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• W2912997222 abstract "While working with Xenopus oocytes in the late 1980s, we stumbled across an unexpected finding; rabbit serum elicited oscillatory chloride currents in the oocytes at dilutions higher than 1,000,000-fold (1.Tigyi G. Henschen A. Miledi R. A factor that activates oscillatory chloride currents in Xenopus oocytes copurifies with a subfraction of serum albumin.J. Biol. Chem. 1991; 266: 20602-20609Abstract Full Text PDF PubMed Google Scholar). We became puzzled by the extreme potency of the putative serum factor that activated IP3 production and Ca2+ release causing the opening of Ca-activated chloride channels in the plasma membrane. Activation of the IP3-Ca2+ signaling pathway was already a known feature of G protein-coupled receptor (GPCR) activation. The serum factor was active in the sera of all vertebrate species tested; whereas, plasma showed minimal activity. Because of its unusually high potency and its presumed GPCR-mediated action, we embarked on a project that has led to the purification of lysophosphatidic acid (LPA) and several of its structural variants (2.Tigyi G. Miledi R. Lysophosphatidates bound to serum albumin activate membrane currents in Xenopus oocytes and neurite retraction in PC12 pheochromocytoma cells.J. Biol. Chem. 1992; 267: 21360-21367Abstract Full Text PDF PubMed Google Scholar). Structure-activity relationship (SAR) studies showed that LPA GPCRs had a preference for agonists that contained fatty acyl groups with one or two double bonds over LPA with saturated fatty acids. Molecular cloning identified the endothelial differentiation gene (EDG) family encoding eight GPCRs, three specific for LPA (LPA1/2/3) and five specific for sphingosine-1-phosphate (S1P) (S1P1/2/3/4/5) (3.Chun J. Blaho V. Frantz A. Hla T. Jones D. Kihara Y. Mizuno H. Moolenaar W. Mpamhanga C. Spiegel S. Yung Y.C. Lysophospholipid (LPA) receptors..In IUPHAR/BPS Guide to PHARMACOLOGY. 2018; (Accessed February 6, 2019, at)http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=36Google Scholar). These eight GPCRs showed highly similar sequences and it soon became possible to express them individually in yeast and mammalian cell types lacking endogenous Ca2+ responses, allowing for the examination of the SAR of the individual LPA receptor subtypes (4.Erickson J.R. Wu J.J. Goddard G. Kawanishi K. Tigyi G. Tomei L.D. Kiefer M.C. The putative lysophosphatidic acid receptor Edg-2/Vzg-1 functionally couples to the yeast response pathway.J. Biol. Chem. 1998; 273: 1506-1510Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar, 5.Fischer D.J. Liliom K. Guo Z. Nusser N. Virag T. Murakami-Murofushi K. Kobayashi S. Erickson J.R. Sun G. Miller D.D. et al.Naturally occurring analogs of lysophosphatidic acid elicit different cellular responses through selective activation of multiple receptor subtypes.Mol. Pharmacol. 1998; 54: 979-988Crossref PubMed Scopus (108) Google Scholar, 6.Fujiwara Y. Osborne D.A. Walker M.D. Wang D.A. Bautista D.A. Liliom K. Van Brocklyn J.R. Parrill A.L. Tigyi G. Identification of the hydrophobic ligand binding pocket of the S1P1 receptor.J. Biol. Chem. 2007; 282: 2374-2385Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 7.Fujiwara Y. Sardar V. Tokumura A. Baker D. Murakami-Murofushi K. Parrill A. Tigyi G. Identification of residues responsible for ligand recognition and regioisomeric selectivity of lysophosphatidic acid receptors expressed in mammalian cells.J. Biol. Chem. 2005; 280: 35038-35050Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar). In addition to the three EDG family LPA GPCRs, a second subfamily with three distinct receptors (designated LPA4/5/6) within the purinergic GPCR cluster has been identified (3.Chun J. Blaho V. Frantz A. Hla T. Jones D. Kihara Y. Mizuno H. Moolenaar W. Mpamhanga C. Spiegel S. Yung Y.C. Lysophospholipid (LPA) receptors..In IUPHAR/BPS Guide to PHARMACOLOGY. 