Linking medicinal cannabis to autotaxin-lysophosphatic acid signaling

Abstract

Autotaxin is primarily known for the formation of lysophosphatidic acid (LPA) from 22 lysophosphatidylcholine (LPC). LPA is an important signaling phospholipid that can bind to six 23 G-protein coupled receptors (LPA1-6). The ATX-LPA signaling axis is a critical component in 24 many physiological and pathophysiological conditions. Here, we describe a potent inhibition 25 of Δ9-trans-tetrahydrocannabinol (THC), the main psychoactive compound of medicinal 26 cannabis and related cannabinoids, on the catalysis of two isoforms of ATX with nanomolar 27 EC50 values. Furthermore, we decipher the binding interface of ATX to THC, and its derivative 28 9(R)-Δ6a,10a-THC (6a10aTHC), by X-ray crystallography.