Involvement of the γ Isoform of cPLA2 in the Biosynthesis of Bioactive N-Acylethanolamines

Arachidonylethanolamide (anandamide) acts as an endogenous ligand of cannabinoid receptors, while other N-acylethanolamines (NAEs), such as palmitylethanolamide and oleylethanolamide, show analgesic, anti-inflammatory, and appetite-suppressing effects through other receptors. In mammalian tissues, NAEs, including anandamide, are produced from glycerophospholipid via N-acyl-phosphatidylethanolamine (NAPE). The ɛ isoform of cytosolic phospholipase A2 (cPLA2) functions as an N-acyltransferase to form NAPE. Since the cPLA2 family consists of six isoforms (α, β, γ, δ, ɛ, and ζ), the present study investigated a possible involvement of isoforms other than ɛ in the NAE biosynthesis. Firstly, when the cells overexpressing one of the cPLA2 isoforms were labeled with [14C]ethanolamine, the increase in the production of [14C]NAPE was observed only with the ɛ-expressing cells. Secondly, when the cells co-expressing ɛ and one of the other isoforms were analyzed, the increase in [14C]N-acyl-lysophosphatidylethanolamine (lysoNAPE) and [14C]NAE was seen with the combination of ɛ and γ isoforms. Furthermore, the purified cPLA2γ hydrolyzed not only NAPE to lysoNAPE, but also lysoNAPE to glycerophospho-N-acylethanolamine (GP-NAE). Thus, the produced GP-NAE was further hydrolyzed to NAE by glycerophosphodiesterase 1. These results suggested that cPLA2γ is involved in the biosynthesis of NAE by its phospholipase A1/A2 and lysophospholipase activities.

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Cytosolic Phospholipase A2 (PLA2G4A) Polymorphisms Associated with Acute Urticaria/angioedema Induced by Nonsteroidal Anti-inflammatory Drugs

Journal of Allergy and Clinical Immunology ◽

10.1016/j.jaci.2020.12.093 ◽

2021 ◽

Vol 147 (2) ◽

pp. AB14

Author(s):

Raquel Jurado Escobar ◽

Jose Triano-Cornejo ◽

Inmaculada Doña ◽

Natalia Pérez Sánchez ◽

Gador Bogas Herrera ◽

...

Keyword(s):

Phospholipase A2 ◽

Cytosolic Phospholipase A2 ◽

Acute Urticaria ◽

Cytosolic Phospholipase ◽

Inflammatory Drugs ◽

Anti Inflammatory

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Inhibitors of Cytosolic Phospholipase A2α as Potential Anti-Inflammatory Drugs

Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry ◽

10.2174/187152306776872488 ◽

2006 ◽

Vol 5 (2) ◽

pp. 149-161 ◽

Cited By ~ 18

Author(s):

Matthias Lehr

Keyword(s):

Phospholipase A2 ◽

Cytosolic Phospholipase A2 ◽

Cytosolic Phospholipase ◽

Inflammatory Drugs ◽

Anti Inflammatory

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Genetic Variants in Cytosolic Phospholipase A2 Associated With Nonsteroidal Anti-Inflammatory Drug–Induced Acute Urticaria/Angioedema

Frontiers in Pharmacology ◽

10.3389/fphar.2021.667824 ◽

2021 ◽

Vol 12 ◽

Author(s):

Raquel Jurado-Escobar ◽

Inmaculada Doña ◽

José Triano-Cornejo ◽

James R. Perkins ◽

Natalia Pérez-Sánchez ◽

...

Keyword(s):

Phospholipase A2 ◽

Drug Hypersensitivity ◽

Cytosolic Phospholipase A2 ◽

Additive Models ◽

Hypersensitivity Reactions ◽

Bonferroni Correction ◽

Acute Urticaria ◽

Cytosolic Phospholipase ◽

Increased Risk ◽

Anti Inflammatory

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the main triggers of drug hypersensitivity reactions, probably due to their high consumption worldwide. The most frequent type of NSAID hypersensitivity is NSAID cross-hypersensitivity, in which patients react to NSAIDs from different chemical groups in the absence of a specific immunological response. The underlying mechanism of NSAID cross-hypersensitivity has been linked to cyclooxygenase (COX)-1 inhibition causing an imbalance in the arachidonic acid pathway. Despite NSAID-induced acute urticaria/angioedema (NIUA) being the most frequent clinical phenotype, most studies have focused on NSAID-exacerbated respiratory disease. As NSAID cross-hypersensitivity reactions are idiosyncratic, only appearing in some subjects, it is believed that individual susceptibility is under the influence of genetic factors. Although associations with polymorphisms in genes from the AA pathway have been described, no previous study has evaluated the potential role of cytosolic phospholipase A2 (cPLA2) variants. This enzyme catalyzes the initial hydrolysis of membrane phospholipids to release AA, which can be subsequently metabolized into eicosanoids. Here, we analyzed for the first time the overall genetic variation in the cPLA2 gene (PLA2G4A) in NIUA patients. For this purpose, a set of tagging single nucleotide polymorphisms (tagSNPs) in PLA2G4A were selected using data from Europeans subjects in the 1,000 Genomes Project, and genotyped with the iPlex Sequenom MassArray technology. Two independent populations, each comprising NIUA patients and NSAID-tolerant controls, were recruited in Spain, for the purposes of discovery and replication, comprising a total of 1,128 individuals. Fifty-eight tagSNPs were successfully genotyped in the discovery cohort, of which four were significantly associated with NIUA after Bonferroni correction (rs2049963, rs2064471, rs12088010, and rs12746200). These polymorphisms were then genotyped in the replication cohort: rs2049963 was associated with increased risk for NIUA after Bonferroni correction under the dominant and additive models, whereas rs12088010 and rs12746200 were protective under these two inheritance models. Our results suggest a role for PLA2G4A polymorphisms in NIUA. However, further studies are required to replicate our findings, elucidate the mechanistic role, and evaluate the participation of PLA2G4A variants in other phenotypes induced by NSAID cross-hypersensitivity.

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