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J. Biol. Chem., Vol. 275, Issue 47, 36781-36786, November 24, 2000

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Molecular Cloning and Characterization of a Novel Type of Histamine Receptor Preferentially Expressed in Leukocytes^*

Tamaki Oda, Noriyuki Morikawa^§, Yoko Saito, Yasuhiko Masuho^¶, and Shun-ichiro Matsumoto^¶

From the  Helix Research Institute, Inc., 1532-3 Yana, Kisarazu-shi, Chiba, 292-0812, Japan, the ^§ Advanced Technology Platform Research Laboratory, Fujisawa Pharmaceutical Co., Ltd., 5-2-3 Tokodai, Tsukuba, Ibaraki, 300-2698, Japan, and the ^¶ Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21 Miyukigaoka, Tsukuba, Ibaraki, 305-8585, Japan

Received for publication, July 20, 2000, and in revised form, August 31, 2000

	ABSTRACT

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

Recently cDNA encoding the histamine H3 receptor was isolated after 15 years of considerable research. However, several studies have proposed heterogeneity of the H3 receptor. We report here the molecular cloning and characterization of a novel type of histamine receptor. A novel orphan G-protein-coupled receptor named GPRv53 was obtained through a search of the human genomic DNA data base and analyzed by rapid amplification of cDNA ends (RACE). GPRv53 possessed the features of biologic amine receptors and had the highest homology with H3 receptor among known G-protein-coupled receptors. Mammalian cells expressing GPRv53 were demonstrated to bind and respond to histamine in a concentration-dependent manner. In functional assays, not only an H3 receptor agonist, R-()-methylhistamine, but also a H3 receptor antagonist, clobenpropit, and a neuroleptic, clozapine, activated GPRv53-expressing cells. Tissue distribution analysis revealed that expression of GPRv53 is localized in the peripheral blood leukocytes, spleen, thymus, and colon, which was totally different from the H3 receptor, whose expression was restricted to the brain. The discovery of the GPRv53 receptor will open a new phase of research on the physiological role of histamine.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

Histamine is an important physiological amine that works as a chemical messenger to exert numerous functions in central and peripheral tissues. These effects are mediated through three pharmacologically distinct subtypes of receptors, i.e. the H1, H2, and H3 receptors, which are all members of the G-protein-coupled receptor (GPCR)¹ family (1). H1 receptor is distributed in the brain, most smooth muscle cells, endothelial cells, adrenal medulla, and heart. H1 receptor plays roles in smooth muscle contraction, stimulation of nitric oxide formation, endothelial cell contraction and in increasing vascular permeability, all of which have close relationships with allergic conditions. H1 receptor preferentially couples to the G_q/11 family of G-proteins and causes mobilization of intracellular Ca²⁺ in a pertussis toxin-insensitive fashion (2, 3). The human H1 receptor gene is localized on chromosome 3p25 (4). The H2 receptor causes cyclic AMP (cAMP) accumulation through activation of a G-protein, G_s, in the gastric cells (5), cardiac tissues (6), and other cell types including smooth muscle cells and immune cells (1). In the gastric cells, H2 receptor has been demonstrated to function as a key molecule for gastric acid secretion, which has been an important drug target for gastrointestinal ulcers (7). A chromosomal mapping study indicated that the H2 receptor gene is located on human chromosome 5 (8). The H3 receptor was originally advocated as a presynaptic autoreceptor for histamine synthesis localized in histamine-containing neuron in the central nervous system (9). Several studies using H3 selective agonists revealed that H3 receptor couples to pertussis toxin-sensitive G_i/o protein (10-12). Recently, Lovenberg et al. (13) reported the isolation of cDNA encoding for human H3 receptor and showed that the receptor-expressing cells virtually inhibited adenylate cyclase in response to H3 receptor agonists. With respect to the H3 receptor, however, there has been increasing pharmacological evidence implying the existence of additional types of receptors, which are still unknown at the molecular level (14-18).

The present study reports the molecular cloning of a novel type of histamine receptor named GPRv53 that is preferentially expressed in the peripheral blood leukocytes. With expression of GPRv53 in mammalian cells, functional assays were carried out to analyze the effects of histamine receptor agonists and antagonists.

