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Linking medicinal cannabis to autotaxin–lysophosphatidic acid signaling

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 (LPA(1–6)). The ATX-LPA signaling axis is a critical component in many physiological and pathophysio...

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Autores principales: Eymery, Mathias C, McCarthy, Andrew A, Hausmann, Jens
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Life Science Alliance LLC 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9834664/
https://www.ncbi.nlm.nih.gov/pubmed/36623871
http://dx.doi.org/10.26508/lsa.202201595
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author Eymery, Mathias C
McCarthy, Andrew A
Hausmann, Jens
author_facet Eymery, Mathias C
McCarthy, Andrew A
Hausmann, Jens
author_sort Eymery, Mathias C
collection PubMed
description 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 (LPA(1–6)). The ATX-LPA signaling axis is a critical component in many physiological and pathophysiological conditions. Here, we describe a potent inhibition of Δ(9)-trans-tetrahydrocannabinol (THC), the main psychoactive compound of medicinal cannabis and related cannabinoids, on the catalysis of two isoforms of ATX with nanomolar apparent EC(50) 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 LPA(1) 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.
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spelling pubmed-98346642023-01-13 Linking medicinal cannabis to autotaxin–lysophosphatidic acid signaling Eymery, Mathias C McCarthy, Andrew A Hausmann, Jens Life Sci Alliance Research Articles 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 (LPA(1–6)). The ATX-LPA signaling axis is a critical component in many physiological and pathophysiological conditions. Here, we describe a potent inhibition of Δ(9)-trans-tetrahydrocannabinol (THC), the main psychoactive compound of medicinal cannabis and related cannabinoids, on the catalysis of two isoforms of ATX with nanomolar apparent EC(50) 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 LPA(1) 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. Life Science Alliance LLC 2023-01-09 /pmc/articles/PMC9834664/ /pubmed/36623871 http://dx.doi.org/10.26508/lsa.202201595 Text en © 2023 Eymery et al. https://creativecommons.org/licenses/by/4.0/This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Articles
Eymery, Mathias C
McCarthy, Andrew A
Hausmann, Jens
Linking medicinal cannabis to autotaxin–lysophosphatidic acid signaling
title Linking medicinal cannabis to autotaxin–lysophosphatidic acid signaling
title_full Linking medicinal cannabis to autotaxin–lysophosphatidic acid signaling
title_fullStr Linking medicinal cannabis to autotaxin–lysophosphatidic acid signaling
title_full_unstemmed Linking medicinal cannabis to autotaxin–lysophosphatidic acid signaling
title_short Linking medicinal cannabis to autotaxin–lysophosphatidic acid signaling
title_sort linking medicinal cannabis to autotaxin–lysophosphatidic acid signaling
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9834664/
https://www.ncbi.nlm.nih.gov/pubmed/36623871
http://dx.doi.org/10.26508/lsa.202201595
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