2018; (Accessed February 6, 2019, at)http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=36Google Scholar). In addition to specific GPCRs, LPA activates multiple molecular targets via direct and specific binding interaction (Table 1). These LPA targets activate distinct cellular signals that mediate cellular responses unique to the target. This article is not intended as a comprehensive overview of the growing field of LPA receptors/targets and biological actions, and the reader should look up the references and review the articles listed in Table 1 for additional information about LPA biology and signaling.TABLE 1Molecular targets and biological responses of LPAMolecular TargetSignaling MechanismBiological ResponseReferenceLPA1 GPCRGq/11, Gi, G12/13, PDZCell migration, bone development, cell proliferation, cortical development, carcinoma cell invasion, metastasis(3.Chun J. Blaho V. Frantz A. Hla T. Jones D. Kihara Y. Mizuno H. Moolenaar W. Mpamhanga C. Spiegel S. Yung Y.C. Lysophospholipid (LPA) receptors..In IUPHAR/BPS Guide to PHARMACOLOGY. 2018; (Accessed February 6, 2019, at)http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=36Google Scholar, 57.Kihara Y. Mizuno H. Chun J. Lysophospholipid receptors in drug discovery.Exp. Cell Res. 2015; 333: 171-177Crossref PubMed Scopus (142) Google Scholar)LPA2 GPCRGq/11, Gi, G12/13, PDZ, LIMCell survival, cell proliferation, cell motility, invasion and metastasis(3.Chun J. Blaho V. Frantz A. Hla T. Jones D. Kihara Y. Mizuno H. Moolenaar W. Mpamhanga C. Spiegel S. Yung Y.C. Lysophospholipid (LPA) receptors..In IUPHAR/BPS Guide to PHARMACOLOGY. 2018; (Accessed February 6, 2019, at)http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=36Google Scholar, 57.Kihara Y. Mizuno H. Chun J. Lysophospholipid receptors in drug discovery.Exp. Cell Res. 2015; 333: 171-177Crossref PubMed Scopus (142) Google Scholar)LPA3 GPCRGq/11, Gi, GsEmbryo implantation, cell motility,(3.Chun J. Blaho V. Frantz A. Hla T. Jones D. Kihara Y. Mizuno H. Moolenaar W. Mpamhanga C. Spiegel S. Yung Y.C. Lysophospholipid (LPA) receptors..In IUPHAR/BPS Guide to PHARMACOLOGY. 2018; (Accessed February 6, 2019, at)http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=36Google Scholar, 57.Kihara Y. Mizuno H. Chun J. Lysophospholipid receptors in drug discovery.Exp. Cell Res. 2015; 333: 171-177Crossref PubMed Scopus (142) Google Scholar)LPA4 GPCRGs, Gq/11, Gi, G12/13,Cell motility, lymphangiogenesis(3.Chun J. Blaho V. Frantz A. Hla T. Jones D. Kihara Y. Mizuno H. Moolenaar W. Mpamhanga C. Spiegel S. Yung Y.C. Lysophospholipid (LPA) receptors..In IUPHAR/BPS Guide to PHARMACOLOGY. 2018; (Accessed February 6, 2019, at)http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=36Google Scholar, 57.Kihara Y. Mizuno H. Chun J. Lysophospholipid receptors in drug discovery.Exp. Cell Res. 2015; 333: 171-177Crossref PubMed Scopus (142) Google Scholar)LPA5 GPCRGq/11, G12/13,Inhibition of T cell receptor, B cell receptor, platelet aggregation(3.Chun J. Blaho V. Frantz A. Hla T. Jones D. Kihara Y. Mizuno H. Moolenaar W. Mpamhanga C. Spiegel S. Yung Y.C. Lysophospholipid (LPA) receptors..In IUPHAR/BPS Guide to PHARMACOLOGY. 