-
[show abstract]
[hide abstract]
ABSTRACT: 1The effects of YM-254890, a specific Gαq/11 inhibitor, on platelet functions, thrombus formation under high-shear rate condition and femoral artery thrombosis in cynomolgus monkeys were investigated.2YM-254890 concentration dependently inhibited ADP-induced intracellular Ca2+ elevation, with an IC50 value of 0.92±0.28 μM.3P-selectin expression induced by ADP or thrombin receptor agonist peptide (TRAP) was strongly inhibited by YM-254890, with IC50 values of 0.51±0.02 and 0.16±0.08 μM, respectively.4YM-254890 had no effect on the binding of fibrinogen to purified GPIIb/IIIa, but strongly inhibited binding to TRAP-stimulated washed platelets.5YM-254890 completely inhibited platelet shape change induced by ADP, but not that induced by collagen, TRAP, arachidonic acid, U46619 or A23187.6YM-254890 attenuated ADP-, collagen-, TRAP-, arachidonic acid- and U46619-induced platelet aggregation with IC50 values of <1 μM, whereas it had no effect on phorbol 12-myristate 13-acetate-, ristocetin-, thapsigargin- or A23187-induced platelet aggregation.7High-shear stress-induced platelet aggregation and platelet-rich thrombus formation on a collagen surface under high-shear flow conditions were concentration dependently inhibited by YM-254890.8The antithrombotic effect of YM-254890 was evaluated in a model of cyclic flow reductions in the femoral artery of cynomolgus monkeys. The intravenous bolus injection of YM-254890 dose dependently inhibited recurrent thrombosis without affecting systemic blood pressure or prolonging template bleeding time.9YM-254890 is a useful tool for investigating Gαq/11-coupled receptor signaling and the physiological roles of Gαq/11.British Journal of Pharmacology (2006) 148, 61–69. doi:10.1038/sj.bjp.0706711
British Journal of Pharmacology 01/2009; 148(1):61 - 69. · 4.41 Impact Factor
-
Mitsuyuki Matsumoto,
Richard E Straub,
Stefano Marenco,
Kristin K Nicodemus,
Shun-Ichiro Matsumoto,
Akihiko Fujikawa,
Sosuke Miyoshi,
Miwako Shobo,
Shinji Takahashi,
Junko Yarimizu, [......],
Hideki Hiyama,
Hiroyuki Ishii,
Ayako Matsuo,
Shintaro Nishimura,
Nobuya Matsuoka,
Masato Kobori,
Hitoshi Matsushime,
Masao Katoh,
Kiyoshi Furuichi,
Daniel R Weinberger
[show abstract]
[hide abstract]
ABSTRACT: The G protein-coupled receptor (GPCR) family is highly diversified and involved in many forms of information processing. SREB2 (GPR85) is the most conserved GPCR throughout vertebrate evolution and is expressed abundantly in brain structures exhibiting high levels of plasticity, e.g., the hippocampal dentate gyrus. Here, we show that SREB2 is involved in determining brain size, modulating diverse behaviors, and potentially in vulnerability to schizophrenia. Mild overexpression of SREB2 caused significant brain weight reduction and ventricular enlargement in transgenic (Tg) mice as well as behavioral abnormalities mirroring psychiatric disorders, e.g., decreased social interaction, abnormal sensorimotor gating, and impaired memory. SREB2 KO mice showed a reciprocal phenotype, a significant increase in brain weight accompanying a trend toward enhanced memory without apparent other behavioral abnormalities. In both Tg and KO mice, no gross malformation of brain structures was observed. Because of phenotypic overlap between SREB2 Tg mice and schizophrenia, we sought a possible link between the two. Minor alleles of two SREB2 SNPs, located in intron 2 and in the 3' UTR, were overtransmitted to schizophrenia patients in a family-based sample and showed an allele load association with reduced hippocampal gray matter volume in patients. Our data implicate SREB2 as a potential risk factor for psychiatric disorders and its pathway as a target for psychiatric therapy.
