Identification of human glycerophosphodiesterase 3 as an ecto phospholipase C that converts the G protein-coupled receptor 55 agonist lysophosphatidylinositol to bioactive monoacylglycerols in cultured mammalian cells

Tsutsumi, Toshihiko; Matsuda, Ryozo; Morito, Katsuya; Kawabata, Ken‐ichi; Yokota, Mika; Nikawadori, Miki; Inoue-Fujiwara, Manami; Kawashima, Satoshi; Hidaka, Mayumi; Yamamoto, Toshiharu; Yamazaki, Naoshi; Tanaka, Tamotsu; Shinohara, Yasuo; Nishi, Hiroyuki; Tokumura, Akira

doi:10.1016/j.bbalip.2020.158761

Cited by 9 publications

(8 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…During the preparation of this article, Tsutsumi et al (29) published similar data reporting the same in vitro enzymatic properties of GDE3. In the present study, we further show that coexpression of GDE3 with GPR55 abrogates interaction of LPI with GPR55, whereas at the vicinity of CB2, GDE3 allows LPI to evoke signaling events identical to those induced by 2-AG.…”

mentioning

confidence: 68%

“…Finally, three additional points are worth mentioning. First, in their recent study also describing GDE3 as an ecto-LPI-PLC, Tsutsumi et al (29) provided evidence that the same switch between GPR55 and cannabinoid signaling could be involved in the maturation of osteoblasts. They also suggested that GDE3 might provide 2-oleoylglycerol from the corresponding LPI to stimulate the fat sensor receptor GPR119.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Glycerophosphodiesterase 3 (GDE3) is a lysophosphatidylinositol-specific ectophospholipase C acting as an endocannabinoid signaling switch

Briand‐Mésange

Pons

Allart

et al. 2020

Journal of Biological Chemistry

View full text Add to dashboard Cite

Endocannaboid signaling plays a regulatory role in various (neuro)biological functions. 2-Arachidonoyglycerol (2-AG) is the most abundant endocannabinoid, and while its canonical biosynthetic pathway involving phosphoinositide-specific phospholipase C and diacylglycerol lipase α is known, alternative pathways remain unsettled. Here, we characterize a non-canonical pathway implicating glycerophosphodiesterase 3 (GDE3, from GDPD2 gene). Human GDE3 expressed in HEK293T cell membranes catalyzed the conversion of lysophosphatidylinositol (LPI) into monoacylglycerol and inositol-1-phosphate. The enzyme was equally active against 1-acyl- and 2-acyl-LPI. When using 2-acyl LPI, where arachidonic acid is the predominant fatty acid, LC-MS analysis identified 2-AG as the main product of LPI hydrolysis by GDE3. Furthermore, inositol-1-phosphate release into the medium occurred upon addition of LPI to intact cells, suggesting that GDE3 is actually an ecto-lysophospholipase C. In cells expressing G-protein-coupled receptor GPR55, GDE3 abolished 1-acyl-LPI-induced signaling. In contrast, upon simultaneous expression of GDE3 and cannabinoid receptor CB2, 2-acyl-LPI evoked the same signal as that induced by 2-AG. These data strongly suggest that, beside simply degrading the GPR55 LPI ligand, GDE3 can act as a switch between GPR55 and CB2 signaling. Coincident with a major expression of both GDE3 and CB2 in spleen, spleens from transgenic mice lacking GDE3 displayed doubling of LPI content, compared to wild type mice. Decreased production of 2-AG in whole spleen was also observed, supporting the in vivo relevance of our findings. These data thus open a new research avenue in the field of endocannabinoid generation and reinforce the view of GPR55/LPI being genuine actors of endocannabinoid system.

show abstract

mentioning

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Glycerophosphodiesterase 3 (GDE3) is a lysophosphatidylinositol-specific ectophospholipase C acting as an endocannabinoid signaling switch

Briand‐Mésange

Pons

Allart

et al. 2020

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Recent studies have shown that MYT1 is also involved in the malignant progression of gastric cancer, liver cancer, and glioblastomas [ 47 – 49 ]. Although glycerophosphodiester phosphodiesterase 2 (GDPD2) is primarily involved in lipid metabolism, its actions in EC and other tumors remain unreported [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

Significance of a PTEN Mutational Status-Associated Gene Signature in the Progression and Prognosis of Endometrial Carcinoma

