Linking the Autotaxin-LPA Axis to Medicinal Cannabis and the Endocannabinoid System

Abstract

Over the past few decades, many current uses for cannabinoids have been described, ranging from controlling epilepsy to neuropathic pain and anxiety treatment. Medicines containing cannabinoids have been approved by both the FDA and the EMA for the control of specific diseases for which there are few alternatives. However, the molecular-level mechanism of action of cannabinoids is still poorly understood. Recently, cannabinoids have been shown to interact with autotaxin (ATX), a secreted lysophospholipase D enzyme responsible for catalyzing lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA), a pleiotropic growth factor that interacts with LPA receptors. In addition, a high-resolution structure of ATX in complex with THC has recently been published, accompanied by biochemical studies investigating this interaction. Due to their LPA-like structure, endocannabinoids have been shown to interact with ATX in a less potent manner. This finding opens new areas of research regarding cannabinoids and endocannabinoids, as it could establish the effect of these compounds at the molecular level, particularly in relation to inflammation, which cannot be explained by the interaction with CB1 and CB2 receptors alone. Further research is needed to elucidate the mechanism behind the interaction between cannabinoids and endocannabinoids in humans and to fully explore the therapeutic potential of such approaches.

Keywords: autotaxin; cannabinoids; endocannabinoid; lysophosphatidic acid; tetrahydrocannabinol.

Figure 1

Chemical structures of the main plant cannabinoids [1].

Figure 2

Chemical structures of human endocannabinoids [1].

Figure 3

Structural comparison of LPA 20:4 and 2-AG.

Figure 4

Structure–function of human proteins interacting with cannabinoids and endocannabinoids [1].