Proceedings of the National Academy of Sciences 05/2008; 105(16):6133-8. · 9.68 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Phase resetting is one of the essential properties of circadian clocks that is required for the adjustment to a particular environment and the induction of Per1 and Per2 clock genes is believed to be a primary molecular event during this process. Although the intracellular signal transduction pathway underlying Per1 gene activation has been well characterized, the mechanisms that control Per2 up-regulation have not yet been elucidated. In our present study, we demonstrate that Gq/11 coupled receptors mediate serum-induced immediate rat Per2 (rPer2) transactivation in Rat-1 fibroblasts via intracellular Ca2+ mobilization. Stimulation of these cells with a high concentration of serum was found to rapidly increase the intracellular Ca2+ levels and strongly up-regulated rPer2 gene. rPer2 induction by serum stimulation was abrogated by intracellular Ca2+ chelation and depletion of intracellular Ca2+ store, which suggests that the calcium mobilization is necessary for the up-regulation of rPer2 gene. In addition, suppression of Gq/11 function was observed to inhibit both Ca2+ mobilization and rPer2 induction. Further, we demonstrated that endothelin-induced acute rPer2 transactivation via Gq/11-coupled endothelin receptors is also suppressed by a Gq/11 specific inhibitor. These findings together suggest that serum and endothelin utilize a common Gq/11-PLC mediated pathway for the transactivation of rPer2, which involves the mobilization of calcium from the intracellular calcium store.
Genes to Cells 10/2006; 11(9):1039-49. · 2.68 Impact Factor
-
Folia Pharmacologica Japonica 08/2006; 128(1):23-31.
-
[show abstract]
[hide abstract]
ABSTRACT: 1 The effects of YM-254890, a specific Galpha(q/11) inhibitor, on platelet functions, thrombus formation under high-shear rate condition and femoral artery thrombosis in cynomolgus monkeys were investigated. 2 YM-254890 concentration dependently inhibited ADP-induced intracellular Ca(2+) elevation, with an IC(50) value of 0.92+/-0.28 microM. 3 P-selectin expression induced by ADP or thrombin receptor agonist peptide (TRAP) was strongly inhibited by YM-254890, with IC(50) values of 0.51+/-0.02 and 0.16+/-0.08 microM, respectively. 4 YM-254890 had no effect on the binding of fibrinogen to purified GPIIb/IIIa, but strongly inhibited binding to TRAP-stimulated washed platelets. 5 YM-254890 completely inhibited platelet shape change induced by ADP, but not that induced by collagen, TRAP, arachidonic acid, U46619 or A23187. 6 YM-254890 attenuated ADP-, collagen-, TRAP-, arachidonic acid- and U46619-induced platelet aggregation with IC(50) values of <1 microM, whereas it had no effect on phorbol 12-myristate 13-acetate-, ristocetin-, thapsigargin- or A23187-induced platelet aggregation. 7 High-shear stress-induced platelet aggregation and platelet-rich thrombus formation on a collagen surface under high-shear flow conditions were concentration dependently inhibited by YM-254890. 8 The antithrombotic effect of YM-254890 was evaluated in a model of cyclic flow reductions in the femoral artery of cynomolgus monkeys. The intravenous bolus injection of YM-254890 dose dependently inhibited recurrent thrombosis without affecting systemic blood pressure or prolonging template bleeding time. 9 YM-254890 is a useful tool for investigating Galpha(q/11)-coupled receptor signaling and the physiological roles of Galpha(q/11).
