PT - JOURNAL ARTICLE AU - Eymery, Mathias C AU - McCarthy, Andrew A AU - Hausmann, Jens TI - Linking medicinal cannabis to autotaxin–lysophosphatidic acid signaling AID - 10.26508/lsa.202201595 DP - 2023 Feb 01 TA - Life Science Alliance PG - e202201595 VI - 6 IP - 2 4099 - https://www.life-science-alliance.org/content/6/2/e202201595.short 4100 - https://www.life-science-alliance.org/content/6/2/e202201595.full SO - Life Sci. Alliance2023 Feb 01; 6 AB - 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.