 607-base pair (bp) fragment was ligated into pBluescript (Stratagene, La Jolla, CA). 35S-UTP-labeled antisense and sense probes for rat GPCR97 were synthesized after linearization with BamHI or HindIII with T7 or T3 RNA polymerase, respectively. The labeled sense strands served as controls and did not show any specific labeling of cellular localization (data not shown). Specific activities of 35S-UTP probes were approximately 2 to 3 × 106 counts per minute/µg. All restriction enzymes and phage RNA polymerases were obtained from Boehringer Mannheim (Indianapolis, IN).
Northern Blot Analysis.
Northern blots obtained from
Clontech (Palo Alto, CA) were hybridized with
-32P-dCTP-labeled (Amersham Pharmacia Biotech,
Piscataway, NJ) human GPCR97 cDNA as described by the manufacturer
(Expresshyb, Clontech). Two million counts per milliliter was used in a
total volume of 10 ml of hybridization buffer and incubated at
68°C for 2 h. The blot was then
washed two times at RT in 2 × standard saline citrate and
0.05% SDS for 30 min each. It was further washed two more times for 30 min each at 60°C and exposed overnight to film.
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Results |
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Top
Summary
Introduction
Experimental Procedures
Results
Discussion
References
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Cloning and Sequence Analysis of GPCR97 cDNA.
GPCR97 was
initially identified as an EST in a basic local alignment search
tool (Altschul et al., 1990) search of the Life Seq database
(Incyte Pharmaceuticals, Palo Alto, CA) with the 2-adrenergic receptor sequence as a query. The
5' end of the GPCR97 EST had approximately 35% homology to the seventh
transmembrane domain of the 2-adrenergic receptor. Semiquantitative
PCR of GPCR97 with cDNA templates from a variety of human tissues
showed expression predominantly in the central nervous system, with the greatest intensity in the thalamus. Therefore, we constructed a
size-selected human thalamus cDNA library and screened it with the
original EST fragment as a labeled probe. From this screen, a
full-length 2.7-kb clone consisting of a 298-bp 5'-untranslated region,
a 1335-bp open reading frame, and a 1100-bp 3'-untranslated region was
obtained. Translation of the open reading frame revealed a 445-amino
acid coding region with low homology (20-27%) to the biogenic amine
subfamily of GPCRs. Most notable was an aspartic acid residue in the
putative transmembrane domain III, the putative binding site for the
primary amine, which is a clear hallmark of the biogenic amine receptor
subfamily (Fig. 1). This conserved aspartic acid residue is shown in the alignment of the predicted amino
acid sequence of GPCR97 with the human histamine
H1 and H2 receptors.
Overall homology between GPCR97 and the H1 and
H2 receptors is 22% and 21.4%, respectively.
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GPCR97-Expressing Cells Inhibit Adenylate Cyclase in Response to
Histamine.
Given the homology of GPCR97 to the biogenic amine
family, we first tested its ability to respond to several of the amine neurotransmitters, measuring either the stimulation of calcium mobilization or the increase or decrease of cAMP accumulation in mouse
L cells. The biogenic amine ligands tested (acetylcholine, dopamine,
imidazole, epinephrine, tryptamine, serotonin, and histamine) were
negative for an increase in both calcium mobilization or in cAMP
accumulation (not shown). However, after forskolin stimulation of basal
cAMP accumulation, there was a selective and marked inhibition of
adenyate cyclase in response to histamine in the transfected cell line
but not in the nontransfected cell line (Fig.
2). This effect was mimicked by the
high-affinity H3 agonist
R--methylhistamine, which has an
EC50 of 1 nM (Fig.
3). In addition, the effect of R--methylhistamine could be blocked by the known
selective H3 antagonists thioperamide and
clobenpropit (Fig. 3) but not by the H1
antagonist diphenhydramine (Fig. 3) or the H2
antagonist ranitidine (not shown).
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GPCR97-Expressing Cells Bind the High-Affinity Histamine
H3 Ligand
R--Methyl[3H]histamine.