British Journal of Pharmacology 05/2006; 148(1):61-9. · 4.41 Impact Factor
-
Shun-Ichiro Matsumoto,
Chihiro Yamazaki,
Koh-Hei Masumoto,
Mamoru Nagano,
Masanori Naito,
Takatoshi Soga,
Hideki Hiyama,
Mitsuyuki Matsumoto, Jun Takasaki,
Masazumi Kamohara,
Ayako Matsuo,
Hiroyuki Ishii,
Masato Kobori,
Masao Katoh,
Hitoshi Matsushime,
Kiyoshi Furuichi,
Yasufumi Shigeyoshi
[show abstract]
[hide abstract]
ABSTRACT: Prokineticins, multifunctional secreted proteins, activate two endogenous G protein-coupled receptors PKR1 and PKR2. From in situ analysis of the mouse brain, we discovered that PKR2 is predominantly expressed in the olfactory bulb (OB). To examine the role of PKR2 in the OB, we created PKR1- and PKR2-gene-disrupted mice (Pkr1(-/-) and Pkr2(-/-), respectively). Phenotypic analysis indicated that not Pkr1(-/-)but Pkr2(-/-)mice exhibited hypoplasia of the OB. This abnormality was observed in the early developmental stages of fetal OB in the Pkr2(-/-) mice. In addition, the Pkr2(-/-) mice showed severe atrophy of the reproductive system, including the testis, ovary, uterus, vagina, and mammary gland. In the Pkr2(-/-) mice, the plasma levels of testosterone and follicle-stimulating hormone were decreased, and the mRNA transcription levels of gonadotropin-releasing hormone in the hypothalamus and luteinizing hormone and follicle-stimulating hormone in the pituitary were also significantly reduced. Immunohistochemical analysis revealed that gonadotropin-releasing hormone neurons were absent in the hypothalamus in the Pkr2(-/-) mice. The phenotype of the Pkr2(-/-) mice showed similarity to the clinical features of Kallmann syndrome, a human disease characterized by association of hypogonadotropic hypogonadism and anosmia. Our current findings demonstrated that physiological activation of PKR2 is essential for normal development of the OB and sexual maturation.
Proceedings of the National Academy of Sciences 03/2006; 103(11):4140-5. · 9.68 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The pharmacological properties of YM-254890, a specific G(alpha)q/11 inhibitor, on acute thrombosis and chronic neointima formation after vascular injury have been investigated. FeCl3 was used to induce vascular injury in the carotid artery of mice. For the thrombosis studies, the test drug was either intravenously or orally administered before vascular injury. For the neointima studies, the test drug was orally administered 1 h before and twice daily for 1 week after vascular injury. Histological analysis was then performed 3 weeks later. YM-254890 significantly inhibited ex vivo platelet aggregation 5 min after intravenous bolus injection at 0.03 mg/kg or more, and 1 h after oral administration at 1 mg/kg. YM-254890 significantly inhibited thrombus formation after intravenous bolus injection at 0.03 mg/kg as well as after oral administration at 1 mg/kg, but tail transection bleeding time was significantly prolonged at 0.1 mg/kg for intravenous injection and 3 mg/kg for oral administration. Furthermore, oral administration of YM-254890 dose-dependently inhibited neointima formation 3 weeks after vascular injury with significant effects at 1 mg/kg twice daily for 1 week. Clopidogrel also significantly inhibited neointima formation at its antithrombotic dose, but its inhibitory potency was less than that of YM-254890. However, YM-254890 significantly reduced systemic blood pressure at doses 3 times higher than those that produced significant inhibitory effects on thrombosis and neointima formation. Though the systemic use of YM-254890 may be limited, owing to its narrow therapeutic window, this unique compound is a useful research tool for investigating the physiological roles of G(alpha)q/11 .
Thrombosis and Haemostasis 08/2005; 94(1):184-92. · 5.04 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Histamine H(4) receptor is considered as a novel therapeutic target for allergic diseases. To enhance the knowledge about species difference, which is essential for drug discovery research, monkey H(4) receptor was identified. Monkey H(4) receptor was characterized to have comparable similarity with its human counterpart. Discovery of monkey H(4) receptor will contribute to a better interpretation of effective drug discovery.