	EXPERIMENTAL PROCEDURES

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

Isolation of cDNA-encoding GPRv53-- By performing a BLAST search (19), three overlapping clones showing homology with GPCR super family genes were found in the HTGS (high through-put genome sequence) division of GenBank^TM (accession numbers AC007922, AC009668, and AP001327). After rapid amplification of cDNA ends (RACE) analysis with human fetus Marathon-Ready cDNA (CLONTECH), full-length open reading frame cDNA of the GPCR (GPRv53) was isolated by a PCR reaction using a set of synthetic oligonucleotide primers, 5'-CTAGTCTAGAATGCCAGATACTAATAGCACAATCAATTTATC-3' and 5 '-CTAGTCTAGATTAAGAAGATACTGACCGACTGTGTTGT-3'. The reaction products were digested with XbaI and ligated into expression vectors pEF-BOS-dhfr (20) and pCEP4E, made from pCEP4 (Invitrogen) by deleting an expression unit of Epstein-Barr virus nuclear antigen EBNA-1. The algorithm proposed by Myers and Miller (21) was used to calculate the percentage of homology between two amino acid sequences.

Luciferase Reporter Assay-- A reporter gene assay was performed to investigate changes in the intracellular levels of cAMP with the method described by Fitzgerald et al. (22) with minor modifications. Briefly, 7 × 10⁴ cells of EBNA-1-expressing HEK293 (293-EBNA, Invitrogen) were harvested on collagen-coated 24-well plates for 24 h, and a GPRv53 expression plasmid and a cAMP-responsive element (CRE)-attached luciferase reporter gene plasmid (CRE-luc), pCRE-luc (Stratagene) were co-transfected using Fugene 6 (Roche Molecular Biochemicals) according to the manufacturer's recommendations. The following day, the cells were treated with reagents (Sigma) in the presence of 1 µM forskolin for 5 h and lysed on ice. Intracellular luciferase activity in aliquots from each lysate was measured using a model LB953 luminometer (EG&G Berthold).

Ca²⁺ Mobilization Assays-- 293-EBNA cells were seeded onto collagen I-coated 96-well black-wall, clear-bottom plates at 2 × 10⁴ cells/well (Becton Dickinson). After overnight culture, equal amounts of GPRv53 and mouse G15 (GenBank^TM accession number P30678) expression plasmids were co-transfected with Fugene 6 and incubated for 24 h. The cells were loaded with 4 µM Fluo-3 AM (Molecular Probes) in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum for 1 h and washed four times with assay buffer (Hanks' balanced salt solution, 20 mM HEPES, pH 7.4), and the change in intracellular Ca²⁺ was measured with a fluorimetric imaging plate reader (FLIPR, Molecular Devices). The maximum change in fluorescence was plotted against the ligand concentration to study the agonist response.

[³H]Histamine Binding Assay-- The GPRv53 expression plasmid was transfected to 293-EBNA cells using Fugene 6, and after 3 days of culture, the cells were collected, and the membrane fraction was prepared as described by Lovenberg et al. (13). For performing binding assay, the membranes were applied into 96-well white microplates with a bound GF/B filter (Packard) and incubated with 10 nM [³H]histamine dihydrochloride (Amersham Pharmacia Biotech) and test reagents for 1 h at 25 °C followed by washing 8 times with ice-cold buffer (50 mM Tris-HCl, 5 mM MgCl₂). [³H]Histamine activity in each well was counted using TopCounteHTS (Packard Instrument Co.), and data were analyzed using Prism (Graphpad Software Inc.).

Tissue Distribution Studies-- Using the full-length coding region of GPRv53 as a ³²P-labeled probe, expression of GPRv53 in human tissues was analyzed with Multiple Tissue Northern (MTN^TM) blot membranes (CLONTECH). To sensitively compare the tissue distribution between GPRv53 and H3 receptor, PCR was carried out using multiple tissue cDNA panels (CLONTECH). A set of primers, 5'-GAATTGTCTGGCTGGATTAATTTGCTAATTTG-3' and 5'-AAGAATGATGTGATGGCAAGGATGTACC-3', was used to detect GPRv53 cDNA, and another set of primers, 5'-TCAGCTACGACCGCTTCCTGTCGGTCAC-3' and 5'-TTGAGTGAGCGCGGCCTCTCAGTGCCCC-3', was used to amplify H3 receptor in the presence of dimethyl sulfoxide (Sigma). The PCR profile used for GPRv53 consisted of 40× (94 °C for 30 s, 55 °C for 30 s, 72 °C for 30 s), and a shuttle-PCR profile, 5× (98 °C for 5 s, 72 °C for 1 min) followed by 5× (98 °C for 5 s, 70 °C for 1 min) and 30× (98 °C for 5 s, 68 °C for 1 min) was used for H3 receptor. To study the expression of GPRv53 in fractionated hematopoietic cells, human mononuclear cells, neutrophils, and eosinophils were isolated from the heparinized blood of healthy volunteers using the Ficoll-Paque (Amersham Pharmacia Biotech) technique and CD16 microbeads (MACS reagents; Miltenyi Biotech). Total RNA was prepared using ISOGEN (Nippon Gene) and converted to cDNA with SuperScript II reverse transcriptase (Life Technologies, Inc.).