To confirm
the H3 pharmacology, we examined whether the
GPCR97-transfected cells could bind the H3 ligand
R--methyl[3H]histamine. For these studies,
we transfected a different cell line (C6 glioma cells) because of its
of ability to grow fast. C6 cells transfected with GPCR97 were able to
bind [3H]R--methylhistamine with
high affinity (Fig. 4, inset), whereas untransfected cells had no demonstrable binding (not shown). In addition, the known H3 agonists (histamine,
imetit, and N-methylhistame) and antagonists (thioperamide
and clobenpropit) could all compete for binding (Fig. 4) with a rank
order of potency consistent with that described for the histamine
H3 receptor (Table
1).
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GPCR97 is Expressed Abundantly in the Central Nervous System.
Because the pharmacological profile of GPCR97 was consistent with the
histamine H3 receptor, we investigated the mRNA
distribution and compared it to the known distribution of
H3 binding sites. Northern blots of human mRNA
showed expression only in the brain, most notably in the thalamus and
the caudate nucleus (Fig. 5). Little
expression was observed in any peripheral tissue examined (heart,
placenta, lung, liver, skeletal muscle, kidney, pancreas, spleen,
thymus, prostate, testis, ovaries, small intestine, colon, stomach,
thyroid, lymph node, trachea, and bone marrow; data not shown). To
obtain a rat homolog of the GPCR97 cDNA, we used oligonucleotide primers designed from the human sequence to amplify a cDNA fragment from RNA extracted from rat brain. This rat cDNA probe (which has 85%
nucleotide identity to human GPCR97) was subsequently used to examine
the tissue distribution of GPCR97-encoded mRNA by in situ hybridization
in rat brain sections. GPCR97 mRNA is abundantly expressed in rat brain
and is most notably observed throughout the thalamus, the ventromedial
hypothalamus, and the caudate nucleus (Fig.
6, A and B). Strong expression was also seen in layers II, V, and VIb of the cerebral cortex, in the pyramidal layers (CA1 and CA2) of the hippocampus, and in olfactory
tubercle (Fig. 6, A and B). Because the H3
receptor functions as an inhibitory presynaptic receptor, it is
expected that the mRNA localization may not exactly match the
functional receptor localization, depending on the axonal length of the
neuron expressing it. For example, noradrenergic cells in the locus
ceruleus project to all areas of the cerebral cortex where histamine,
via H3 receptors, is known to regulate
noradrenaline release (Schlicker et al., 1989; Smits and Mulder, 1991).
Therefore, it was predicted and confirmed that the mRNA for GPCR97 was
expressed in the locus ceruleus (Fig. 6, C and E). In addition, because
the H3 receptor has also been functionally
demonstrated on the histamine terminals in the cerebral cortex (Arrang
et al., 1983), its mRNA must also be located in the histaminergic cell
bodies in the tuberomammillary nuclei. This was also confirmed for
GPCR97 (Fig. 6D).
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; Molderings et al., 1992; Bertaccini and Coruzzi, 1995;
Imamura et al., 1995; Stark et al., 1996a). GPCR97 mRNA was
detected by PCR amplification in RNA extracted from human small
intestine, testis, and prostate tissues, but was not detected in these
tissues by Northern blot analysis (not shown). If GPCR97 was only
expressed in the neuronal plexus, its overall low abundance in a whole
tissue preparation could account for this discrepancy. We are currently
investigating via in situ hybridization whether the GPCR97 receptor
mRNA is produced in the ganglia of the autonomic and enteric nervous
systems. An alternative explanation for the absence of clear peripheral
expression could be the existence of additional subtypes of the
H3 receptor, which previously has been suggested
based on pharmacological evidence (West et al., 1990; Raible et al.,
1994; Leurs et al., 1996; Schlicker et al., 1996).
