Synthesis and Evaluation of Lysophosphatidylserine Analogues as Inducers of Mast Cell Degranulation. Potent Activities of Lysophosphatidylthreonine and Its 2-Deoxy Derivative

Iwashita, Masazumi; Makide, Kumiko; Nonomura, Taro; Misumi, Yoshimasa; Otani, Yuko; Ishida, Mayuko; Taguchi, Ryo; Tsujimoto, Masafumi; Aoki, Junken; Arai, Hiroyuki; Ohwada, Tomohiko

doi:10.1021/jm900598m

Cited by 70 publications

(91 citation statements)

References 14 publications

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“…Taken together, different expression and functional systems did not provide evidence for activation of the human and mouse GPR34 by P-lyso-PS, contrary to previous findings (16,51). Differences in the functional assay setup and cellular expression systems and differences in the purity and chemical composition of P-lyso-PS used may account for this discrepancy.…”

Section: Figure 2 Functional Expression Of Gpr34 Orthologs and Mutancontrasting

confidence: 89%

“…1) and is further supported by a recent study showing that lyso-phosphatidylthreonine induces mast cell degranulation with higher potency than lyso-PS. However, lyso-phosphatidylthreonine did not activate GPR34 (51). It remains open whether lyso-PS induces histamine release through phospholipase C-mediated Ca 2ϩ increase via another currently unknown pertussis toxin-sensitive GPCR or via a pertussis toxin-insensitive pathway (18,20).…”

Section: Gpr34-deficient Mice Show No Obvious Phenotype Under Specifimentioning

confidence: 99%

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Altered Immune Response in Mice Deficient for the G Protein-coupled Receptor GPR34

Liebscher¹,

Müller

Teupser

et al. 2011

Journal of Biological Chemistry

103

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The X-chromosomal GPR34 gene encodes an orphan G i protein-coupled receptor that is highly conserved among vertebrates. To evaluate the physiological relevance of GPR34, we generated a GPR34-deficient mouse line. GPR34-deficient mice were vital, reproduced normally, and showed no gross abnormalities in anatomical, histological, laboratory chemistry, or behavioral investigations under standard housing. Because GPR34 is highly expressed in mononuclear cells of the immune system, mice were specifically tested for altered functions of these cell types. Following immunization with methylated BSA, the number of granulocytes and macrophages in spleens was significantly lower in GPR34-deficient mice as in wild-type mice. GPR34-deficient mice showed significantly increased paw swelling in the delayed type hypersensitivity test and higher pathogen burden in extrapulmonary tissues after pulmonary infection with Cryptococcus neoformans compared with wild-type mice. The findings in delayed type hypersensitivity and infection tests were accompanied by significantly different basal and stimulated TNF-␣, GM-CSF, and IFN-␥ levels in GPR34-deficient animals. Our data point toward a functional role of GPR34 in the cellular response to immunological challenges. G protein-coupled receptors (GPCR)2 form the largest gene family among transmembrane receptors, including more than 900 genes in humans and other mammals (1). A great number of stimuli, such as light, hormones, neurotransmitters, peptides, and nucleotides, activate the distinct receptors. Nonodorant receptors form about one-third of the GPCR repertoire. Although more than 200 non-odorant GPCR have been assigned to specific agonists and functions, about 155 socalled "orphan" GPCR (2) await identification of their physiological relevance. The importance of GPCR in controlling almost every physiological function makes this receptor family the most frequently used target for therapeutic drugs. Therefore, unveiling the function of orphan GPCR is a central issue in academic and industrial research.Among the five structurally different GPCR families (1, 3), the rhodopsin-like receptors form the largest in humans and other vertebrates. The rhodopsin-like family is divided further into subfamilies and groups. The P2Y 12 -like receptor group includes the ADP receptors P2Y 12 and P2Y 13 , the UDP-glucose receptor P2Y 14 , and the orphan receptors GPR87, GPR82, and GPR34 (4). Apart from the ADP receptor P2Y 12 , which has a central role in platelet aggregation and is the therapeutic target of clopidogrel (5, 6), very little is known about the function of the other members of this group.GPR34, an orphan receptor of the P2Y 12 -like receptor group, was first discovered by mining GenBank TM for novel GPCR sequences and homology cloning and has been assigned to the human X chromosome (7,8). Phylogenetic studies revealed that GPR34 has been highly conserved over the past 450 million years of vertebrate evolution, and no GPR34-deficient vertebrate has been identified yet (9). To date, there i...

