| Diacylglycerol lipase β (DAGLβ) is one of two closely related serine hydrolase isozymes that hydrolyze diacylglycerol (DAG) at the sn‑1 position to generate 2‑arachidonoylglycerol (2‑AG), a major endocannabinoid ligand for cannabinoid CB1 and CB2 receptors. DAGLβ is a membrane‑associated protein with multiple transmembrane domains and a large C‑terminal cytoplasmic region containing the catalytic triad, and this architecture supports its localization to intracellular membranes and lipid‑rich compartments where it accesses DAG pools generated downstream of phospholipase‑coupled receptor signaling. DAGLβ is preferentially expressed in cells of the mononuclear phagocytic system and other immune‑related cell types, and it converts arachidonic‑acid‑containing DAG into 2‑AG and free arachidonic acid, thereby feeding both endocannabinoid signaling and downstream eicosanoid production that modulate inflammatory and nociceptive pathways. DAGLβ‑derived 2‑AG and arachidonic acid contribute to macrophage‑driven inflammation, LPS‑induced allodynia, and pro‑tumorigenic signaling in cancers such as intrahepatic cholangiocarcinoma, where upregulation of DAGLβ is associated with metastasis and correlates with AP‑1‑driven transcriptional circuits and inflammatory feed‑forward loops, and pharmacological or genetic inhibition of DAGLβ reduces local 2‑AG and eicosanoid levels, dampens pro‑inflammatory cytokine output, and reverses inflammatory and neuropathic pain phenotypes in model systems. DAGLα is the dominant isoform for synaptic 2‑AG, but DAGLβ also contributes to neuronal and microglial 2‑AG pools in cell‑type‑specific settings, and its activity is tightly regulated by Ca²⁺‑dependent signaling, receptor‑coupled DAG generation, and post‑translational modifications. |
Lane 1: MCF7, Lane 2: THP-1, Lane 3: RAW, Lane 4: Neuro-2a