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Discussion |
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Top
Summary
Introduction
Experimental Procedures
Results
Discussion
References
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The present data describes the cloning and characterization of a
novel GPCR, GPCR97, with a pharmacology and a tissue distribution that
is consistent with the histamine H3 receptor
subtype. We found that cells transfected with GPCR97 were able to
inhibit adenylate cyclase in response to histamine. Because the two
known cloned histamine receptors, H1 and
H2, activate phosphoinositide hydrolysis and
stimulation of adenylate cyclase, respectively, the inhibition of
adenylate cyclase that we observed is a new finding for a cloned
histamine receptor. It should be noted that previous experiments with
pertussis toxin- and histamine-stimulated 35S-GTP
S binding have suggested that the
H3 receptor might be
Gi-linked (Clark et al., 1993; Laitinen and
Jokinen, 1998). Because the putative H3 histamine
receptor has been pharmacologically defined (Arrang et al., 1987; Leurs
et al., 1998), we were able to test known selective agonists and
antagonists. The selective H3 agonist R--methylhistamine was able to potently and
dose-dependently inhibit forskolin-stimulated adenylate cyclase, an
effect that was mimicked by two additional H3
agonists, imitet and N--methylhistamine (data not shown).
In addition, the effect of R--methylhistamine was blocked
by the selective H3 antagonists thioperamide and
clobenpropit but not by the H1 or
H2 antagonists diphenhydramine or ranitidine. GPCR97-transfected cells also bound the high-affinity
H3 agonist R--methyl[3H]histamine. All of the tested
H3 agonists and antagonist could compete for specific
R--methyl[3H]histamine binding with
similar potencies to those reported for these compounds to brain
membranes (Hill et al., 1997). It has been suggested that clozapine may
impart some of its antipsychotic effects in humans through
H3 receptor antagonism (Kathmann et al., 1994;
Rodrigues et al., 1995; Stark et al., 1996b). We found that clozapine
did not significantly compete for binding to the recombinant human
receptor (Table 1). These differences in pharmacology may be because of
species differences or possible H3
heterogeneity (West et al., 1990).
One of the most striking features of this receptor is the abundant expression in the central nervous system, particularly in the caudate, the thalamus, and the cortex. Thus, it is surprising that this receptor cDNA has eluded so many cloning attempts over the years. To explain the previous unsuccessful attempts to clone the H3 receptor, we compared the sequence of GPCR97 to that of the H1 and H2 receptors (Fig. 1). The low overall homology among these three receptors suggests, in retrospect, that low-stringency hybridization approaches or degenerate PCR would not have been fruitful. In addition, we searched the public EST databases with the entire H3 receptor mRNA sequence. We found that the H3 receptor exists in the public domain in several clones derived from human brain libraries. However, all of these clones primarily contain only a 3'-untranslated sequence, suggesting that there may be some secondary structure present that prevents a full-length H3 encoding mRNA from being efficiently copied by reverse transcription. Our success in screening the human thalamus may be due to its abundance in that specific brain region, coupled with the fact that we size-selected for mRNAs greater than 2.5 kb.
There are many questions that remain to be answered about the histamine H3 receptor that we can now begin to answer with the cDNA. For example, are there additional H3 receptor subtypes? What additional neurotransmitter systems are regulated by histamine H3 receptors? Are H3 receptors expressed on nonneuronal cells in the periphery? We are currently seeking to answer some of these questions. In addition, we are inactivating the H3 receptor gene in mice (i.e., knockout mice) to identify its role in central nervous system function and memory control and as a means to look for additional phenotypes, which may lead to a better understanding of the physiological role of H3 receptors in normal and pathological states.
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Acknowledgments |
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We thank Jose Galindo for his great help in assembling the sequence information and K.C. Joy for performing reverse transcription-PCR experiments. We also thank Drs. Lars Karlsson, Nigel Shankley, and Josee Leysen for providing insightful discussion.
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Footnotes |
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Received February 12, 1999; Accepted April 2, 1999
Send reprint requests to: Dr. Timothy W. Lovenberg, R.W. Johnson Pharmaceutical Research Institute, 3535 General Atomics Ct., San Diego, CA. E-mail: tlovenbe{at}prius.jnj.com
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Abbreviations |
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GPCR, G protein-coupled receptor; EST, expressed sequence tag; cAMP, cyclic AMP; PCR, polymerase chain reaction.