Journal of Pharmacological Sciences 08/2005; 98(3):319-22. · 2.08 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: G-protein-coupled receptors (GPCRs) are important mediators of signal transduction and are therefore potential targets for pharmacological therapeutics. Here, we report the identification and characterization of an orphan GPCR, termed GPRg1, which was found in the GenBank database following searches with GPCR query sequences. Quantitative PCR analysis revealed that GPRg1 transcripts are expressed almost exclusively in the brain. Moreover, in situ hybridization experiments in brain demonstrated that GPRg1 is abundantly expressed in the ventrolateral region of caudate putamen, the habenular nucleus, the zona incerta, and the medial mammillary nucleus. In addition, overexpression of GPRg1 in 293-EBNA cells activates serum response factor mediated transcription, which was completely inhibited by the Gq/11 selective inhibitor YM-254890, indicating the coupling of GPRg1 with Gq/11. These findings suggest that GPRg1 is a candidate receptor for novel physiologically bioactive substrates and that it plays important roles in the central nervous system.
Biochemical and Biophysical Research Communications 06/2005; 331(1):363-9. · 2.48 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Proadrenomedullin N-terminal 20 peptide (PAMP[1-20]/PAMP-20) and its truncated analog, PAMP[9-20]/PAMP-12, are endogenous peptides that elicit hypotension through inhibiting catecholamine secretion from sympathetic nerve endings and adrenal chromaffin cells. Although the binding sites for PAMP are widely distributed, the nature of its receptor has been elusive. In an effort to identify potential PAMP receptor(s), we found that a human G-protein-coupled receptor, MrgX2, was specifically activated by PAMP. Although a previous study revealed that MrgX2 was a receptor for cortistatin, a neuropeptide involved in sleep regulation and locomotor activity, our present data indicated that the rank order of the agonistic effect against MrgX2 was "PAMP-12> or =cortistatin>PAMP-20". These activities were confirmed by the inhibition of the forskolin-elevated cAMP accumulation, Ca(2+) mobilization, and [(35)S]guanosine 5'-(gamma-thio)triphosphate binding assays. These findings suggest that MrgX2 couples with not only G(alpha q) but also G(alpha i), consistent with previous reports on the pharmacological profile of PAMP signaling. Furthermore, by immunostaining, we found that MrgX2 was expressed in the adrenal chromaffin cells as well as the dorsal root ganglia. From these results, we concluded that MrgX2 is a potential human PAMP-12 receptor that regulates catecholamine secretion from adrenal glands. The present discovery will eventually lead to a better understanding of the pathophysiological role of proadrenomedullin peptides.
Biochemical and Biophysical Research Communications 05/2005; 330(4):1146-52. · 2.48 Impact Factor
-
Takatoshi Soga,
Takahide Ohishi,
Tetsuo Matsui,
Tetsu Saito,
Mitsuyuki Matsumoto, Jun Takasaki,
Shun-Ichiro Matsumoto,
Masazumi Kamohara,
Hideki Hiyama,
Shigeru Yoshida,
Kazuhiro Momose,
Yoshitaka Ueda,
Hitoshi Matsushime,
Masato Kobori,
Kiyoshi Furuichi
[show abstract]
[hide abstract]
ABSTRACT: A lysophospholipid series, such as lysophosphatidic acid, lysophosphatidylserine, and lysophosphatidylcholine (LPC), is a bioactive lipid mediator with diverse physiological and pathological functions. LPC has been reported to induce insulin secretion from pancreatic beta-cells, however, the precise mechanism has remained elusive to date. Here we show that an orphan G-protein-coupled receptor GPR119 plays a pivotal role in this event. LPC potently enhances insulin secretion in response to high concentrations of glucose in the perfused rat pancreas via stimulation of adenylate cyclase, and dose-dependently induces intracellular cAMP accumulation and insulin secretion in a mouse pancreatic beta-cell line, NIT-1 cells. The Gs-protein-coupled receptor for LPC was identified as GPR119, which is predominantly expressed in the pancreas. GPR119-specific siRNA significantly blocked LPC-induced insulin secretion from NIT-1 cells. Our findings suggest that GPR119, which is a novel endogenous receptor for LPC, is involved in insulin secretion from beta-cells, and is a potential target for anti-diabetic drug development.
