Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain

TLDR

Diacylglycerol lipase activity is essential for axonal growth and retrograde synaptic signaling, as it synthesizes the endocannabinoid 2‑AG and requires CB1 receptor function. The study aims to clone and enzymatically characterize the first specific sn‑1 DAG lipases. The authors cloned the genes and performed enzymatic assays to assess their activity. They identified two closely related genes whose expression shifts from embryonic axonal tracts to adult dendritic fields, correlating with 2‑AG production and release, thereby explaining a developmental switch in endocannabinoid signaling and suggesting therapeutic potential.

Abstract

Diacylglycerol (DAG) lipase activity is required for axonal growth during development and for retrograde synaptic signaling at mature synapses. This enzyme synthesizes the endocannabinoid 2-arachidonoyl-glycerol (2-AG), and the CB1 cannabinoid receptor is also required for the above responses. We now report on the cloning and enzymatic characterization of the first specific sn-1 DAG lipases. Two closely related genes have been identified and their expression in cells correlated with 2-AG biosynthesis and release. The expression of both enzymes changes from axonal tracts in the embryo to dendritic fields in the adult, and this correlates with the developmental change in requirement for 2-AG synthesis from the pre- to the postsynaptic compartment. This switch provides a possible explanation for a fundamental change in endocannabinoid function during brain development. Identification of these enzymes may offer new therapeutic opportunities for a wide range of disorders.