Wang

Liu

et al. 2022

Oxidative Medicine and Cellular Longevity

View full text Add to dashboard Cite

Background. PTEN mutations have been reported to be involved in the development and prognosis of endometrial carcinoma (EC). However, a prognostic gene signature associated with PTEN mutational status has not yet been developed. In this study, we generated a PTEN mutation-associated prognostic gene signature for EC. Methods. We obtained the single-nucleotide variation and transcriptomic profiling data from The Cancer Genome Atlas database as training data and implemented the least absolute shrinkage and selection operator (LASSO) Cox regression algorithm to establish a PTEN mutation-associated prognostic gene signature. The overall survival rates of the high-risk and low-risk groups were determined with the Kaplan-Meier (K-M) method, and the accuracy of risk score prediction was tested by using the receiver operating characteristic (ROC) curve. Results. The K-M curves revealed that the EC patients with PTEN mutations augured favorable survival outcomes. Differential expression analysis between the EC patients with PTEN mutation and wild-type PTEN identified 224 differentially expressed genes (DEGs). Eighty-four DEGs that manifested prognostic value were fitted into the LASSO-Cox analysis, and a PTEN gene signature with seven mutation-associated prognostic genes that showed robust prognostic ability was constructed; this signature was then successfully validated in the other two datasets from the cBioPortal database as well as with 60 clinical specimens. Furthermore, the PTEN mutation-associated prognostic gene signature proved to be an independent prognostic predictor of EC. Remarkably, the EC patients in the high-risk group were characterized by higher tumor stages and grades as well as lower tumor mutation burden with respect to EC, with a poor survival outcome. Collectively, the PTEN mutation-associated prognostic gene signature that we developed could now be used as a favorable prognostic biomarker for EC. Conclusion. In summary, we developed and validated a prognostic predictor for EC associated with PTEN mutational status that may be used as a favorable prognostic biomarker and therapeutic target for EC.

show abstract

“…There are data that suggest GPR55s association with the eCB system, as it can heterodimerize with CB2 [186]. In addition, glycerophosphodiesterase 3 can metabolize GPR55 ligand, arachidonoyl lysophosphatidylinositol (LPI), into 2-AG and also act as a signaling switch between GPR55 and CB2, thereby linking GRP55 to canonical cannabinoid receptors [187,188]. Moreover, neurological studies indicate that exogenous cannabinoids (i.e., CBD) also act on other noncanonical cannabinoid-sensitive receptors, such as transient receptor potential vanilloid 1 and opioid receptor µ and δ [189], that may be of interest in peripheral tissues.…”

Section: Other Receptors That Are Targeted By Cannabinoidsmentioning

confidence: 99%

Metabolic Consequences of Gestational Cannabinoid Exposure

Lee

Hardy

2021

IJMS

View full text Add to dashboard Cite

Up to 20% of pregnant women ages 18–24 consume cannabis during pregnancy. Moreover, clinical studies indicate that cannabis consumption during pregnancy leads to fetal growth restriction (FGR), which is associated with an increased risk of obesity, type II diabetes (T2D), and cardiovascular disease in the offspring. This is of great concern considering that the concentration of Δ9- tetrahydrocannabinol (Δ9-THC), a major psychoactive component of cannabis, has doubled over the last decade and can readily cross the placenta and enter fetal circulation, with the potential to negatively impact fetal development via the endocannabinoid (eCB) system. Cannabis exposure in utero could also lead to FGR via placental insufficiency. In this review, we aim to examine current pre-clinical and clinical findings on the direct effects of exposure to cannabis and its constituents on fetal development as well as indirect effects, namely placental insufficiency, on postnatal metabolic diseases.

show abstract

Identification of human glycerophosphodiesterase 3 as an ecto phospholipase C that converts the G protein-coupled receptor 55 agonist lysophosphatidylinositol to bioactive monoacylglycerols in cultured mammalian cells

Cited by 9 publications

References 61 publications

Glycerophosphodiesterase 3 (GDE3) is a lysophosphatidylinositol-specific ectophospholipase C acting as an endocannabinoid signaling switch

Glycerophosphodiesterase 3 (GDE3) is a lysophosphatidylinositol-specific ectophospholipase C acting as an endocannabinoid signaling switch

Significance of a PTEN Mutational Status-Associated Gene Signature in the Progression and Prognosis of Endometrial Carcinoma

Metabolic Consequences of Gestational Cannabinoid Exposure

Contact Info

Product

Resources

About