	RESULTS

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

Cloning of GPRv53 cDNA-- Using the primary structures of known GPCRs as query sequences, a novel human genomic DNA sequence that possessed the characteristics of the GPCR super family was identified in the GenBank^TM clones. Based on that sequence, rapid amplification of cDNA ends (RACE) analysis was performed, and full-length cDNA of the novel GPCR, designated GPRv53, was isolated. GPRv53 was deduced to consist of 390 amino acids and shared several features conserved within GPCR members for amine ligands (23) such as 1) a Asp residue in TM1, 2) a DRY motif at TM2, 3) a disulfide bond between the first and third extracellular loops, 4) a Trp residue in TM4 and TM6, 5) a Pro residue in TM5 and TM6, 6) a NPXXY motif in TM7, and 7) a potential palmitoylation site in the C-terminal tail. Comparison of the amino acid sequence with known GPCRs revealed that GPRv53 showed the greatest homology with a recently cloned histamine H3 receptor (37.4%, Fig. 1), whereas it showed 23.0% with H1 and 21.6% with H2 receptors (Table I). Analysis of the GenBank^TM genomic DNA data base elucidated that GPRv53 gene is located in chromosome 18q11.2, and its coding region consists of three exons (1st exon, amino acid numbers 1-65; 2nd exon, amino acid numbers 65-119; and 3rd exon, amino acid numbers 120-390).

View larger version (77K): [in this window] [in a new window]   Fig. 1.   Amino acid alignments of GPRv53 and histamine H3 receptor. Identical amino acids are boxed. Putative transmembrane regions (TM1-7) are underlined. The nucleotide sequence data reported here have been submitted to the DDBJ, EMBL, and GenBankTM nucleotide sequence data bases as accession number AB044934.

Functional Activation of GPRv53-expressing Cells-- To determine whether GPRv53 is a novel histamine receptor, GPRv53 was transiently expressed in 293-EBNA cells and subjected to functional assays. The changes in intracellular cAMP were investigated using a CRE-luc reporter assay system, which had been demonstrated to work equally well with direct measurement of the intracellular cAMP concentration (22, 24-27). As shown in Fig. 2a, histamine inhibited forskolin-stimulated CRE-luc activity in a concentration-dependent manner. Other biologic amines, including acetylcholine, dopamine, epinephrine, imidazole, serotonine, and tryptamine, had no effect on GPRv53-mediated CRE-luc activity (data not shown). The effect of histamine was completely abolished with pretreatment by pertussis toxin, suggesting that GPRv53 activated the G_i/o pathway. Direct measurement of the cAMP concentration also revealed that histamine inhibited the accumulation of cAMP in GPRv53-expressing cells (data not shown). Next, two known H3 receptor anagonists, thioperamide and clobenpropit, were investigated for their activity on GPRv53 in the reporter gene assay. Thioperamide blocked the histamine activity on GPRv53, whereas clobenpropit showed agonistic activity in a concentration-dependent manner (Fig. 2b). Histamine H1 or H2 receptor-selective ligands (pyrilamine, diphenhydramine, and cimetidine) were negative for activation or inhibition of GPRv53 in the reporter gene assay (data not shown).

View larger version (24K): [in this window] [in a new window]   Fig. 2.   Studies of GPRv53 with histamine and H3 receptor-selective ligands in reporter gene assay. a, CRE-luc activity of forskolin-stimulated GPRv53-expressing 293-EBNA cells. Forskolin-stimulated (1 µM) intracellular luciferase activity was measured with (white bar) or without (black bar) pretreatment with 100 ng/ml pertussis toxin for 12 h. The experiment shown is a representative of three experiments performed in triplicate. b, effects of known H3 receptor antagonists. GPRv53-expressing cells were preincubated with 10 pM to 1 µM thioperamide (black bar) or clobenpropit (white bar) for 15 min before the challenge of 1 µM forskolin and 5 nM histamine. The experiment shown is a representative of six experiments performed in triplicate.