2018; (Accessed February 6, 2019, at)http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=36Google Scholar, 57.Kihara Y. Mizuno H. Chun J. Lysophospholipid receptors in drug discovery.Exp. Cell Res. 2015; 333: 171-177Crossref PubMed Scopus (142) Google Scholar, 58.Hu J. Oda S.K. Shotts K. Donovan E.E. Strauch P. Pujanauski L.M. Victorino F. Al-Shami A. Fujiwara Y. Tigyi G. et al.Lysophosphatidic acid receptor 5 inhibits B cell antigen receptor signaling and antibody response.J. Immunol. 2014; 193: 85-95Crossref PubMed Scopus (27) Google Scholar, 59.Oda S.K. Strauch P. Fujiwara Y. Al-Shami A. Oravecz T. Tigyi G. Pelanda R. Torres R.M. Lysophosphatidic acid inhibits CD8 T cell activation and control of tumor progression.Cancer Immunol. Res. 2013; 1: 245-255Crossref PubMed Scopus (54) Google Scholar, 60.Khandoga A.L. Fujiwara Y. Goyal P. Pandey D. Tsukahara R. Bolen A. Guo H. Wilke N. Liu J. Valentine W.J. et al.Lysophosphatidic acid-induced platelet shape change revealed through LPA(1–5) receptor-selective probes and albumin.Platelets. 2008; 19: 415-427Crossref PubMed Scopus (38) Google Scholar)LPA6 GPCRGs, Gi, G12/13,Hair growth, vascular development(3.Chun J. Blaho V. Frantz A. Hla T. Jones D. Kihara Y. Mizuno H. Moolenaar W. Mpamhanga C. Spiegel S. Yung Y.C. Lysophospholipid (LPA) receptors..In IUPHAR/BPS Guide to PHARMACOLOGY. 2018; (Accessed February 6, 2019, at)http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=36Google Scholar, 57.Kihara Y. Mizuno H. Chun J. Lysophospholipid receptors in drug discovery.Exp. Cell Res. 2015; 333: 171-177Crossref PubMed Scopus (142) Google Scholar)PPARγGenes with PPRE elementsRegulation of lipid uptake, metabolism, arterial wall remodeling and neointima(61.Cheng Y. Makarova N. Tsukahara R. Guo H. Shuyu E. Farrar P. Balazs L. Zhang C. Tigyi G. Lysophosphatidic acid-induced arterial wall remodeling: requirement of PPARgamma but not LPA1 or LPA2 GPCR.Cell. Signal. 2009; 21: 1874-1884Crossref PubMed Scopus (37) Google Scholar, 62.McIntyre T.M. Pontsler A.V. Silva A.R. St Hilaire A. Xu Y. Hinshaw J.C. Zimmerman G.A. Hama K. Aoki J. Arai H. et al.Identification of an intracellular receptor for lysophosphatidic acid (LPA): LPA is a transcellular PPARgamma agonist.Proc. Natl. Acad. Sci. USA. 2003; 100: 131-136Crossref PubMed Scopus (458) Google Scholar, 63.Tsukahara T. The role of PPARgamma in the transcriptional control by agonists and antagonists.PPAR Res. 2012; 2012: 362361Crossref PubMed Scopus (22) Google Scholar, 64.Tsukahara T. Matsuda Y. Haniu H. Lysophospholipid-related diseases and PPARgamma signaling pathway.Int. J. Mol. Sci. 2017; 18: E2730Crossref PubMed Scopus (25) Google Scholar, 65.Tsukahara T. Tsukahara R. Yasuda S. Makarova N. Valentine W.J. Allison P. Yuan H. Baker D.L. Li Z. Bittman R. et al.Different residues mediate recognition of 1-O-oleyllysophosphatidic acid and rosiglitazone in the ligand binding domain of peroxisome proliferator-activated receptor gamma.J. Biol. Chem. 2006; 281: 3398-3407Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 66.Zhang C. Baker D.L. Yasuda S. Makarova N. Balazs L. Johnson L.R. Marathe G.K. McIntyre T.M. Xu Y. Prestwich G.D. et al.Lysophosphatidic acid induces neointima formation through PPARgamma activation.J. Exp. Med. 2004; 199: 763-774Crossref PubMed Scopus (173) Google Scholar)TRPV1 channelCa2+ influxNociception and itch(39.Morales-Lázaro S.L. Serrano-Flores B. Llorente I. Hernandez-Garcia E. Gonzalez-Ramirez R. Banerjee S. Miller D. Gududuru V. Fells J. Norman D. et al.Structural determinants of the transient receptor potential 1 (TRPV1) channel activation by phospholipid analogs.J. Biol. Chem. 2014; 289: 24079-24090Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar, 40.Nieto-Posadas A. Picazo-Juarez G. Llorente I. Jara-Oseguera A. Morales-Lazaro S. Escalante-Alcalde D. Islas L.D. Rosenbaum T. Lysophosphatidic acid directly activates TRPV1 through a C-terminal binding site.Nat. Chem. Biol. 2011; 8 ([Erratum. 