Regulation of distribution of extracellular Edg receptor family ligands and their physiological roles

2005 Fiscal Year Final Research Report Summary

• Project/Area Number: 15370051
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Functional biochemistry
• Research Institution: Gunma University
• Principal Investigator: OKAJIMA Fumikazu GUNMA UNIVERSITY, Institute for Molecular and Cellular Regulation, Professor, 生体調節研究所, 教授 (30142748)
• Co-Investigator(Kenkyū-buntansha): TOMURA Hideaki GUNMA UNIVERSITY, Institute for Molecular and Cellular Regulation, Associate professor, 生体調節研究所, 助教授 (70217553) ; SATO Koichi GUNMA UNIVERSITY, Institute for Molecular and Cellular Regulation, Research associate, 生体調節研究所, 助手 (00302498) ; TAMOTO Koichi HEALTH SCIENCES UNIVERSITY OFHOKKAIDO, Faculty of Pharmaceutical Sciences, Associate professor, 薬学部, 助教授 (50088861)
• Project Period (FY): 2003 – 2005
• Keywords: sphingosine 1-phosphate / lysophosphatidic acid / lipid mediator / G-protein-coupled receptor / lipoprotein / vascular endothelial cell / vascular smooth muscle cell / proton-sensing receptor

Research Abstract

We examined the regulation of distribution of extracellular sphingosine 1-phosphate (S1P) and lysophosphatidic acid (LPA), and their physiological roles. (1) S1P as a mediator of lipoprotein actions in vascular cells : We showed a good correlation between HDL-S1P and HDL-cholesterol. In order to identify the receptor subtypes involved in HDL and S1P actions in vascular endothelial cells, we used antis enseoligonucleotides or siRNA specific S1P receptor subtypes and demonstrated that cell survival is mainly mediated by S1P1, cell migration is by both S1P1 and S1P3, and inhibition of TNF-α-induced adhesion molecule expression is by mainly S1P1. In vascular smooth muscle cells, it was shown that S1P2 receptor mediates cAMP accumulation and inhibition of cell migration. These results suggest that S1P receptors are useful therapeutic targets for vascular diseases. (2) Characterization of an LPA receptor antagonist and its application : We characterized Ki16425 as an LPA receptor antagonist and showed that this drug is effective for inhibiting motility of cancer cells such as pancreatic cancer cells and glioma cells. (3) Role of lipid mediator in central nervous system : We identified autotaxin, a lysophospholipase D, as a neurite retraction factor in cerebrospinal fluid. (4) A novel function of lysolipid receptors : We demonstrated that TDAG8, which has been shown to be a receptor for lipid molecule psychosine, senses extracellular proton or pH, resulting in activation of adenylyl cyclase. We also demonstrated by using siRNA techniques that extracellular acidic pH induces prostaglandin production and cAMP accumulation through OGR1, one of GPCRs with a similar primary structure to TDAG8, in human vascular SMC. Thus, OGR1 family GPCRs are functional receptors for sensing extracellular pH.

Research Products

• [Journal Article] Sphingosine 1-phosphate receptors mediate stimulatory and inhibitory signalings for expression of adhesion molecules in endothelial cells. (2006)
  • Author(s): Kimura, T
  • Journal Title: Cell. Signal 18 Pages: 841-850
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Simvastatin induces heat shock factor 1 in vascular endothelial cells. (2006)
  • Author(s): Uchiyama T
  • Journal Title: Atherosclerosis. (印刷中)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Sphingosine 1-phosphate receptors mediate stimulatory and inhibitory signalings for expression of adhesion molecules in endothelial cells. (2006)
  • Author(s): Kimura, T., Tomura, H., Mogi, C., Kuwabara, A., Ishiwara, M., Shibasawa, K., Sato, K., Ohwada, S., Im, DS., Kurose, H., Ishizuka, T., Murakami, M., Okajima, F.