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References |
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Top
Summary
Introduction
Experimental Procedures
Results
Discussion
References
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A. Torrent, D. Moreno-Delgado, J. Gomez-Ramirez, D. Rodriguez-Agudo, C. Rodriguez-Caso, F. Sanchez-Jimenez, I. Blanco, and J. Ortiz H3 Autoreceptors Modulate Histamine Synthesis through Calcium/Calmodulin- and cAMP-Dependent Protein Kinase Pathways Mol. Pharmacol., January 1, 2005; 67(1): 195 - 203. [Abstract] [Full Text] [PDF]
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A. Slominski, D. J. Tobin, S. Shibahara, and J. Wortsman Melanin Pigmentation in Mammalian Skin and Its Hormonal Regulation Physiol Rev, October 1, 2004; 84(4): 1155 - 1228. [Abstract] [Full Text] [PDF]
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R. L. Thurmond, P. J. Desai, P. J. Dunford, W.-P. Fung-Leung, C. L. Hofstra, W. Jiang, S. Nguyen, J. P. Riley, S. Sun, K. N. Williams, et al. A Potent and Selective Histamine H4 Receptor Antagonist with Anti-Inflammatory Properties J. Pharmacol. Exp. Ther., April 1, 2004; 309(1): 404 - 413. [Abstract] [Full Text]
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R. A. Bakker, D. M. Weiner, T. ter Laak, T. Beuming, O. P. Zuiderveld, M. Edelbroek, U. Hacksell, H. Timmerman, M. R. Brann, and R. Leurs 8R-Lisuride Is a Potent Stereospecific Histamine H1-Receptor Partial Agonist Mol. Pharmacol., March 1, 2004; 65(3): 538 - 549. [Abstract] [Full Text] [PDF]
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K. Takahashi, S. Tokita, and H. Kotani Generation and Characterization of Highly Constitutive Active Histamine H3 Receptors J. Pharmacol. Exp. Ther., October 1, 2003; 307(1): 213 - 218. [Abstract] [Full Text] [PDF]
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F. Gbahou, A. Rouleau, S. Morisset, R. Parmentier, S. Crochet, J.-S. Lin, X. Ligneau, J. Tardivel-Lacombe, H. Stark, W. Schunack, et al. Protean agonism at histamine H3 receptors in vitro and in vivo PNAS, September 16, 2003; 100(19): 11086 - 11091. [Abstract] [Full Text] [PDF]
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C. Gengs, H.-T. Leung, D. R. Skingsley, M. I. Iovchev, Z. Yin, E. P. Semenov, M. G. Burg, R. C. Hardie, and W. L. Pak The Target of Drosophila Photoreceptor Synaptic Transmission Is a Histamine-gated Chloride Channel Encoded by ort (hclA) J. Biol. Chem., October 25, 2002; 277(44): 42113 - 42120. [Abstract] [Full Text] [PDF]
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F. Gantner, K. Sakai, M. W. Tusche, W. W. Cruikshank, D. M. Center, and K. B. Bacon Histamine H4 and H2 Receptors Control Histamine-Induced Interleukin-16 Release from Human CD8+ T Cells J. Pharmacol. Exp. Ther., October 1, 2002; 303(1): 300 - 307. [Abstract] [Full Text] [PDF]
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J. Gomez-Ramirez, J. Ortiz, and I. Blanco Presynaptic H3 Autoreceptors Modulate Histamine Synthesis through cAMP Pathway Mol. Pharmacol., January 1, 2002; 61(1): 239 - 245. [Abstract] [Full Text] [PDF]
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K. Wieland, G. Bongers, Y. Yamamoto, T. Hashimoto, A. Yamatodani, W. M. B. P. Menge, H. Timmerman, T. W. Lovenberg, and R. Leurs Constitutive Activity of Histamine H3 Receptors Stably Expressed in SK-N-MC Cells: Display of Agonism and Inverse Agonism by H3 Antagonists J. Pharmacol. Exp. Ther., December 1, 2001; 299(3): 908 - 914. [Abstract] [Full Text] [PDF]