2012. Nat. Chem. Biol. 8: 737.]): 78-85Crossref PubMed Scopus (148) Google Scholar, 67.Chemin J. Patel A. Duprat F. Zanzouri M. Lazdunski M. Honore E. Lysophosphatidic acid-operated K+ channels.J. Biol. Chem. 2005; 280: 4415-4421Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar, 68.Kittaka H. Uchida K. Fukuta N. Tominaga M. Lysophosphatidic acid-induced itch is mediated by signalling of LPA5 receptor, phospholipase D and TRPA1/TRPV1.J. Physiol. 2017; 595: 2681-2698Crossref PubMed Scopus (58) Google Scholar)TRPA1 channelCa2+ influxItch sensation(68.Kittaka H. Uchida K. Fukuta N. Tominaga M. Lysophosphatidic acid-induced itch is mediated by signalling of LPA5 receptor, phospholipase D and TRPA1/TRPV1.J. Physiol. 2017; 595: 2681-2698Crossref PubMed Scopus (58) Google Scholar, 69.Hernández-Araiza I. Morales-Lazaro S.L. Canul-Sanchez J.A. Islas L.D. Rosenbaum T. Role of lysophosphatidic acid in ion channel function and disease.J. Neurophysiol. 2018; 120: 1198-1211Crossref PubMed Scopus (16) Google Scholar)M-type K+ channelK+ influxIncreased cell excitability(69.Hernández-Araiza I. Morales-Lazaro S.L. Canul-Sanchez J.A. Islas L.D. Rosenbaum T. Role of lysophosphatidic acid in ion channel function and disease.J. Neurophysiol. 2018; 120: 1198-1211Crossref PubMed Scopus (16) Google Scholar, 70.Telezhkin V. Reilly J.M. Thomas A.M. Tinker A. Brown D.A. Structural requirements of membrane phospholipids for M-type potassium channel activation and binding.J. Biol. Chem. 2012; 287: 10001-10012Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar)VillinLPA binding, carrier, sequestrationEpithelial cell migration, lamellipodia formation(71.Khurana S. Tomar A. George S.P. Wang Y. Siddiqui M.R. Guo H. Tigyi G. Mathew S. Autotaxin and lysophosphatidic acid stimulate intestinal cell motility by redistribution of the actin modifying protein villin to the developing lamellipodia.Exp. Cell Res. 2008; 314: 530-542Crossref PubMed Scopus (32) Google Scholar)GelsolinLPA binding, carrier, sequestrationRegulation of actin polymerization and inhibition of inflammation(72.Arora P.D. Janmey P.A. McCulloch C.A. A role for gelsolin in stress fiber-dependent cell contraction.Exp. Cell Res. 1999; 250: 155-167Crossref PubMed Scopus (25) Google Scholar, 73.Goetzl E.J. Lee H. Azuma T. Stossel T.P. Turck C.W. Karliner J.S. Gelsolin binding and cellular presentation of lysophosphatidic acid.J. Biol. Chem. 2000; 275: 14573-14578Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar, 74.Karliner J.S. Honbo N. Summers K. Gray M.O. Goetzl E.J. The lysophospholipids sphingosine-1-phosphate and lysophosphatidic acid enhance survival during hypoxia in neonatal rat cardiac myocytes.J. Mol. Cell. Cardiol. 2001; 33: 1713-1717Abstract Full Text PDF PubMed Scopus (158) Google Scholar, 75.Meerschaert K. De Corte V. De Ville Y. Vandekerckhove J. Gettemans J. Gelsolin and functionally similar actin-binding proteins are regulated by lysophosphatidic acid.EMBO J. 1998; 17: 5923-5932Crossref PubMed Scopus (83) Google Scholar, 76.Mintzer E. Sargsyan H. Bittman R. Lysophosphatidic acid and lipopolysaccharide bind to the PIP2-binding domain of gelsolin.Biochim. Biophys. Acta. 2006; 1758: 85-89Crossref PubMed Scopus (23) Google Scholar, 77.Osborn T.M. Dahlgren C. Hartwig J.H. Stossel T.P. 