TY - JOUR T1 - Linking medicinal cannabis to autotaxin–lysophosphatidic acid signaling JF - Life Science Alliance JO - Life Sci. Alliance DO - 10.26508/lsa.202201595 VL - 6 IS - 2 SP - e202201595 AU - Mathias C Eymery AU - Andrew A McCarthy AU - Jens Hausmann Y1 - 2023/02/01 UR - https://www.life-science-alliance.org/content/6/2/e202201595.abstract N2 - Autotaxin is primarily known for the formation of lysophosphatidic acid (LPA) from lysophosphatidylcholine. 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 apparent 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 lysophosphatidylcholine stimulation. Our results establish a functional interaction of THC with autotaxin–LPA signaling and highlight novel aspects of medicinal cannabis therapy. ER -