Dataset Information

Endocannabinoid biosynthetic enzymes regulate pain response via LKB1–AMPK signaling

ABSTRACT: 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.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cell Culture

SUBMITTER: Miaomiao Chen

LAB HEAD: Ku-lung Hsu

PROVIDER: PXD047413 | Pride | 2024-01-02

REPOSITORIES: Pride

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			Action	DRS
	20210701_0623_MC_TW_LLQE_BMDM_Mem_LWT_HKO_LPS_chemo_32.raw	Raw
	20210701_0623_MC_TW_LLQE_BMDM_Mem_LWT_HKO_LPS_chemo_32.raw_20230203.mgf	Mgf
	20210701_0623_MC_TW_LLQE_BMDM_Mem_LWT_HKO_LPS_chemo_32.raw_20230203.mzid.gz	Mzid
	20210701_0623_MC_TW_LLQE_BMDM_Mem_LWT_HKO_PBS_chemo_32.raw	Raw
	20210701_0623_MC_TW_LLQE_BMDM_Mem_LWT_HKO_PBS_chemo_32.raw_20230203.mgf	Mgf

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Endocannabinoid biosynthetic enzymes regulate pain response via LKB1-AMPK signaling.

Chen Miaomiao M Shin Myungsun M Ware Timothy B TB Donvito Giulia G Muchhala Karan H KH Mischel Ryan R Mustafa Mohammed A MA Serbulea Vlad V Upchurch Clint M CM Leitinger Norbert N Akbarali Hamid I HI Lichtman Aron H AH Hsu Ku-Lung KL

Proceedings of the National Academy of Sciences of the United States of America 20231218 52

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 mechan ...[more]

PMID: 38109529

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