  • Journal Title: Cell.Signal. 18 Pages: 841-850
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Simvastatin induces heat shock factor 1 in vascular endothelial cells. (2006)
  • Author(s): Uchiyama T, Atsuta H, Utsugi T, Ohyama Y, Nakamura T, Nakai A, Nakata M, Maruyama I, Tomura H, Okajima F, Tomono S, Kawazu S, Nagai R, Krarbayashi M
  • Journal Title: Atherosclerosis (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Enhancement of sphingosine 1-phosphate-induced phospholipase C activation during g(0)-g(1) transition in rat hepatocytes. (2005)
  • Author(s): Im DS
  • Journal Title: J Pharmacol Sci 95 Pages: 284-290
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] TDAG8 is a Proton-Sensing and Psychosine-Sensitive G-Protein-Coupled Receptor. (2005)
  • Author(s): Wang, JQ
  • Journal Title: J. Biol. Chem. 279: Pages: 45626-45633
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 9HODE stimulates cell proliferation and extracellular matrix synthesis in human mesangial cells via PPARgamma. (2005)
  • Author(s): Negishi M
  • Journal Title: Exp Biol Med 229 Pages: 1053-1060
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Differential change of Ins-P3-Ca2+ signaling during culture of rat hepatocytes (2005)
  • Author(s): Im DS
  • Journal Title: Cell. Signaling 17 Pages: 83-91
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] High-density lipoprotein inhibits migration of vascular smooth muscle cells through its sphingosine 1-phosphate component. (2005)
  • Author(s): Tamama, K
  • Journal Title: Atherosclerosis 178 Pages: 19-23
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Correlation of high density lipoprotein (HDL)-associated sphingosine 1-phosphate with serum levels of HDL-cholesterol and apolipoproteins. (2005)
  • Author(s): Zhang B
  • Journal Title: Atherosclerosis. 178 Pages: 199-205
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Identification of Autotaxin as a Neurite Retraction-Inducing Factor of PC12 Cells in Cerebrospinal Fluid and Its Possible Sources. (2005)
  • Author(s): Sato K
  • Journal Title: J. Neurochem 92 Pages: 904-914
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Sphingosine-1-Phosphate Receptors Mediate the Lipid-Induced cAMP Accumulation Through Cyclooxygenase-2/Prostaglandin I2 Pathway in Human Coronary Artery Smooth Muscle Cells. (2005)
  • Author(s): Damirin A
  • Journal Title: Mol. Pharmacol. 67 Pages: 1177-1185
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Study on Action Mode of Sphingosine 1-Phosphate in Rat Hepatocytes. (2005)
  • Author(s): Im YJ
  • Journal Title: J Pharmacol Sci 97 Pages: 443-446
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Sphingosine 1-phosphate inhibits migration and RANTES production in human bronchial smooth muscle cells. (2005)
  • Author(s): Kawata T
  • Journal Title: Biochim. Biophys. Res. Commun. 26 Pages: 64-69
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Role of p38 mitogen-activated kinase and c-Jun terminal kinase in migration response to lysophosphatidic acid and sphingosine-1-phosphate in glioma cells. (2005)
  • Author(s): Malchinkhuu, E
  • Journal Title: Oncogene 24 Pages: 6676-6688
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Proton-sensing and lysolipid-sensitive G-protein-coupled receptors : A novel type of multi-functional receptors. (2005)
  • Author(s): Tomura, H
  • Journal Title: Cell. Signal. 17 Pages: 1466-1476
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Prostaglandin I2 Production and cAMP Accumulation in Response to Acidic Extracellular pH Through OGR1 in Human Aortic Smooth Muscle Cells. (2005)
  • Author(s): Tomura, H
  • Journal Title: J. Biol. Chem 41 Pages: 34458-34464
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Sphingosylphosphorylcholine Antagonizes Proton-Sensing OGR1-Mediated Inositol Phosphate Production and cAMP Accumulation (2005)
  • Author(s): Mogi, C
  • Journal Title: J. Pharmacol. Sci 99 Pages: 160-167
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Differential change of Ins-P3-Ca2+ signaling during culture of rat hepatocytes. (2005)
  • Author(s): Im DS, Nagano K, Katada T, Okajima F, Ui M
  • Journal Title: Cell.Signaling 17 Pages: 83-91
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] High-density lipoprotein inhibits migration of vascular smooth muscle cells through its sphingosine 1-phosphate component. (2005)
  • Author(s): Tamama, K, Tomura, H., Sato, K., Malchinkhuu, E., Damirin, A., Kimura, T., Kuwabara, A., Murakami, M., Okajima, F.
