Farnesyl phosphates are endogenous ligands of lysophosphatidic acid receptors: Inhibition of LPA GPCR and activation of PPARs

Liliom, Károly; Tsukahara, Tamotsu; Tsukahara, Ryoko; Zelman-Femiak, Monika; Świeżewska, Ewa; Tigyi, Gábor

doi:10.1016/j.bbalip.2006.09.012

Cited by 24 publications

(17 citation statements)

References 39 publications

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“…FPP acts on other membrane receptors: it activates GPR92 and inhibits LPA2 and LPA3 receptors (26,32). In the present study, another activating ligand for GPR92, NAG failed to elevate intracellular Ca 2ϩ level in the keratinocyte experiments.…”

Section: Discussionmentioning

confidence: 53%

“…RR and the shRNA also prevented FPP-evoked pain behavior, supporting this notion. As well, it is not possible that LPA2 or LPA3 receptor is involved because FPP leads to the opposite result through the receptor inhibition (FPP blocked the LPAinduced intracellular Ca 2ϩ increase in the observations of Liliom et al (32)) Differential roles of FPP may be expected in the different receptor expressers.…”

Section: Discussionmentioning

confidence: 96%

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Farnesyl Pyrophosphate Is a Novel Pain-producing Molecule via Specific Activation of TRPV3

Bang

Yoo

Yang

et al. 2010

Journal of Biological Chemistry

115

107

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Temperature-sensitive transient receptor potential ion channels (thermoTRPs) expressed in epidermal keratinocytes and sensory afferents play an important role as peripheral pain detectors for our body. Many natural and synthetic compounds have been found to act on the thermoTRPs leading to altered nociception, but little is known about endogenous painful molecules activating TRPV3. Here, we show that farnesyl pyrophosphate (FPP), an intermediate metabolite in the mevalonate pathway, specifically activates TRPV3 among six thermoTRPs using Ca 2؉ imaging and electrophysiology with cultured keratinocytes and TRPV3-overexpressing cells. Agonistic potencies of related compounds in the FPP metabolism were ignorable. Voltage-dependence of TRPV3 was shifted by FPP, which appears to be the activation mechanism. An intraplantar injection of FPP acutely elicits nociceptive behaviors in inflamed animals, indicating that FPP is a novel endogenous pain-producing substance via TRPV3 activation. Co-culture experiments demonstrated that this FPP-evoked signal in the keratinocytes is transmitted to sensory neurons. In addition, FPP reduced TRPV3 heat threshold resulting in heightened behavioral sensitivity to noxious heat. Taken together, our data suggest that FPP is the firstly identified endogenous TRPV3 activator that causes nociception. Our results may provide useful chemical information to elucidate TRPV3 physiology and novel pain-related metabolisms.Skin keratinocytes and sensory neurons express sensor ion channels that detect changes in the external or internal environments. TRPV3 channel has been found to be expressed in the skin keratinocytes of mice and humans and in the sensory neurons of humans and is activated by temperatures exceeding 33°C (1-3). Studies using TRPV3-knock-out mice or TRPV3-overexpressing transgenic mice have demonstrated that TRPV3 is involved in behavioral responses to innocuous and noxious heat (4 -5).Searching for pharmacological tools to modulate TRPV3 activity seems active (see review, Ref. 6). Several phytosubstances and synthetic compounds, such as camphor, menthol, carvacrol, citral, incensole acetate, and 2-aminoethoxydiphenyl borate (2-APB) 2 are shown to activate TRPV3 (4, 7-13). It has been reported that some of endogenous molecules are able to modulate TRPV3 activation. For example, unsaturated fatty acids potentiated TRPV3 activation by 2-APB (14). S-Nitrosylation of the channel protein activates TRPV3, as well as other TRPVs (15). Ca 2ϩ and calmodulin suppressed the sensitization of TRPV3 to recurrent stimuli (16). However, little is known about endogenous compounds that are able to directly and specifically activate TRPV3.A variety of metabolites are formed in the human body as a result of the diverse biochemical processes and some of the metabolites are potentially involved in pain development (17). Farnesyl pyrophosphate (FPP) is an intermediate molecule in the cholesterol synthesis pathway. In the present study, we examined whether FPP is an activator for TRPV3. We performed Ca 2ϩ ...