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Section: Figure 2 Functional Expression Of Gpr34 Orthologs and Mutancontrasting

confidence: 89%

Section: Gpr34-deficient Mice Show No Obvious Phenotype Under Specifimentioning

confidence: 99%

Altered Immune Response in Mice Deficient for the G Protein-coupled Receptor GPR34

Liebscher¹,

Müller

Teupser

et al. 2011

Journal of Biological Chemistry

103

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“…Thus, it was once proposed that LysoPS enhanced mast cell degranulation through GPR34. However, as stated above, LPT, a potent inducer of mast cell degranulation, did not activate GPR34 ( 22 ). In addition, peritoneal mast cells from GPR34-defi cient mice still responded to LysoPS ( 41 ).…”

Section: Gpr34/lpsmentioning

confidence: 70%

“…In vitro, LysoPS enhances histamine release from peritoneal rodent mast cells triggered by the cross-linking of high-affi nity IgE receptors (Fc RI). It also induces rapid degranulation of mast cells and consequent anaphylactic shock and hypothermia when administered intravenously in rodents ( 21,22 ). The mast cell degranulation-stimulating activity is not induced by other LysoGPs including LPA, LPC, LPE, LPG, and LPI, and strictly requires the serine residue of LysoPS.…”

Section: Actions Of Lysopsmentioning

confidence: 99%

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Novel lysophosphoplipid receptors: their structure and function

Makide

Uwamizu

Shinjo

et al. 2014

Journal of Lipid Research

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141

133

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This article is available online at http://www.jlr.org with plasma concentrations of 10-30 nM and several hundred nanomoles, respectively ( 3, 4 ). Both LPA and S1P have critical roles in multiple cellular events through G protein-coupled receptors (GPCRs). Six GPCRs have been identifi ed for LPA (LPA 1-6 ) and fi ve GPCRs have been identifi ed for S1P (S1P 1-5 ) ( 5 ), and nomenclature of these LysoGPs receptors has recently been proposed by Kihara et al. ( 6 ). These receptors are grouped into two classes, the Edg and P2Y families, respectively. LPA 1-3 and all fi ve of the S1P receptors, S1P [1][2][3][4][5] , are members of the Edg family, while LPA 4-6 are members of the P2Y family. In addition, LPA is an endogenous ligand for PPAR ␥ ( 7 ), and was shown to activate transient receptor potential cation channel subfamily V member 1 (TRPV1) channels leading to an infl ux of Ca 2+ ions through TRPV1 ( 8 ). Studies on gene-targeted mice and human genetic diseases have clearly shown that each receptor has specifi c roles in both physiological and pathological conditions. For example, LPA has a pivotal role in neurogenesis ( 9 ) and has also been implicated in the development of lung fi brosis ( 10 ) via LPA 1 . LPA exhibits unique roles in implantation of fertilized eggs via LPA 3 ( 11 ) and hair follicle formation via LPA 6 ( 12 ). LPA is produced by at least two pathways where multiple phospholipase activities are involved ( 3 ). Lysophospholipase D/autotaxin/NPP2 produces LPA from LysoGPs such as LPC, while phosphatidic acid (PA)-selective PLA 1 ␣ (PA-PLA 1 ␣ ) and PA-PLA 1 ␤ produce LPA from PA by their PLA 1 activities. In contrast, S1P is produced intracellularly by phosphorylation Abstract It is now accepted that lysophospholipids (LysoGPs) have a wide variety of functions as lipid mediators that are exerted through G protein-coupled receptors (GPCRs) specifi c to each lysophospholipid. While the roles of some LysoGPs, such as lysophosphatidic acid and sphingosine 1-phosphate, have been thoroughly examined, little is known about the roles of several other LysoGPs, such as lysophosphatidylserine (LysoPS), lysophosphatidylthreonine, lysophosphatidylethanolamine, lysophosphatidylinositol (LPI), and lysophosphatidylglycerol. Recently, a GPCR was found for LPI (GPR55) and three GPCRs (GPR34/LPS 1 , P2Y10/ LPS 2 , and GPR174/LPS 3 ) were found for LysoPS. In this review, we focus on these newly identifi ed GPCRs and summarize the actions of LysoPS and LPI as lipid mediators.

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Insights into the Molecular Recognition Process in Organocatalytic Chemoselective Monoacylation of 1,5‐Pentanediol

et al. 2016

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Monoacylation of long‐chain linear diols often encounters difficulties associated with unavoidable overacylation affording the diacylate. However, several C1‐ and C2‐symmetrical pyrrolidinopyridine (PPY) catalysts were found to effectively promote the chemoselective monoacylation of 1,5‐pentanediol. The effects of catalyst structure on the performance for the monoacylation were investigated. The amide carbonyl group(s) in the pyrrolidine ring in both C1‐ and C2‐symmetrical catalysts was(were) suggested to play the key role in selective monoacylation. On the other hand, the indolyl NH group in the amide side chain of the catalysts was found to be critically important for further increasing the chemoselectivity of monoacylation only when the catalyst has a C2‐symmetrical structure. The effects of the catalyst structure on the chemoselective monoacylation were elucidated by DFT calculations, and the origin of the precise molecular recognition for 1,5‐pentanediol by the catalysts and transition state (TS) stabilization effects by these functionalities were disclosed.magnified image

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Synthesis and Evaluation of Lysophosphatidylserine Analogues as Inducers of Mast Cell Degranulation. Potent Activities of Lysophosphatidylthreonine and Its 2-Deoxy Derivative

Cited by 70 publications

References 14 publications

Altered Immune Response in Mice Deficient for the G Protein-coupled Receptor GPR34

Altered Immune Response in Mice Deficient for the G Protein-coupled Receptor GPR34

Novel lysophosphoplipid receptors: their structure and function

Insights into the Molecular Recognition Process in Organocatalytic Chemoselective Monoacylation of 1,5‐Pentanediol

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