Lysophosphatidic acid-induced platelet shape change revealed through LPA<sub>1–5</sub>receptor-selective probes and albumin

Khandoga, Anna L.; Fujiwara, Yuko; Goyal, Pankaj; Pandey, Dharmendra; Tsukahara, Ryoko; Bolen, Alyssa L.; Guo, Huazhang; Wilke, N.; Liu, J.; Valentine, William J.; Durgam, Gangadhar G.; Miller, Duane D.; Jiang, Guotai; Prestwich, Glenn D.; Tigyi, Gábor; Siess, Wolfgang

doi:10.1080/09537100802220468

Cited by 40 publications

(47 citation statements)

References 34 publications

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“…However, there are also discrepancies. Whereas albumin inhibits LPA-induced platelet activation, this effect is not observed in LPA 5 -transfected cells (28), and LPA does not elevate cAMP levels in platelets, which is observed in LPA 5 -transfected cells (18). These findings argue against the involvement of LPA 5 in platelet activation.…”

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confidence: 49%

“…LPA 5 receptor mRNA is one of the most abundant LPA GPCR mRNAs in human platelets (28,30). Recently, we found that heterologously expressed LPA 5 showed similar SAR to that of platelets with preference to alkyl-glycerophosphate (AGP, also known as alkyl-LPA) over acyl-LPA (28). However, there are also discrepancies.…”

mentioning

confidence: 83%

“…At the same time, a decrease in cAMP is insufficient to produce full platelet activation, suggesting other signaling events are needed for full platelet activation (29). LPA 5 receptor mRNA is one of the most abundant LPA GPCR mRNAs in human platelets (28,30). Recently, we found that heterologously expressed LPA 5 showed similar SAR to that of platelets with preference to alkyl-glycerophosphate (AGP, also known as alkyl-LPA) over acyl-LPA (28).…”

mentioning

confidence: 94%

“…Effect of LPA 5 Agonists and Antagonists on Platelet Activation-LPA 5 represents the most abundant LPA receptor mRNA transcript in human platelets (28). Therefore, we examined the effects of the LPA 5 agonists (Table 5) and antagonists ( Table 6) that we identified in this study on LPA-induced platelet shape change (Table 7).…”

Section: Agreement Of the Predictions Based On The Mutant Protein Modmentioning

confidence: 99%

“…LPA 5 couples to G 12/13 -mediated Rho activation and G q -mediated phospholipase C activation. Similarly in platelets, LPA stimulates Rho and Ca 2ϩ mobilization; low LPA concentrations induce Rho/ Rho kinase-mediated shape change, and higher LPA concentrations stimulate an increase of cytosolic Ca 2ϩ and aggregation (25)(26)(27)(28). LPA 5 can also mediate an increase in intracellular cAMP production independent of G s (18), and cAMP formation inhibits platelet activation, which implies that LPA 5 activation could inhibit platelet aggregation.…”

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confidence: 99%

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Unique Ligand Selectivity of the GPR92/LPA5 Lysophosphatidate Receptor Indicates Role in Human Platelet Activation

Williams

Khandoga²,

Goyal³

et al. 2009

Journal of Biological Chemistry

139

140

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Lysophosphatidic acid (LPA) is a ligand for LPA 1-3 of the endothelial differentiation gene family G-protein-coupled receptors, and LPA 4 -8 is related to the purinergic family G-protein-coupled receptor. Because the structure-activity relationship (SAR) of GPR92/LPA 5 is limited and whether LPA is its preferred endogenous ligand has been questioned in the literature, in this study we applied a combination of computational and experimental site-directed mutagenesis of LPA 5 residues predicted to interact with the headgroup of LPA. Four residues involved in ligand recognition in LPA 5 were identified as follows: R2.60N mutant abolished receptor activation, whereas H4.64E, R6.62A, and R7.32A greatly reduced receptor activation. We also investigated the SAR of LPA 5 using LPA analogs and other non-lysophospholipid ligands. SAR revealed that the rank order of agonists is alkyl glycerol phosphate > LPA > farnesyl phosphates Ͼ Ͼ N-arachidonoylglycine. These results confirm LPA 5 to be a bona fide lysophospholipid receptor. We also evaluated several compounds with previously established selectivity for the endothelial differentiation gene receptors and found several that are LPA 5 agonists. A pharmacophore model of LPA 5 binding requirements was developed for in silico screening, which identified two non-lipid LPA 5 antagonists. Because LPA 5 transcripts are abundant in human platelets, we tested its antagonists on platelet activation and found that these non-lipid LPA 5 antagonists inhibit platelet activation. The present results suggest that selective inhibition of LPA 5 may provide a basis for future anti-thrombotic therapies.Lysophosphatidic acid (LPA, 2 1-radyl-2-hydroxy-sn-3-glycero phosphate) specifically interacts with several protein targets that regulate physiological and pathophysiological processes (1-3). LPA targets include specific G-protein-coupled receptors (GPCRs) that mediate a wide variety of biological effects, including cell proliferation (4), cell survival (5), cell migration (6), and platelet aggregation (7,8). GPCRs are the largest family of transmembrane receptors and represent targets of many therapeutics (9). Eight LPA-specific mammalian GPCRs, LPA 1-8 , have been identified to date (10 -12). Among the eight LPA receptors, LPA 1 , LPA 2 , and LPA 3 are members of the endothelial differentiation gene (EDG) family (13), and the transmembrane domains of human LPA 1-3 show 81% homology with each other (14). The five other members of the EDG family are specific for the related lysophospholipid sphingosine 1-phosphate (S1P). The structural foundation for LPA selectivity over S1P has been linked to a single amino acid at position 3.29, a conserved glutamine in the LPA-specific and glutamate in the S1P-specific members of the EDG family (14 -16). However, the recently identified non-EDG family LPA receptors, LPA 4 /p2y9 (13), LPA 5 /GPR92 (17, 18), LPA 6 /GPR87 (19), LPA 7 /p2y5 (12), and LPA 8 /p2y10 (10), are more closely related to the purinoreceptor gene cluster and share less than 20% amino acid...