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Section: Discussionmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 96%

Farnesyl Pyrophosphate Is a Novel Pain-producing Molecule via Specific Activation of TRPV3

Bang

Yoo

Yang

et al. 2010

Journal of Biological Chemistry

115

107

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“…The docking simulations also predicted NAG to be a weak activator of the LPA 5 based on weak interactions with the mutated residues Arg-2.60, Arg-6.62, Arg-7.32, and His-4.64 within the binding pocket of our model (Table 2). Based on these predictions, we examined the activation of LPA 5 by NAG, FPP, and FMP, which we had earlier identified as endogenous antagonists of EDG LPA receptors (42). Among this subset of ligands, LPA 18:1 was the most potent in mobilizing Ca 2ϩ in RH7777 cells transiently transfected with LPA 5 (Fig.…”

Section: Selection Of Mutationmentioning

confidence: 99%

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

Self Cite

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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“…A separate study with 3T3-L1 cells also showed that 50 mmol/L farnesol, a level comparable to those used in the present study, activated PPARg in a reporter assay; farnesol had the highest potency among several isoprenoids evaluated therein in activating PPARg-regulated FABP4 expression. 6 Farnesyl phosphate and FPP competed with rosiglitazone for PPARg binding with IC50 values for ligand displacement approximating 19 mmol/L, a value much lower than that of farnesol; the latter was nevertheless more efficacious in activating PPARg in CV-1 cells transfected with a reporter gene, 19 suggesting a possible farnesol metabolite with higher potency than those of the phosphorylated products of farnesol. In human HCT, 116 colorectal cancer cells, farnesol at 50 and 100 mmol/L increased PPARg promoter activity, an effect that mediates the growth-inhibitory activity of farnesol.…”

Section: Discussionmentioning

confidence: 99%

Trans, trans-farnesol as a mevalonate-derived inducer of murine 3T3-F442A pre-adipocyte differentiation

Torabi

2015

Exp Biol Med (Maywood)

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Based on our finding that depletion of mevalonate-derived metabolites inhibits adipocyte differentiation, we hypothesize that trans, trans-farnesol (farnesol), a mevalonate-derived sesquiterpene, induces adipocyte differentiation. Farnesol dosedependently (25-75 lmol/L) increased intracellular triglyceride content of murine 3T3-F442A pre-adipocytes measured by AdipoRed TM Assay and Oil Red-O staining. Concomitantly, farnesol dose-dependently increased glucose uptake and glucose transport protein 4 (GLUT4) expression without affecting cell viability. Furthermore, quantitative real-time polymerase chain reaction and Western blot showed that farnesol increased the mRNA and protein levels of peroxisome proliferator-activated receptor g (PPARg), a key regulator of adipocyte differentiation, and the mRNA levels of PPARg-regulated fatty acid-binding protein 4 and adiponectin; in contrast, farnesol downregulated Pref-1 gene, a marker of pre-adipocytes. GW9662 (10 mmol/L), an antagonist of PPARg, reversed the effects of farnesol on cellular lipid content, suggesting that PPARg signaling pathway may mediate the farnesol effect. Farnesol (25-75 lmol/L) did not affect the mRNA level of 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme in the mevalonate pathway. Farnesol may be the mevalonate-derived inducer of adipocyte differentiation and potentially an insulin sensitizer via activation of PPARg and upregulation of glucose uptake.

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Farnesyl phosphates are endogenous ligands of lysophosphatidic acid receptors: Inhibition of LPA GPCR and activation of PPARs

Cited by 24 publications

References 39 publications

Farnesyl Pyrophosphate Is a Novel Pain-producing Molecule via Specific Activation of TRPV3

Farnesyl Pyrophosphate Is a Novel Pain-producing Molecule via Specific Activation of TRPV3

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

Trans, trans-farnesol as a mevalonate-derived inducer of murine 3T3-F442A pre-adipocyte differentiation

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