Biochemical and Biophysical Research Communications 02/2005; 326(4):744-51. · 2.48 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: YM-254890, which was isolated from the culture broth of Chromobacterium sp., inhibits ADP-induced platelet aggregation and has antithrombotic and thrombolytic effects. YM-254890 blocks Galpha(q/11)-coupled ADP receptor P2Y1-mediated Ca(2+) mobilization. Here we report that YM-254890 is a selective Galpha(q/11) inhibitor. YM-254890 blocked Ca(2+) mobilization mediated by several Galpha(q/11)-coupled receptors but not by Galpha(i)- or Galpha(15)-coupled receptor, indicating that phospholipase Cbeta activation and subsequent signaling molecules are not the target of YM-254890. YM-254890 completely prevented the serum response factor (SRF)-mediated gene transcription induced by Galpha(q)R183C, which is constitutively active in a receptor-dependent manner because of its reduced k(cat) of GTP hydrolysis. Conversely, YM-254890 had only a modest effect on the SRF-mediated gene transcription by Galpha(q)Q209L, which is GTPase-deficient (activated) Galpha(q). These suggested that the acting point of YM-254890 is receptor-Galpha(q) interaction or the subsequent guanine nucleotide exchange step. The fact that YM-254890 (i) inhibited the SRF-mediated gene transcription by Galpha(qi5), which interacts with Galpha(i)-coupled receptor and possesses the effector function of Galpha(q), and (ii) had no effect on the K(d) value of high affinity [(3)H]2MeSADP binding to P2Y1, which reflects the agonist-receptor-Galpha ternary complex, suggested that receptor-Galpha(q/11) interaction is not the target of YM-254890. On the other hand, specific [(35)S]GTPgammaS binding to Galpha(q/11) stimulated by the M1 muscarinic acetylcholine receptor and P2Y1 were inhibited by YM-254890. These data indicate that YM-254890 blocks the exchange of GDP for GTP in Galpha(q/11) activation. This novel Galpha(q/11)-selective inhibitor is a promising and powerful tool for studying Galpha(q/11) protein activation, Galpha(q/11) -coupled receptor signaling, and Galpha(q/11)-mediated biological events.
Journal of Biological Chemistry 12/2004; 279(46):47438-45. · 4.77 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: YM-254890, which was isolated from the culture broth of Chromobacterium sp., inhibits ADP-induced platelet aggregation and has antithrombotic and thrombolytic effects. YM-254890 blocks Gαq/11-coupled ADP receptor P2Y1-mediated Ca2+ mobilization. Here we report that YM-254890 is a selective Gαq/11 inhibitor. YM-254890 blocked Ca2+ mobilization mediated by several Gαq/11-coupled receptors but not by Gαi- or Gα15-coupled receptor, indicating that phospholipase Cβ activation and subsequent signaling molecules are not the target of YM-254890.
YM-254890 completely prevented the serum response factor (SRF)-mediated gene transcription induced by GαqR183C, which is constitutively active in a receptor-dependent manner because of its reduced kcat of GTP hydrolysis. Conversely, YM-254890 had only a modest effect on the SRF-mediated gene transcription by GαqQ209L, which is GTPase-deficient (activated) Gαq. These suggested that the acting point of YM-254890 is receptor-Gαq interaction or the subsequent guanine nucleotide exchange step. The fact that YM-254890 (i) inhibited the SRF-mediated gene
transcription by Gαqi5, which interacts with Gαi-coupled receptor and possesses the effector function of Gαq, and (ii) had no effect on the Kd value of high affinity [3H]2MeSADP binding to P2Y1, which reflects the agonist-receptor-Gα ternary complex, suggested that receptor-Gαq/11 interaction is not the target of YM-254890. On the other hand, specific [35S]GTPγS binding to Gαq/11 stimulated by the M1 muscarinic acetylcholine receptor and P2Y1 were inhibited by YM-254890. These data indicate that YM-254890
blocks the exchange of GDP for GTP in Gαq/11 activation. This novel Gαq/11-selective inhibitor is a promising and powerful tool for studying Gαq/11 protein activation, Gαq/11 -coupled receptor signaling, and Gαq/11-mediated biological events.
