‘Crystal’ Clear? Lysophospholipid Receptor Structure Insights and Controversies

Blaho, Victoria A.; Chun, Jerold

doi:10.1016/j.tips.2018.08.006

Cited by 34 publications

(31 citation statements)

References 83 publications

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“…However, LPA is a family of structurally related compounds composed by saturated fatty acids (16:0, 18:0) and unsaturated fatty acids (16:1, 18:1, 18:2, 18:3, 20:4) which show differential biological activities by activating different receptors in human and rat (Tokumura et al 1986, Gerrard & Robinson 1989, Eichholtz et al 1993, Baker et al 2000, Sano et al 2002, Sugiura et al 2002. In biological fluids, LPA is generally bound to chaperones (Mills & Moolenaar 2003, Blaho & Chun 2018. In plasma, 16:0 is the predominant species, while 18:0, 18:1, 18:2, 18:3 and 20:4 forms are present at lower concentrations (Akira et al 1986, Choi et al 2010.…”

Section: General Characteristics Of Lpamentioning

confidence: 99%

Novel role for lysophosphatidic acid in vascular remodeling at the maternal–fetal interface

et al. 2020

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Lysophosphatidic acid (LPA) belongs to the group of phosphorylated lipids reported as crucial mediators in the physiology of reproduction. LPA binds to G-protein-coupled receptors and regulates a wide range of female reproductive functions. This bioactive lipid has also been implicated in vascular functions during physiological and pathological conditions. In this regard, the establishment of a successful pregnancy requires proper coordination of vascular processes and remodeling of maternal blood vessels during early gestation. During this process, first trimester cytotrophoblast changes from an invasive to an endovascular phenotype and transforms uterine spiral arteries which are the nutrient supply for placenta and fetus. Here we present an overview of LPA participation in vascular remodeling and highlight the importance of LPA–LPA3 signaling during early gestation at the maternal–fetal interface.

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Section: General Characteristics Of Lpamentioning

confidence: 99%

Novel role for lysophosphatidic acid in vascular remodeling at the maternal–fetal interface

et al. 2020

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“…The actions of LPA1 in Schwann cells affecting PSNL phenotypes have not, to our knowledge, been previously reported, and the observed phenotype was unexpected with regard to the clear and differential time-dependence of the effect. Explanations for these temporal changes in pain protection may be due to differences in de novo synthesis of LPA and the varied activation states documented for LPA1 (8,11,(35)(36)(37)(38) that may occur in neurons and Schwann cells. Such LPA signaling effects could be altered by receptor removal to produce the time-course differences observed for PSNLinitiated pain rescue.…”

Section: Discussionmentioning

confidence: 99%

“…The generated Lpar1 conditional mutant mice will be useful in identifying cell types involved directly with LPA1 signaling in neuropathic pain as well as many other conditions and disease models (6)(7)(8)(9)(10)(11)(12)37,45,50,51). The tractability of LPA1 as a member of the lysophospholipid receptor family supports its potential as a druggable GPCR target (8,10,35,36) for the development of improved therapies targeting specific Lpar1 expressing cell types.…”

Section: Discussionmentioning

confidence: 99%

“…One identified modulator of neuropathic pain is the bioactive lipid lysophosphatidic acid (LPA). LPA normally signals through six known G protein-coupled receptors, Lpar1-6 (6), which are involved in myriad biological and pathological processes affecting most of the physiological systems in the body, including the nervous system (6)(7)(8)(9)(10)(11)(12)(13). LPA1 is also expressed in the peripheral nervous system (PNS) and CNS.…”

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ConditionalLpar1gene targeting identifies cell types mediating neuropathic pain

Rivera

Lin

Bornhop

et al. 2020

Preprint

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LPA1 is one of the six known receptors (LPA1-6) for lysophosphatidic acid (LPA). Constitutive Lpar1 null mutant mice have been instrumental in identifying roles for LPA-LPA1 signaling in neurobiological processes, brain development, and behavior as well as modelling human neurological diseases like neuropathic pain. Constitutive Lpar1 null mutant mice are protected from partial sciatic nerve ligation (PSNL)-induced neuropathic pain, however Lpar1 expressing cell types that are functionally responsible for mediating this protective effect are unknown. Here we report generation of a Lpar1 flox/flox conditional null mutant mouse that allows cre-mediated conditional deletion combined with its use in a PSNL pain model. Lpar1 flox/flox mice were crossed with cre transgenic lines driven by neural gene promoters for nestin (all neural cells), synapsin (neurons), or P0 (Schwann cells). CD11b-cre transgenic mice were also used to delete Lpar1 in microglia. PSNL-initiated pain responses were reduced following cre-mediated Lpar1 deletion with all 3 neural promoters but not the microglial promoter, supporting involvement of Schwann cells and central and/or peripheral neurons in mediating pain. Interestingly, rescue responses that were due to conditional deletion were non-identical,

