Journal Article Ppublish 3 citations
PubMed: 38109529 DOI: 10.1073/pnas.2304900120
Endocannabinoid biosynthetic enzymes regulate pain response via LKB1-AMPK signaling.
Proc Natl Acad Sci U S A 120(52):e2304900120
Authors: Miaomiao Chen, Myungsun Shin, Timothy B Ware, Giulia Donvito, Karan H Muchhala, Ryan Mischel, Mohammed A Mustafa, Vlad Serbulea, Clint M Upchurch, Norbert Leitinger, Hamid I Akbarali, Aron H Lichtman, Ku-Lung Hsu
Affiliations
- Department of Chemistry, University of Virginia, Charlottesville, VA 22904.
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298.
- Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22908.
- Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23298.
- Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908.
- University of Virginia Cancer Center, Cancer Biology Program, University of Virginia, Charlottesville, VA 22903.
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.
MeSH
Cells, Pain, Lipoprotein Lipase, Macrophages, Enzymes, Endocannabinoids
Cited by
- Pathology of pain and its implications for therapeutic interventions. Signal Transduct Target Ther, 2024
- Endocannabinoid biosynthetic enzymes regulate pain response via LKB1-AMPK signaling. Proc Natl Acad Sci U S A, 2023
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