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confidence: 49%

mentioning

confidence: 83%

mentioning

confidence: 94%

Section: Agreement Of the Predictions Based On The Mutant Protein Modmentioning

confidence: 99%

mentioning

confidence: 99%

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Unique Ligand Selectivity of the GPR92/LPA5 Lysophosphatidate Receptor Indicates Role in Human Platelet Activation

Williams

Khandoga²,

Goyal³

et al. 2009

Journal of Biological Chemistry

139

140

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LPA₁, LPA₂, LPA₄, and LPA₆ receptor expression during mouse brain development

Suckau

Gross

Schrötter

et al. 2019

Developmental Dynamics

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Background LPA is a small bioactive phospholipid that acts as an extracellular signaling molecule and is involved in cellular processes, including cell proliferation, migration, and differentiation. LPA acts by binding and activating at least six known G protein–coupled receptors: LPA 1–6 . In recent years, LPA has been suggested to play an important role both in normal neuronal development and under pathological conditions in the nervous system. Results We show the expression pattern of LPA receptors during mouse brain development by using qRT‐PCR, in situ hybridization, and immunocytochemistry. Only LPA 1 , LPA 2, LPA 4, and LPA 6 mRNA transcripts were detected throughout development stages from embryonic day 16 until postnatal day 30 of hippocampus, neocortex, cerebellum, and bulbus olfactorius in our experiments, while expression of LPA 3 and LPA 5 genes was below detection level. In addition to our qRT‐PCR results, we also analyzed the cellular protein expression of endogenous LPA receptors, with focus on LPA 1 and LPA 2 within postnatal brain slices and primary neuron differentiation with and without cytoskeleton stabilization and destabilization. Conclusions The expression of LPA receptors changes depends on the developmental stage in mouse brain and in cultured hippocampal primary neurons. Interestingly, we found that commercially available antibodies for LPA receptors are largely unspecific.

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Lysophosphatidic acid up-regulates IL-10 production to inhibit TNF-α synthesis in Mϕs stimulated with LPS

Ciesielska

Hromada-Judycka

Ziemlińska

et al. 2019

Journal of Leukocyte Biology

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Bacterial LPS strongly induces pro-inflammatory responses of M s after binding to CD14 protein and the TLR4/MD-2 receptor complex. The LPS-triggered signaling can be modulated by extracellular lysophosphatidic acid (LPA), which is of substantial importance for M functioning under specific pathophysiological conditions, such as atherosclerosis. The molecular mechanisms of the crosstalk between the LPS-and LPA-induced signaling, and the LPA receptors involved, are poorly known. In this report, we show that LPA strongly inhibits the LPS-induced TNF-production at the mRNA and protein levels in primary M s and M -like J774 cells. The decreased TNF-production in LPA/LPS-stimulated cells is to high extent independent of NF-B but is preceded by enhanced expression and secretion of the anti-inflammatory cytokine IL-10. The IL-10 elevation and TNFreduction are both abrogated upon depletion of the LPA 5 and LPA 6 receptors in J774 cells and can be linked with LPA-mediated activation of p38. We propose that the binding of LPA to LPA 5 and LPA 6 fine-tunes the LPS-induced inflammatory response by activating p38, and up-regulating IL-10 and down-regulating TNF-production. K E Y W O R D SCD14, inflammatory response, LPA receptor, TLR4

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Lysophosphatidic acid-induced platelet shape change revealed through LPA_1–5receptor-selective probes and albumin

Cited by 40 publications

References 34 publications

Unique Ligand Selectivity of the GPR92/LPA5 Lysophosphatidate Receptor Indicates Role in Human Platelet Activation

Unique Ligand Selectivity of the GPR92/LPA5 Lysophosphatidate Receptor Indicates Role in Human Platelet Activation

LPA₁, LPA₂, LPA₄, and LPA₆ receptor expression during mouse brain development

Lysophosphatidic acid up-regulates IL-10 production to inhibit TNF-α synthesis in Mϕs stimulated with LPS

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Lysophosphatidic acid-induced platelet shape change revealed through LPA1–5receptor-selective probes and albumin

Cited by 40 publications

References 34 publications

Unique Ligand Selectivity of the GPR92/LPA5 Lysophosphatidate Receptor Indicates Role in Human Platelet Activation

Unique Ligand Selectivity of the GPR92/LPA5 Lysophosphatidate Receptor Indicates Role in Human Platelet Activation

LPA1, LPA2, LPA4, and LPA6 receptor expression during mouse brain development

Lysophosphatidic acid up-regulates IL-10 production to inhibit TNF-α synthesis in Mϕs stimulated with LPS

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Lysophosphatidic acid-induced platelet shape change revealed through LPA_1–5receptor-selective probes and albumin

LPA₁, LPA₂, LPA₄, and LPA₆ receptor expression during mouse brain development