The mobilization of intracellular Ca²⁺ through GPRv53 activation was evaluated using FLIPR system. To carry out the assay, GPRv53 was transiently co-expressed in 293-EBNA cells with a "promiscuous" G15, which is able to couple non-selectively with a large variety of GPCRs and transduce intracellular signals through the phospholipase C pathway (28). Histamine, clobenpropit, R-()-methylhistamine (RMeH, H3 receptor agonist), and clozapine (neuroleptic) caused activation of GPRv53, exhibiting EC₅₀ values of 9.95, 8.22, 172, and 1290 nM, respectively (Fig. 3). No response was observed by treatment with thioperamide. The value of Ca²⁺ mobilization induced by clobenpropit was about 60% that of the value induced by the other agonists. The activity on GPRv53 with clobenpropit or thioperamide in the FLIPR study was in good agreement with the results obtained from the reporter gene assay. No signal was detected for 293-EBNA cells expressing GPRv53 or G15 alone (data not shown).

View larger version (25K): [in this window] [in a new window]   Fig. 3.   Functional activation of GPRv53 using FLIPR. 293-EBNA cells transiently transfected with GPRv53 and G15 were treated with various concentrations of histamine (), RMeH (), clobenpropit (), thioperamide (), or clozapine (). Each point represents the mean value of triplicate determinations from a single experiment performed four to five times.

Radiolabeled [³H]Histamine Binding Assay-- [³H]Histamine was used to determine the binding affinity of histamine for GPRv53. The membrane fraction prepared from 293-EBNA cells expressing GPRv53 was specifically and saturably bound to radiolabeled histamine with a K_d value of 17.2 nM (Fig. 4a). There was no specific binding observed for the membrane fraction from parental 293-EBNA cells (data not shown). The rank order of affinity on GPRv53 to compete with [³H]histamine was histamine, clobenpropit > thioperamide, RMeH > clozapine, exhibiting IC₅₀ values of 2.48, 3.06, 231.6, 232.5, and 978 nM, respectively (Fig. 4b).

View larger version (27K): [in this window] [in a new window]   Fig. 4.   Saturable binding studies of radiolabeled histamine to GPRv53-transfected 293-EBNA cells. a, saturation isotherm was obtained using [3H]histamine and GPRv53-expressing cell membrane. Total binding (), specific binding (), and nonspecific binding () are shown. Inset, Scatchard analysis of the specific binding isotherm. Each point represents the mean value of duplicate determination from a single experiment three times performed. b, competition binding assays for GPRv53. Various concentrations of histamine (), RMeH (), clobenpropit (), thioperamide (), or clozapine () were challenged to GPRv53 in the presence of 10 nM of [3H]histamine. Each point represents the mean value of duplicate determinations from a single experiment performed at least two times.

Tissue Distribution of GPRv53 in Human Tissues-- Northern blot analysis of human tissues revealed that expression of GPRv53 was detected only in peripheral blood leukocytes (Fig. 5a). In addition to peripheral blood leukocytes, PCR analysis for human tissue cDNA also detected GPRv53 expression in the thymus, small intestine, spleen, and colon (Fig. 5b). In contrast, a specific signal for histamine H3 receptor was found only in the brain, which is in good agreement with the earlier observation of Lovenberg et al. (13). PCR analysis of fractionated blood cells indicated that GPRv53 was expressed more abundantly on eosinophils than on mononuclear cells or neutrophils (Fig. 5c).

View larger version (51K): [in this window] [in a new window]   Fig. 5.   Tissue distribution of GPRv53 in human tissues. a, Northern blot analysis of GPRv53 expression. Multiple Tissue Northern (MTNTM) blot membranes (CLONTECH) were used to analyze GPRv53 expression. The arrow indicates detected mRNA for GPRv53 in peripheral blood leukocytes at 4.5 kilobases. Lower panel, hybridization with -actin cDNA. b, PCR analysis of GPRv53 and histamine H3 receptor expression. Amplification with the gene-specific primer for GPRv53 is shown in the top panel, histamine H3 receptor is shown in the middle panel, and G3PDH is shown in the bottom panel. c, expression of GPRv53 in hematopoietic cells. cDNA of mononuclear cells (lanes 1 and 4), neutrophils (lanes 2 and 5), and eosinophils (lanes 3 and 6) were prepared from the blood of two independent healthy donors (lanes 1-3, donor A; lanes 4-6, donor B), and GPRv53 expression was analyzed in each cell fraction by performing PCR reactions.