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Res. 2007; 143: 130-135Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar)Fragmin and adseverinInhibition of PI 4,5-P2 binding and enhanced phosphorylation by c-srcInhibition of actin severing(75.Meerschaert K. De Corte V. De Ville Y. Vandekerckhove J. Gettemans J. Gelsolin and functionally similar actin-binding proteins are regulated by lysophosphatidic acid.EMBO J. 1998; 17: 5923-5932Crossref PubMed Scopus (83) Google Scholar)Gintonin latex-like proteinLPA-binding carrierLPA delivery to LPA GPCR(72.Arora P.D. Janmey P.A. McCulloch C.A. A role for gelsolin in stress fiber-dependent cell contraction.Exp. Cell Res. 1999; 250: 155-167Crossref PubMed Scopus (25) Google Scholar) Open table in a new tab We developed homology models of the EDG family S1P and LPA GPCRs (8.Bautista D.L. Baker D.L. Wang D. Fischer D.J. Van Brocklyn J. Spiegel S. Tigyi G. Parrill A.L. Dynamic modeling of EDG1 receptor structural changes induced by site-directed mutations.Theochem. 2000; 529: 219-224Crossref Scopus (13) Google Scholar, 9.Parrill A.L. Wang D-A. Bautista D.L. Van Brocklyn J.R. Lorincz Z. Fischer D.J. Baker D.L. Liliom K. Spiegel S. Tigyi G. Identification of Edg1 receptor residues that recognize sphingosine 1-phosphate.J. Biol. Chem. 2000; 275: 39379-39384Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar, 10.Wang D.A. Lorincz Z. Bautista D.L. Liliom K. Tigyi G. Parrill A.L. A single amino acid determines ligand specificity of the S1P1 (EDG1) and LPA1 (EDG2) phospholipid growth factor receptors.J. Biol. Chem. 2001; 276: 49213-49220Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar, 11.Sardar V.M. Bautista D.L. Fischer D.J. Yokoyama K. Nusser N. Virag T. Wang D. Baker D.L. Tigyi G. Parrill A.L. Molecular basis for lysophosphatidic acid receptor antagonist selectivity.Biochim. Biophys. Acta. 2002; 1582: 309-317Crossref PubMed Scopus (78) Google Scholar). The models were validated with extensive site-directed mutagenesis that revealed several previously unknown features of the EDG family of GPCRs. One such striking discovery was the identification of a single amino acid residue, glutamate 3.29, in the third putative transmembrane domain of S1P1 that, when mutated to glutamine, converted the specificity of the GPCRs from S1P to LPA (10.Wang D.A. Lorincz Z. Bautista D.L. Liliom K. Tigyi G. Parrill A.L. A single amino acid determines ligand specificity of the S1P1 (EDG1) and LPA1 (EDG2) phospholipid growth factor receptors.J. Biol. Chem. 2001; 276: 49213-49220Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar). Whereas all S1P receptors have a conserved glutamate that is predicted to ion-pair with the amine moiety of S1P, all LPA-specific members contain a conserved glutamine predicted to hydrogen bond with the hydroxyl group of LPA. Furthermore, computational predictions from the models identified two additional conserved positively charged amino acids, arginine 3.28 and lysine/arginine 7.34, in every EDG GPCR, that were required for activation by the cognate ligand (6.Fujiwara Y. Osborne D.A. Walker M.D. Wang D.A. Bautista D.A. Liliom K. Van Brocklyn J.R. Parrill A.L. Tigyi G. Identification of the hydrophobic ligand binding pocket of the S1P1 receptor.J. Biol. Chem. 2007; 282: 2374-2385Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 