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T. Nguyen, D. A. Shapiro, S. R. George, V. Setola, D. K. Lee, R. Cheng, L. Rauser, S. P. Lee, K. R. Lynch, B. L. Roth, et al. Discovery of a Novel Member of the Histamine Receptor Family Mol. Pharmacol., March 1, 2001; 59(3): 427 - 433. [Abstract] [Full Text]
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R. B. Silver, C. J. Mackins, N. C. E. Smith, I. L. Koritchneva, K. Lefkowitz, T. W. Lovenberg, and R. Levi Coupling of histamine H3 receptors to neuronal Na+/H+ exchange: A novel protective mechanism in myocardial ischemia PNAS, February 15, 2001; (2001) 51599198. [Abstract] [Full Text]
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G. Drutel, N. Peitsaro, K. Karlstedt, K. Wieland, M. J. Smit, H. Timmerman, P. Panula, and R. Leurs Identification of Rat H3 Receptor Isoforms with Different Brain Expression and Signaling Properties Mol. Pharmacol., January 1, 2001; 59(1): 1 - 8. [Abstract] [Full Text]
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T. W. Lovenberg, J. Pyati, H. Chang, S. J. Wilson, and M. G. Erlander Cloning of Rat Histamine H3 Receptor Reveals Distinct Species Pharmacological Profiles J. Pharmacol. Exp. Ther., June 1, 2000; 293(3): 771 - 778. [Abstract] [Full Text]
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J. Sirois, G. Menard, A. S. Moses, and E. Y. Bissonnette Importance of Histamine in the Cytokine Network in the Lung Through H2 and H3 Receptors: Stimulation of IL-10 Production J. Immunol., March 15, 2000; 164(6): 2964 - 2970. [Abstract] [Full Text] [PDF]
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R. Levi and N. C. E. Smith Histamine H3-Receptors: A New Frontier in Myocardial Ischemia J. Pharmacol. Exp. Ther., March 1, 2000; 292(3): 825 - 830. [Abstract] [Full Text]
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T. Oda, N. Morikawa, Y. Saito, Y. Masuho, and S.-i. Matsumoto Molecular Cloning and Characterization of a Novel Type of Histamine Receptor Preferentially Expressed in Leukocytes J. Biol. Chem., November 17, 2000; 275(47): 36781 - 36786. [Abstract] [Full Text] [PDF]
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Y. Zheng, B. Hirschberg, J. Yuan, A. P. Wang, D. C. Hunt, S. W. Ludmerer, D. M. Schmatz, and D. F. Cully Identification of Two Novel Drosophila melanogaster Histamine-gated Chloride Channel Subunits Expressed in the Eye J. Biol. Chem., January 11, 2002; 277(3): 2000 - 2005. [Abstract] [Full Text] [PDF]
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R. B. Silver, K. S. Poonwasi, N. Seyedi, S. J. Wilson, T. W. Lovenberg, and R. Levi Decreased intracellular calcium mediates the histamine H3-receptor-induced attenuation of norepinephrine exocytosis from cardiac sympathetic nerve endings PNAS, January 8, 2002; 99(1): 501 - 506. [Abstract] [Full Text] [PDF]
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R. B. Silver, C. J. Mackins, N. C. E. Smith, I. L. Koritchneva, K. Lefkowitz, T. W. Lovenberg, and R. Levi Coupling of histamine H3 receptors to neuronal Na+/H+ exchange: A novel protective mechanism in myocardial ischemia PNAS, February 27, 2001; 98(5): 2855 - 2859. [Abstract] [Full Text] [PDF]
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), with diphenhydramine (
),
with thioperamide (
), or with clobenpropit (
). All values are
determined in triplicate. Error bars represent S.E.M.
) are shown. Bottom, competition
binding of [3H]R-
1/slope from the linear Scatchard transformation.
pIC50 values were determined by a single site curve fitting
program (Prism; GraphPad Software, San Diego, CA) and converted to
pKI values according to Cheng and Prusoff (1973)
