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更新于：2025-05-07

DAGL-β

更新于：2025-05-07

基本信息

别名

DAGL-beta、DAGLB、DAGLBETA

+ [7]

简介

Lipase that catalyzes the hydrolysis of arachidonic acid (AA)-esterified diacylglycerols (DAGs) to produce the principal endocannabinoid, 2-arachidonoylglycerol (2-AG) which can be further cleaved by downstream enzymes to release arachidonic acid (AA) for cyclooxygenase (COX)-mediated eicosanoid production (PubMed:14610053). Preferentially hydrolyzes DAGs at the sn-1 position in a calcium-dependent manner and has negligible activity against other lipids including monoacylglycerols and phospholipids (PubMed:14610053). Plays a key role in the regulation of 2-AG and AA pools utilized by COX1/2 to generate lipid mediators of macrophage and microglia inflammatory responses. Functions also as a polyunsaturated fatty acids-specific triacylglycerol lipase in macrophages. Plays an important role to support the metabolic and signaling demands of macrophages (By similarity).

关联

项与 DAGL-β 相关的药物

ML294

靶点

DAGL-β

作用机制

DAGL-β inhibitors

在研机构-

原研机构

The Scripps Research Institute

在研适应症-

非在研适应症

食欲减退 [+4]

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 DAGL-β 相关的临床结果

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100 项与 DAGL-β 相关的转化医学

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0 项与 DAGL-β 相关的专利（医药）

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项与 DAGL-β 相关的文献（医药）

2024-08-01·British Journal of Pharmacology

P2X₇ receptor‐dependent increase in endocannabinoid 2‐arachidonoyl glycerol production by neuronal cells in culture: Dynamics and mechanism

Article

作者: Dong, Ao ; English, Anthony ; Stella, Nephi ; Bruchas, Michael R. ; Whittington, Dale ; van der Stelt, Mario ; Sarroza, Dennis ; Li, Yulong ; Malamas, Michael ; Land, Benjamin B. ; Singh, Simar ; Zweifel, Larry ; Makriyannis, Alexandros

Background and PurposeNeurotransmission and neuroinflammation are controlled by local increases in both extracellular ATP and the endocannabinoid 2‐arachidonoyl glycerol (2‐AG). While it is known that extracellular ATP stimulates 2‐AG production in cells in culture, the dynamics and molecular mechanisms that underlie this response remain poorly understood. Detection of real‐time changes in eCB levels with the genetically encoded sensor, GRABeCB2.0, can address this shortfall.Experimental Approach2‐AG and arachidonoylethanolamide (AEA) levels in Neuro2a (N2a) cells were measured by LC‐MS, and GRABeCB2.0 fluorescence changes were detected using live‐cell confocal microscopy and a 96‐well fluorescence plate reader.Key Results2‐AG and AEA increased GRABeCB2.0 fluorescence in N2a cells with EC50 values of 81 and 58 nM, respectively; both responses were reduced by the cannabinoid receptor type 1 (CB1R) antagonist SR141617 and absent in cells expressing the mutant‐GRABeCB2.0. ATP increased only 2‐AG levels in N2a cells, as measured by LC‐MS, and induced a transient increase in the GRABeCB2.0 signal within minutes primarily via activation of P2X7 receptors (P2X7R). This response was dependent on diacylglycerol lipase β activity, partially dependent on extracellular calcium and phospholipase C activity, but not controlled by the 2‐AG hydrolysing enzyme, α/β‐hydrolase domain containing 6 (ABHD6).Conclusions and ImplicationsConsidering that P2X7R activation increases 2‐AG levels within minutes, our results show how these molecular components are mechanistically linked. The specific molecular components in these signalling systems represent potential therapeutic targets for the treatment of neurological diseases, such as chronic pain, that involve dysregulated neurotransmission and neuroinflammation.

2024-06-01·Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease

Endocannabinoid remodeling in murine cachexic muscle associates with catabolic and metabolic regulation

Article

作者: Hiroux, Charlotte ; Dalle, Sebastiaan ; Koppo, Katrien

Muscle degeneration is a common feature in cancer cachexia that cannot be reversed. Recent advances show that the endocannabinoid system, and more particularly cannabinoid receptor 1 (CB1), regulates muscle processes, including metabolism, anabolism and regenerative capacity. However, it is unclear whether muscle endocannabinoids, their receptors and enzymes are responsive to cachexia and exercise. Therefore, this study investigated whether cachexia and exercise affected muscle endocannabinoid signaling, and whether CB1 expression correlated with markers of muscle anabolism, catabolism and metabolism. Male BALB/c mice were injected with PBS (CON) or C26 colon carcinoma cells (C26) and had access to wheel running (VWR) or remained sedentary (n = 5-6/group). Mice were sacrificed 18 days upon PBS/tumor cell injection. Cachexic mice exhibited a lower muscle CB1 expression (-43 %; p < 0.001) and lower levels of the endocannabinoid anandamide (AEA; -22 %; p = 0.044), as well as a lower expression of the AEA-synthesizing enzyme NAPE-PLD (-37 %; p < 0.001), whereas the expression of the AEA degrading enzyme FAAH was higher (+160 %; p < 0.001). The 2-AG-degrading enzyme MAGL, was lower in cachexic muscle (-34 %; p = 0.007), but 2-AG and its synthetizing enzyme DAGLβ were not different between CON and C26. VWR increased muscle CB1 (+25 %; p = 0.005) and increased MAGL expression (+30 %; p = 0.035). CB1 expression correlated with muscle mass, markers of metabolism (e.g. p-AMPK, PGC1α) and of catabolism (e.g. p-FOXO, LC3b, Atg5). Our findings depict an emerging role of the endocannabinoid system in muscle physiology. Future studies should elaborate how this translates into potential therapies to combat cancer cachexia, and other degenerative conditions.

2023-12-26·Proceedings of the National Academy of Sciences1区 · 综合性期刊

Endocannabinoid biosynthetic enzymes regulate pain response via LKB1–AMPK signaling

1区 · 综合性期刊

Article

作者: Donvito, Giulia ; Mischel, Ryan ; Akbarali, Hamid I ; Chen, Miaomiao ; Ware, Timothy B ; Upchurch, Clint M ; Shin, Myungsun ; Muchhala, Karan H ; Serbulea, Vlad ; Mustafa, Mohammed A ; Hsu, Ku-Lung ; Leitinger, Norbert ; Lichtman, Aron H

Diacylglycerol lipase-beta (DAGLβ) serves as a principal 2-arachidonoylglycerol (2-AG) biosynthetic enzyme regulating endocannabinoid and eicosanoid metabolism in immune cells including macrophages and dendritic cells. Genetic or pharmacological inactivation of DAGLβ ameliorates inflammation and hyper-nociception in preclinical models of pathogenic pain. These beneficial effects have been assigned principally to reductions in downstream proinflammatory lipid signaling, leaving alternative mechanisms of regulation largely underexplored. Here, we apply quantitative chemical- and phospho-proteomics to find that disruption of DAGLβ in primary macrophages leads to LKB1–AMPK signaling activation, resulting in reprogramming of the phosphoproteome and bioenergetics. Notably, AMPK inhibition reversed the antinociceptive effects of DAGLβ blockade, thereby directly supporting DAGLβ–AMPK crosstalk in vivo. Our findings uncover signaling between endocannabinoid biosynthetic enzymes and ancient energy-sensing kinases to mediate cell biological and pain responses.

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