10.Wang D.A. Lorincz Z. Bautista D.L. Liliom K. Tigyi G. Parrill A.L. A single amino acid determines ligand specificity of the S1P1 (EDG1) and LPA1 (EDG2) phospholipid growth factor receptors.J. Biol. Chem. 2001; 276: 49213-49220Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar, 11.Sardar V.M. Bautista D.L. Fischer D.J. Yokoyama K. Nusser N. Virag T. Wang D. Baker D.L. Tigyi G. Parrill A.L. Molecular basis for lysophosphatidic acid receptor antagonist selectivity.Biochim. Biophys. Acta. 2002; 1582: 309-317Crossref PubMed Scopus (78) Google Scholar). The computational modeling, SAR, and mutagenesis all pointed out that the glycerol backbone was not a required structural component of a minimal LPA ligand (12.Deng W. Shuyu E. Tsukahara R. Valentine W.J. Durgam G. Gududuru V. Balazs L. Manickam V. Arsura M. VanMiddlesworth L. et al.The lysophosphatidic acid type 2 receptor is required for protection against radiation-induced intestinal injury.Gastroenterology. 2007; 132: 1834-1851Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar). Based on this hypothesis, we explored the ligand properties of fatty alcohol phosphates as ligands of LPA GPCRs. The choice of the fatty alcohol phosphate scaffold was based on the importance of the glycerol backbone required for substrate recognition by phospholipases, to which this scaffold is resistant (13.Virag T. Elrod D.B. Liliom K. Sardar V.M. Parrill A.L. Yokoyama K. Durgam G. Deng W. Miller D.D. Tigyi G. Fatty alcohol phosphates are subtype-selective agonists and antagonists of lysophosphatidic acid receptors.Mol. Pharmacol. 2003; 63: 1032-1042Crossref PubMed Scopus (71) Google Scholar). To further enhance the stability of the ligands, we inserted a thiophosphate in place of the phosphate group, as thiophosphates also show increased resistance to cleavage by many lipases. Octadecyl thiophosphate (OTP; licensed under the trade name Rx100) showed full agonist activity at LPA2 and LPA5, with reasonable submicromolar potency at all LPA GPCRs (Table 2) (14.Kuo B. Szabó E. Lee S.L. Balogh A. Norman D.D. Inoue A. Ono Y. Aoki J. Tigyi G.J. The LPA2 receptor agonist radioprotectin-1 spares LGR-5 positive intestinal stem cells from radiation injury in murine enteroids.Cell. Signal. 2018; 51: 23-33Crossref PubMed Scopus (14) Google Scholar). Resistance to degradation by phospholipases and lipid phosphatases is the likely cause for the long ∼10.5 h plasma half-life of OTP in Rhesus monkey plasma (15.Kosanam H. Ma F. He H. Ramagiri S. Gududuru V. Tigyi G.J. Van Rompay K. Miller D.D. Yates C.R. Development of an LC-MS/MS assay to determine plasma pharmacokinetics of the radioprotectant octadecenyl thiophosphate (OTP) in monkeys.J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2010; 878: 2379-2383Crossref PubMed Scopus (7) Google Scholar). OTP has an oral bioavailability of approximately 80%, is highly protein bound (>99%), and is metabolically (S9 fractions and human liver microsomes) and chemically (37°C) stable. The majority of our efficacy studies with OTP have been performed using the oral or subcutaneous route of administration. Intraperitoneal administration is also another route of administration that is widely used in exploratory and proof-of-concept studies. Continued development includes optimizing dosing schedules and clinically relevant routes of administration. The improved in vivo stability over LPA combined with the drug-like properties of OTP prompted us to explore the biological actions of this LPA mimic in vitro and in vivo. As