Journal of Biological Chemistry 11/2004; 279(46):47438-47445. · 4.77 Impact Factor
-
Masatoshi Taniguchi,
Ken-Ichi Suzumura,
Koji Nagai,
Tomihisa Kawasaki, Jun Takasaki,
Mitsuhiro Sekiguchi,
Yumiko Moritani,
Tetsu Saito,
Kazumi Hayashi,
Shigeo Fujita,
Shin-Ichi Tsukamoto,
Ken-Ichi Suzuki
[show abstract]
[hide abstract]
ABSTRACT: The structure elucidation and biological activity of novel YM-254890 (1) analogues and semi-synthetic derivatives are described. Three natural analogues, YM-254891 (2), YM-254892 (3), and YM-280193 (4), were isolated from the fermentation broth of Chromobacterium sp. QS3666, and two hydrogenated derivatives, YM-385780 (5) and YM-385781 (6), were synthesized from YM-254890. Their structures were determined by one- and two-dimensional NMR studies and mass spectrometry. Among these compounds, two natural analogues 2-3 which possessed acyl groups at beta-HyLeu-1 and one derivative 6 whose conformation was similar to that of 1 showed comparable Galpha(q/11) inhibitory activity to that of 1. This indicates that the acyl beta-HyLeu residue plays an important role in activity and also that the alpha,beta-unsaturated carbonyl group of the N-MeDha residue is not critical to activity. The other hydrogenated derivative 5 had significantly less activity, which could be attributed to conformational differences.
Bioorganic & Medicinal Chemistry 07/2004; 12(12):3125-33. · 2.92 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We examined the antithrombotic and thrombolytic effects of the G(q/11) inhibitor YM-254890 in an electrically-induced carotid artery thrombosis model in rats. YM-254890 dose-dependently inhibited ex vivo ADP-induced platelet aggregation after i.v. bolus injection. In the thrombosis study, YM-254890 dosedependently prolonged time to occlusion at doses of 3 and 10 g/kg i.v. and decreased occlusion rate at 10 g/kg i.v. In the thrombolysis study, YM-254890 at 30 micro g/kg i.v. shortened the time to reperfusion and prevented reocclusion after thrombolysis with a modified tissue-type plasminogen activator. YM-254890, at 10 micro g/kg and more, significantly improved carotid patency status after thrombolysis. However, at 30 micro g/kg and more, YM-254890 decreased systemic blood pressure. These results suggest that YM-254890 may be effective for treating G(q)-mediated diseases, and that YM-254890 is a useful tool for investigating the biological roles of G(q/11).
Thrombosis and Haemostasis 10/2003; 90(3):406-13. · 5.04 Impact Factor
-
Masatoshi Taniguchi,
Koji Nagai,
Nakako Arao,
Tomihisa Kawasaki,
Tetsu Saito,
Yumiko Moritani, Jun Takasaki,
Kazumi Hayashi,
Shigeo Fujita,
Ken-ichi Suzuki,
Shin-ichi Tsukamoto
[show abstract]
[hide abstract]
ABSTRACT: A novel platelet aggregation inhibitor, YM-254890, was isolated from the culture broth of strain QS3666. This strain was isolated from a soil sample collected at Okutama, Tokyo, Japan, and was identified as Chromobacterium sp. by morphological and physiological criteria. YM-254890 was purified from the culture supernatant by solvent extraction, ODS and silica gel flash chromatography, followed by preparative HPLC. YM-254890 inhibited ADP-induced platelet aggregation in human platelet-rich plasma with an IC50 value below 0.6 microM by blocking the P2Y1 receptor-signal transduction pathway.