	DISCUSSION

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

This paper describes molecular cloning of a novel histamine receptor, GPRv53, that has 37.4% homology with histamine H3 receptor. In functional assays, a selective H3 receptor agonist, RMeH, activated GPRv53 at severalfold weaker potency than histamine did, and an H3 receptor selective antagonist, thioperamide, inhibited GPRv53 activation with histamine. The most surprising observation obtained in this report is that an H3-selective antagonist, clobenpropit, and a neuroleptic, clozapine, exerted agonistic activity on GPRv53. The fact that clobenpropit induced about 60% of intrinsic GPRv53 activity compared with histamine indicates that it works as a partial agonist of GPRv53. As far as we know, this is the first finding that clobenpropit exerts agonistic activity on a certain receptor in addition to antagonistic activity on H3 receptor. With respect to the action of clozapine, our result is in good agreement with earlier reports demonstrating that clozapine shows affinity for histamine receptor (29, 30). Clinically, clozapine treatment involves the risk of causing serious agranulocytosis (31, 32). The relatively restricted expression of GPRv53 on peripheral blood leukocytes suggests that agonistic action of clozapine on GPRv53 may have some relevance to the pathogenesis of the drug-induced agranulocytosis, but this requires further investigation.

Activation of GPRv53 allowed coupling with pertussis toxin-sensitive G_i/o. On the other hand, it is noteworthy that ligand-induced Ca²⁺ mobilization was observed when GPRv53 was co-expressed with G15, which is distributed mainly in the hematopoietic cells (33, 34). The fact that GPRv53 expression can also be found preferentially in leukocytes suggests that GPRv53 induces activation of G_15/16 as a natural second messenger pathway.

Several studies suggest that receptor subtypes exist for the histamine H3 receptor. West et al. (14) propose the existence of histamine H3a and H3b receptors, with different binding affinities for thioperamide, in the rat brain. Similar indications were obtained for mouse brain, guinea pig ileum, and guinea pig jejunum (15, 16). Concomitant with the lack of peripheral tissue expression of a recently cloned H3 receptor (13), it is important to clarify the heterogeneity of H3 receptors at the molecular level in order to study the pathophysiological roles of histamine. GPRv53 differs from these proposed H3a or H3b based on the current results that 1) the potency of RMeH for GPRv53 was much less than that of histamine for GPRv53, 2) expression of GPRv53 could hardly be detected in the brain, and 3) clobenpropit did not work as an antagonist but worked as an agonist of GPRv53. In addition, the original definition of H3 receptor, a presynaptic autoreceptor for histamine release in histaminergic neurons in the brain (9), is hardly adoptable for the character of GPRv53. Hence, GPRv53 can be surmised to be a novel histamine H4 receptor. Actually, previous works propose the existence of a novel histamine receptor, which is different from H1, H2, or H3 receptor. Schworer et al. (17) report that the porcine small intestine contains an H3-like receptor that is pharmacologically distinct from the proposed H3a and H3b (17). Their findings agree well with our result that H4 receptor (GPRv53) was expressed in the small intestine. Raible et al. (18) also report that eosinophils express a novel type of histamine receptor that has the characteristics of binding to RMeH at low affinity, being antagonized by thioperamide, and causing calcium mobilization via agonist binding. These observations are in good agreement with the profiles of the present H4 receptor, whose expression can be found in eosinophils. The functions of H4 receptor in the physiology and pathology of small intestine and eosinophils need to be elucidated in the future.

	ACKNOWLEDGEMENTS

We thank E. Nitsuu for skilled technical assistance with DNA sequencing and Drs. M. Suwa, T. Sugiyama, K. Yoshida, N. Seki, and H. Koga for helpful suggestions. We are grateful to Dr. Shigekazu Nagata for providing pEF-BOS and Dr. S. Nishijima for constructing pCEP4E. We also thank Drs. J. Takasaki, M. Kamohara, T. Saito, K. Furuichi, and M. Matsumoto for valuable discussions and assistance in performing functional assays.

	FOOTNOTES

^* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EMBL Data Bank with accession number(s) AB044934.

To whom correspondence should be addressed: Molecular Medicine Lab., Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. Tel.: 81-298 54-1610; Fax: 81-298 52-5444; E-mail: matsumot@yamanouchi.co.jp.

Published, JBC Papers in Press, September 5, 2000, DOI 10.1074/jbc.M006480200

	ABBREVIATIONS

The abbreviations used are: GPCR, G-protein-coupled receptor; CRE, cyclic AMP-responsive element; luc, luciferase; TM, transmembrane; RMeH, R-()-methylhistamine; FLIPR, fluorescence imaging plate reader; PCR, polymerase chain reaction.

	REFERENCES

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