  • Journal Title: Atherosclerosis 178 Pages: 19-23
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Correlation of high density lipoprotein (HDL)-associated sphingosine 1-phosphate with serum levels of HDL-cholesterol and apolipoproteins. (2005)
  • Author(s): Zhang B, Tomura H, Kuwabara A, Kimura T, Miura S, Noda K, Okajima F, Saku K
  • Journal Title: Atherosclerosis 178 Pages: 199-205
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Identification of Autotaxin as a Neurite Retraction-Inducing Factor of PC12 Cells in Cerebrospinal Fluid and Its Possible Sources. (2005)
  • Author(s): Sato K, Malchinkhuu E, Muraki T, Ishikawa K, Hayashi K, Tosaka M, Mochiduki A, Inoue K, Tomura H, Mogi C, Nochi H, Tamoto K, Okajima F
  • Journal Title: J.Neurochem. 92 Pages: 904-914
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Sphingosine-1-Phosphate Receptors Mediate the Lipid-Induced cAMP Accumulation Through Cyclooxygenase-2/Prostaglandin I2 Pathway in Human Coronary Artery Smooth Muscle Cells. (2005)
  • Author(s): Damirin A, Tomura H, Komachi M, Tobo M, Sato K, Mogi C, Nochi H, Tamoto K, Okajima F
  • Journal Title: Mol.Pharmacol. 67 Pages: 1177-1185
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Study on Action Mode of Sphingosine 1-Phosphate in Rat Hepatocytes. (2005)
  • Author(s): Im YJ, Im DS, Lee YK, Lee EH, Sato K, Tomura H, Katada T, Ui M, Okajima F
  • Journal Title: J Pharmacol Sci. 97 Pages: 443-446
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Sphingosine 1-phosphate inhibits migration and RANTES production in human bronchial smooth muscle cells. (2005)
  • Author(s): Kawata T, Ishizuka T, Tomura H, Hisada T, Dobashi K, Tsukagoshi H, Ishiwara M, Kurose H, Mori M, Okajima F
  • Journal Title: Biochim.Biophys.Res.Commun. 331 Pages: 640-647
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Role of p38 mitogen-activated kinase and c-Jun terminal kinase in migration response to lysophosphatidic acid and sphingosine-1-phosphate in glioma cells. (2005)
  • Author(s): Malchinkhuu, E., Sato, K., Horiuchi, Y., Mogi, C., Ohwada, S., Ishiuchi, S., Saito, N., Kurose, H., Tomura, H., Okajima, F
  • Journal Title: Oncogene 24 Pages: 6676-6688
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Proton-sensing and lysolipid-sensitive G-protein-coupled receptors : A novel type of multi-functional receptors. (2005)
  • Author(s): Tomura, H., Mogi, C., Sato, K., Okajima, F.
  • Journal Title: Cell.Signal. 17 Pages: 1466-1476
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Prostaglandin 12 Production and cAMP Accumulation in Response to Acidic Extracellular pH Through OGR1 in Human Aortic Smooth Muscle Cells. (2005)
  • Author(s): Tomura H., Wang, JQ., Komachi, M., Damirin, A., Mogi, C., Tobo, M., Kon, J., Misawa, N., Sato, K., Okajima.F.
  • Journal Title: J.Biol.Chem. 41 Pages: 34458-34464
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Sphingosylphosphorylcholine Antagonizes Proton-Sensing OGR1-Mediated Inositol Phosphate Production and cAMP Accumulation. (2005)
  • Author(s): Mogi, C., Tomura.H., Tobo, M., Wang, JQ., Damirin, A., Kon, J., Komachi, M., Hashimoto, K., Sato, K., Okajima, F.