a result of these improvements, OTP was licensed by RxBio Inc. and named Rx100. OTP/Rx100 is the most advanced LPA mimic and is nearing filing of an Investigational New Drug application.TABLE 21. Rx100 has favorable drug profile including drug substance stability ≥5 years at refrigerated temperaturesChemical formulaC18H37O3SPMolecular weight364.52Salt formL-LysineAqueous solubility>250 mg/mlEC50 at human LPA1/2/3/4/5 (nM) in Ca2+ mobilization assay850, 23, 120, 950, 3PharmacokineticsaIn Rhesus macaques.T1/2 10.5 ha In Rhesus macaques. Open table in a new tab Many reports have established that LPA has a major action in promoting cell survival by preventing programmed cell death elicited by different cellular stresses ranging from serum withdrawal to radiation-induced DNA damage (16.Deng W. Balazs L. Wang D.A. Van Middlesworth L. Tigyi G. Johnson L.R. Lysophosphatidic acid protects and rescues intestinal epithelial cells from radiation- and chemotherapy-induced apoptosis.Gastroenterology. 2002; 123: 206-216Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar, 17.Deng W. Poppleton H. Yasuda S. Makarova N. Shinozuka Y. Wang D.A. Johnson L.R. Patel T.B. Tigyi G. Optimal lysophosphatidic acid-induced DNA synthesis and cell migration but not survival require intact autophosphorylation sites of the epidermal growth factor receptor.J. Biol. Chem. 2004; 279: 47871-47880Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, 18.Deng W. Wang D.A. Gosmanova E. Johnson L.R. Tigyi G. LPA protects intestinal epithelial cells from apoptosis by inhibiting the mitochondrial pathway.Am. J. Physiol. Gastrointest. Liver Physiol. 2003; 284: G821-G829Crossref PubMed Scopus (70) Google Scholar, 19.Lin F.T. Lai Y.J. Makarova N. Tigyi G. Lin W.C. The lysophosphatidic acid 2 receptor mediates down-regulation of Siva-1 to promote cell survival.J. Biol. Chem. 2007; 282: 37759-37769Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar). A unique feature of the anti-apoptotic effect of LPA was that it not only prevented programmed cell death when administered prior to triggering apoptosis, but it was also capable of rescuing cells that were otherwise condemned to apoptosis (16.Deng W. Balazs L. Wang D.A. Van Middlesworth L. Tigyi G. Johnson L.R. Lysophosphatidic acid protects and rescues intestinal epithelial cells from radiation- and chemotherapy-induced apoptosis.Gastroenterology. 2002; 123: 206-216Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar). OTP treatment also arrested the progression of the apoptotic cascade in cultured cells (16.Deng W. Balazs L. Wang D.A. Van Middlesworth L. Tigyi G. Johnson L.R. Lysophosphatidic acid protects and rescues intestinal epithelial cells from radiation- and chemotherapy-induced apoptosis.Gastroenterology. 2002; 123: 206-216Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar). In addition, OTP prevented death in mice and Rhesus macaques when exposed to lethal levels of ionizing radiation (see below) (Fig. 1A, B) (20.Deng W. Kimura Y. Gududuru V. Wu W. Balogh A. Szabo E. Thompson K.E. Yates C.R. Balazs L. Johnson L.R. et al.Mitigation of the hematopoietic and gastrointestinal acute radiation syndrome by octadecenyl thiophosphate, a small molecule mimic of lysophosphatidic acid.Radiat. Res. 2015; 183: 465-475Crossref PubMed Scopus (28) Google Scholar, 21.Patil R. Szabo E. Fells J.I. Balogh A. Lim K.G. Fujiwara Y. Norman D.D. Lee S.C. Balazs L. Thomas F. et al.Combined mitigation of the gastrointestinal and hematopoietic acute radiation syndromes by an LPA2 receptor-specific nonlipid agonist.Chem. Biol. 2015; 22: 206-216Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar). Experiments have pointed to the unique anti-apoptotic action of the LPA2 GPCR subtype coupled to G protein-mediated and non-G protein-mediated pathways (12.Deng W. Shuyu E. Tsukahara R. Valentine W.J. Durgam G. Gududuru V. Balazs L. Manickam V. Arsura M. 