2. Academic Validation
  3. Endocannabinoid biosynthetic enzymes regulate pain response via LKB1-AMPK signaling

Endocannabinoid biosynthetic enzymes regulate pain response via LKB1-AMPK signaling

  • Proc Natl Acad Sci U S A. 2023 Dec 26;120(52):e2304900120. doi: 10.1073/pnas.2304900120.
Miaomiao Chen # 1,  Myungsun Shin # 1,  Timothy B Ware # 1,  Giulia Donvito 2,  Karan H Muchhala 2,  Ryan Mischel 2,  Mohammed A Mustafa 2,  Vlad Serbulea 3,  Clint M Upchurch 3,  Norbert Leitinger 3,  Hamid I Akbarali 2,  Aron H Lichtman 2 4,  Ku-Lung Hsu 1 3 5 6
Affiliations

Affiliations

  • 1 Department of Chemistry, University of Virginia, Charlottesville, VA 22904.
  • 2 Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298.
  • 3 Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22908.
  • 4 Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23298.
  • 5 Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908.
  • 6 University of Virginia Cancer Center, Cancer Biology Program, University of Virginia, Charlottesville, VA 22903.
  • # Contributed equally.
PMID: 38109529 DOI: 10.1073/pnas.2304900120
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.

Keywords

AMPK; activity based protein profiling; diacylglycerol lipase; endocannabinoids; inflammation.

Figures