  • Journal Title: J.Pharmacol.Sci. 99 Pages: 160-167
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The action mode of lysophosphatidylcholine in human monocytes. (2004)
  • Author(s): Yun MR
  • Journal Title: J Pharmacol Sci 94 Pages: 45-50
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Lysophosphatidic Acid in Malignant Ascites Stimulates Motility of Human Pancreatic Cancer Cells Through LPA_1 (2004)
  • Author(s): Yamada T
  • Journal Title: J. Biol. Chem. 279 Pages: 6595-6605
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Effects of interleukin-1beta and prostaglandin E2 on prostaglandin D synthase production in cultivated rat leptomeningeal cells. (2004)
  • Author(s): Muraki T
  • Journal Title: J Cereb Blood Flow Metab. 24 Pages: 409-418
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The action mode of lysophosphatidylcholine in human monocytes. (2004)
  • Author(s): Yun MR, Okajima F, Im DS
  • Journal Title: J Pharmacol Sci. 94 Pages: 45-50
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Lysophosphatidic Acid in Malignant Ascites Stimulates Motility of Human Pancreatic Cancer Cells Through LPA_1. (2004)
  • Author(s): Yamada T, Sato K, Komachi M, Malchinkhuu E, Tobo M, Kimura T, Kuwabara A, Yanagita Y, Ikeya T, Tanahashi Y, Ogawa T, Ohwada S, Morishita Y, Ohta H, Im DS, Tamoto K, Tomura H, Okajima F
  • Journal Title: J.Biol.Chem. 279 Pages: 6595-6605
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Effects of interleukin-1beta and prostaglandin E2 on prostaglandin D synthase production in cultivated rat leptomeningeal cells. (2004)
  • Author(s): Muraki T, Fujimori K, Ishizaka M, Ohe Y, Urade Y, Okajima F, Ishikawa K
  • Journal Title: J Cereb Blood Flow Metab 24 Pages: 409-418
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Enhancement of sphingosine 1-phosphate-induced phospholipase C activation during g(0)-g(1) transition in rat hepatocytes. (2004)
  • Author(s): Im DS, Tomura H, Tobe M, Sato K, Okajima F
  • Journal Title: J Pharmacol Sci. 95 Pages: 284-290
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] TDAG8 is a Proton-Sensing and Psychosine-Sensitive G-Protein-Coupled Receptor. (2004)
  • Author(s): Wang, JQ., Kon, J., Mogi, C., Tobo, M., Damirin, A., Sato, K., Komachi, M., Malchinkhuu, E., Murata, N., imura, T., Kuwabara, A., Wakamatsu, K., Koizumi, T., Uede, T., Tsujimoto, G., Kurose, H., Sato, T., Harada, A., Misawa, N., Tomura.H., Okajima, F
  • Journal Title: J.Biol.Chem. 279 Pages: 45626-45633
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] 9HODE stimulates cell proliferation and extracellular matrix synthesis in human mesangial cells via PPARgamma. (2004)
  • Author(s): Negishi M, Shimizu H, Okada S, uwabara A, Okajima F, Mori M
  • Journal Title: Exp Biol Med. 229 Pages: 1053-1060
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Assessment of the role of sphingosine 1-phosphate and its receptors in high-density lipoprotein-induced stimulation of astroglial cell function. (2003)
  • Author(s): Malchinkhuu E
  • Journal Title: Biochem. J. 370 Pages: 817-827
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Analysis of vasopressin-induced Ca2+ increase in rat hepatocytes (2003)
  • Author(s): Kim HS
  • Journal Title: Arch Pharm Res 26 Pages: 64-69
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] High-Density Lipoprotein Stimulates Endothelial Cell Migration and Survival Through Sphingosine 1-Phosphate and Its Receptors. (2003)