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“…These concordant results support the utility of BSI in competition assays in which antagonists and orthosteric ligands share the same binding pocket. The mechanism through which LPA 1 -ligand binding alters the BSI signal is unknown, but it may reflect the actions within the "baggy" LPA 1 binding pocket (13,16) whose occupancy with agonist or antagonist induces LPA 1 conformational changes differently. Thus, BSI is also useful for assessing competitive binding, at least to an orthosteric binding site.…”

Section: K D Determination Of a Synthetic Lpa 1 Antagonist And Its Usmentioning

confidence: 99%

Lysophospholipid G protein-coupled receptor binding parameters as determined by backscattering interferometry

Mizuno

Kihara

Kussrow

et al. 2019

Journal of Lipid Research

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This article is available online at http://www.jlr.org binding parameters as determined by backscattering interferometry. J. Lipid Res. 2019. 60: 212-217.Supplementary key words lipid • phospholipids • endocannabinoid • optical measurement • molecular interaction • binding assay Lysophospholipid (LP) signaling involving cognate G protein-coupled receptors (GPCRs) for lysophosphatidic acid (LPA), sphingosine-1-phosphate (S1P), and other lipids has revealed a vast biology affecting the development and function of most, if not all, organ systems and shown etiological or therapeutic involvement in diseases, including those of the nervous and immune systems, as well as in disease conditions like cancer and fibrosis (1-9). A key step in LP signaling is orthosteric GPCR engagement by binding of a cognate ligand to its receptor, followed by G-protein transduction (10, 11). LP receptor binding is thus a necessary step for both naturally occurring lipids and synthetic ligands that, combined with other members of the GPCR superfamily, account for 40% of currently marketed drugs (12).LP GPCRs are members of the rhodopsin-like family of receptors (class A) from which 40 lipid GPCRs have now been identified (7). Crystal structures for seven lipid GPCRs have been solved including three LP receptors [LPA 1 (13), LPA 6 (14), and S1P 1 (15)] (16).Despite these receptor structural advances, classical pharmacological GPCR-ligand binding assays using radioligands Abstract Lysophosphatidic acid (LPA) activates cognate G protein-coupled receptors (GPCRs) to initiate biological signaling cascades. Lysophospholipid (LP) receptor binding properties remain incompletely assessed because of difficulties with ligand lipophilicity and lipid "stickiness." These inherent attributes produce high levels of nonspecific binding within cell-membrane preparations used to assess GPCRs, as has been shown in classical binding assays using radiolabeled ligands, making accurate measurements of lipid binding kinetics difficult to achieve. Backscattering interferometry (BSI) is an optical technology that measures molecular binding interactions by reporting changes in the refractive index of a solution after binding events. Here, we report the use of BSI to assess LPA 1 for its ability to bind to naturally occurring lipids and a synthetic LPA 1 antagonist (ONO-9780307), under both primary-and competition-binding conditions. Assessment of 12 different lipids demonstrated that the known LP ligand, 1-oleoyl-LPA, as well as an endocannabinoid metabolite, anandamide phosphate, are specific ligands for LPA 1 , whereas other LPs tested were not. Newly determined dissociation constants (K d values) for orthosteric lipid ligands approximated 10 9 M, substantially lower (i.e., with higher affinity) than measured K d values in classical binding or cell-based assays. These results demonstrate that BSI may have particular utility in assessing binding interactions between lipid receptors and their lipid ligands and could provide new screening approaches for lipid recept...

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‘Crystal’ Clear? Lysophospholipid Receptor Structure Insights and Controversies

Cited by 34 publications

References 83 publications

Novel role for lysophosphatidic acid in vascular remodeling at the maternal–fetal interface

Novel role for lysophosphatidic acid in vascular remodeling at the maternal–fetal interface

ConditionalLpar1gene targeting identifies cell types mediating neuropathic pain

Lysophospholipid G protein-coupled receptor binding parameters as determined by backscattering interferometry

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