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The lysophosphatidic acid 2 receptor mediates down-regulation of Siva-1 to promote cell survival.J. Biol. Chem. 2007; 282: 37759-37769Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 22.Shuyu E. Lai Y.J. Tsukahara R. Chen C.S. Fujiwara Y. Yue J. Yu J.H. Guo H. Kihara A. Tigyi G. et al.Lysophosphatidic acid 2 receptor-mediated supramolecular complex formation regulates its antiapoptotic effect.J. Biol. Chem. 2009; 284: 14558-14571Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar). Truncation and site-directed mutagenesis studies conducted with the EDG receptors that otherwise share ∼80% sequence identity in their transmembrane regions suggested that the unique signaling actions of LPA2 are tied to the C terminus of this receptor subtype that shows less than 25% homology with the other two EDG family LPA GPCRs (19.Lin F.T. Lai Y.J. Makarova N. Tigyi G. Lin W.C. The lysophosphatidic acid 2 receptor mediates down-regulation of Siva-1 to promote cell survival.J. Biol. Chem. 2007; 282: 37759-37769Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 22.Shuyu E. Lai Y.J. Tsukahara R. Chen C.S. Fujiwara Y. Yue J. Yu J.H. Guo H. Kihara A. Tigyi G. et al.Lysophosphatidic acid 2 receptor-mediated supramolecular complex formation regulates its antiapoptotic effect.J. Biol. Chem. 2009; 284: 14558-14571Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar). Only LPA2 contains a C-terminal -S-x-L/V sequence PDZ-protein-recognition motif and a -C311x-x-C- LIM protein binding motif near its C-terminal tail (Fig. 2) (22.Shuyu E. Lai Y.J. Tsukahara R. Chen C.S. Fujiwara Y. Yue J. Yu J.H. Guo H. Kihara A. Tigyi G. et al.Lysophosphatidic acid 2 receptor-mediated supramolecular complex formation regulates its antiapoptotic effect.J. Biol. Chem. 2009; 284: 14558-14571Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar). The LPA2 PDZ-recognition motif has been shown to mediate the interaction with Na-H exchange response factor (NHERF)1, NHERF2 (23.Li C. Dandridge K.S. Di A. Marrs K.L. Harris E.L. Roy K. Jackson J.S. Makarova N.V. Fujiwara Y. Farrar P.L. et al.Lysophosphatidic acid inhibits cholera toxin-induced secretory diarrhea through CFTR-dependent protein interactions.J. Exp. Med. 2005; 202: 975-986Crossref PubMed Scopus (128) Google Scholar), membrane associated guanylate kinase WW and PDZ domain containing protein (MAGI)-2, MAGI-3, neurabin, PDZ-RhoGEF, and LARG proteins (22.Shuyu E. Lai Y.J. Tsukahara R. Chen C.S. Fujiwara Y. Yue J. Yu J.H. Guo H." @default.
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• W2912997222 date "2019-03-01" @default.
• W2912997222 modified "2023-10-17" @default.
• W2912997222 title "Lysophosphatidic acid type 2 receptor agonists in targeted drug development offer broad therapeutic potential" @default.
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• W2912997222 doi "https://doi.org/10.1194/jlr.s091744" @default.
• W2912997222 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6399510" @default.
• W2912997222 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/30692142" @default.
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