  • Author(s): Kimura T
  • Journal Title: Arterioscler Thromb Vasc Biol 23 Pages: 1283-1288
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Ki16425, a Subtype-Selective Antagonist for EDG-Family Lysophosphatidic Acid Receptors. (2003)
  • Author(s): Ohta H
  • Journal Title: Mol Pharmacol 64 Pages: 994-1005
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] TA-270, An Anti-Asthmatic Agent, Inhibits Leukotriene Production Induced By IgE Receptor Stimulation In RBL-2H3 Cells. (2003)
  • Author(s): Ishiwara M
  • Journal Title: J. Pharmacol. Exp. Therap 307 Pages: 583-588
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Assessment of the role of sphingosine 1-phosphate and its receptors in high-density lipoprotein-induced stimulation of astroglial cell function. (2003)
  • Author(s): Malchinkhuu E, Sato K, Muraki T, Ishikawa K, Kuwabara A, Okajima F
  • Journal Title: Biochem.J. 370 Pages: 817-827
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Analysis of vasopressin-induced Ca2+ increase in rat hepatocytes. (2003)
  • Author(s): Kim HS, Okajima F, Im DS
  • Journal Title: Arch Pharm Res 26 Pages: 64-69
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] High-Density Lipoprotein Stimulates Endothelial Cell Migration and Survival Through Sphingosine 1-Phosphate and Its Receptors. (2003)
  • Author(s): Kimura T, Sato K, Malchinkhuu E, Tomura H, Tamama K, Kuwabara A, Murakami M, Okajima F
  • Journal Title: Arterioscler Thromb Vasc Biol. 23 Pages: 1283-1288
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Ki16425, a Subtype-Selective Antagonist for EDG-Family Lysophosphatidic Acid Receptors. (2003)
  • Author(s): Ohta H, Sato K, Murata N, Damirin A, Malchinkhuu E, Kon J, Kimura T, Tobo M, Yamazaki Y, Watanabe T, Yagi M, Sato M, Suzuki R, Murooka H, Sakai T, Nishitoba T, Im DS, Nochi H, Tamoto K, Tomura H, Okajima F
  • Journal Title: Mol Pharmacol. 64 Pages: 994-1005
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] TA-270, An Anti-Asthmatic Agent, Inhibits Leukotriene Production Induced By IgE Receptor Stimulation In RBL-2H3 Cells. (2003)
  • Author(s): Ishiwara M, Aoki Y, Takagaki H, Ui M, Okajima F
  • Journal Title: J.Pharmacol.Exp.Therap. 307 Pages: 583-588
  • Description: 「研究成果報告書概要(欧文)」より
• [Book] 情報伝達物質 : アデニル酸シクラーゼ (生物薬科学実験講座、石橋貞彦, 市川厚, 堅田利明編集) (2005)
  • Author(s): 岡島史和
  • Total Pages: 13(333-345)
  • Publisher: 広川書店、東京、
  • Description: 「研究成果報告書概要(和文)」より
• [Book] Encyclopedia of Endocrine Dideases (Phosphatidyl Turnover and Receptors) (2004)
  • Author(s): Okajima, F
  • Total Pages: 7(597-603)
  • Publisher: Elsevier Academic Press, Oxford, UK
  • Description: 「研究成果報告書概要(和文)」より
• [Patent(Industrial Property Rights)] 内皮細胞障害抑制物質とその利用法 (2005)
  • Inventor(s): 岡島史和
  • Industrial Property Rights Holder: 国立大学法人群馬大学
  • Industrial Property Number: 特願2005-50819
  • Filing Date: 2005-02-25
  • Description: 「研究成果報告書概要(和文)」より
• [Patent(Industrial Property Rights)] 動脈硬化予防物質とその利用法 (2004)
  • Inventor(s): 岡島史和
  • Industrial Property Rights Holder: 国立大学法人群馬大学
  • Industrial Property Number: 特願2004-279967
  • Filing Date: 2004-09-27
  • Description: 「研究成果報告書概要(和文)」より
• [Patent(Industrial Property Rights)] 内皮細胞障害保護作用物質とその利用法 (2004)
  • Inventor(s): 岡島史和
  • Industrial Property Rights Holder: 国立大学法人群馬大学
  • Industrial Property Number: 特願2004-280022
  • Filing Date: 2004-09-27
  • Description: 「研究成果報告書概要(和文)」より