The Journal of Antibiotics 05/2003; 56(4):358-63. · 1.65 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Nicotinic acid and its derivative, Acipimox, have been widely used in the treatment of hyperlipidemia. Pharmacological studies have demonstrated that they exert the beneficial effect through the activation of a Gi-protein-coupled receptor on adipocyte, which has remained elusive to date. Here we show that a novel GPCR, designated HM74b because of its high similarity to HM74, is a receptor for nicotinic acid. HM74b mRNA is found in human, murine, and rat adipose tissues. Nicotinic acid and Acipimox inhibit forskolin-stimulated intracellular cAMP accumulation in human HM74b-expressing cells and activate GTP gamma S binding in a dose-dependent manner. [3H]Nicotinic acid specifically binds to HM74b-expressing membrane and its binding is replaced by Acipimox. This finding will open a new phase of research on the physiological role of nicotinic acid and will be a clue to develop novel antihyperlipidemic drugs.
Biochemical and Biophysical Research Communications 04/2003; 303(1):364-9. · 2.48 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Recent studies have identified two novel biofunctional proteins, termed prokineticin 1/EG-VEGF and prokineticin 2, which were mammalian homologues of mamba MIT1 and frog Bv8. Prokineticins have been demonstrated to exert their physiological functions through G-protein coupled receptors (GPCRs). In this study, we report the molecular identification of two endogenous prokineticin receptors, designated PK-R1 and PK-R2, through a search of the human genomic DNA database. PK-R1, locating in chromosome 2, and PK-R2, locating in chromosome 20p13, shared 87% homology, which was an extremely high value among known GPCRs. In functional assays, mammalian cells expressing PK-Rs responded to prokineticins in a concentration-dependent manner. Tissue distribution analysis revealed that expression of PK-R1 was observed in the testis, medulla oblongata, skeletal muscle and skin, while that of PK-R2 showed preferential expression in the central nervous system. The tissue distribution of PK-Rs reported in this paper suggests that the prokineticins play multifunctional roles in vivo.
Biochimica et Biophysica Acta 01/2003; 1579(2-3):173-9. · 4.66 Impact Factor
-
Tamaki Oda,
Shun-ichiro Matsumoto,
Yasuhiko Masuho, Jun Takasaki,
Mitsuyuki Matsumoto,
Masazumi Kamohara,
Tetsu Saito,
Takahide Ohishi,
Takatoshi Soga,
Hideki Hiyama,
Hitoshi Matsushime,
Kiyoshi Furuichi
[show abstract]
[hide abstract]
ABSTRACT: The cDNA encoding histamine H4 receptor was cloned from the porcine spleen cDNA library. Porcine H4 receptor, which shares 72% homology with its human counterpart, bound to histamine in receptor-expressing mammalian cells. Isolation of the porcine H4 receptor, which is important for understanding of the pharmacology, will aid in better interpretation of physiological role of this subtype of histamine receptor.
Biochimica et Biophysica Acta 06/2002; 1575(1-3):135-8. · 4.66 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Leukotriene B4 is a potent lipid mediator known to be implicated mainly in inflammatory actions. Previous pharmacological studies indicated
the existence of only one class of G protein-coupled receptor for leukotriene B4, for which a candidate gene, namely BLT, had been identified. Here we report the isolation of another gene encoding a functional
G protein-coupled receptor for leukotriene B4, named JULF2. JULF2 is a novel G protein-coupled receptor of 358 amino acids that shares 36.6% amino acid identity with human
BLT. According to genomic information, the JULF2 gene is located on the chromosome 14, about 4 kilobases upstream of the BLT
gene. During screening of endogenous ligands for JULF2, we found that leukotriene B4 induced inhibition of forskolin-stimulated cAMP accumulation in Chinese hamster ovary cells, stably expressing JULF2. Additionally,
Chinese hamster ovary cells expressing exogenous JULF2 showed chemotactic responses with leukotriene B4 in a pertussis toxin-sensitive manner. A large amount of JULF2 mRNA was detected in the human spleen and the peripheral blood
leukocytes. Furthermore, JULF2 mRNA was expressed in mononuclear lymphocytes, in which BLT mRNA was barely detected. The discovery
of this second leukotriene B4 receptor will eventually lead to a better understanding of the classification of leukotriene B4 receptors and reconsideration of the pathophysiological role of leukotriene B4.
Journal of Biological Chemistry 08/2000; 275(35):27000-27004. · 4.77 Impact Factor
