Linking medicinal cannabis to autotaxin-lysophosphatic acid signaling

Abstract

AbstractAutotaxin is primarily known for the formation of lysophosphatidic acid (LPA) from lysophosphatidylcholine (LPC). LPA is an important signaling phospholipid that can bind to six G-protein coupled receptors (LPA1-6). The ATX-LPA signaling axis is a critical component in many physiological and pathophysiological conditions. Here, we describe a potent inhibition of Δ9-trans-tetrahydrocannabinol (THC), the main psychoactive compound of medicinal cannabis and related cannabinoids, on the catalysis of two isoforms of ATX with nanomolar EC50 values. Furthermore, we decipher the binding interface of ATX to THC, and its derivative 9(R)-Δ6a,10a-THC (6a10aTHC), by X-ray crystallography. Cellular experiments confirm this inhibitory effect, revealing a significant reduction of internalized LPA1 in the presence of THC with simultaneous ATX and LPC stimulation. Our results establish a functional interaction of THC with autotaxin-lysophosphatidic acid signaling and highlight novel aspects of medicinal cannabis therapy.