The endocannabinoid 2-arachidonoylglycerol is released and transported on demand via extracellular microvesicles

While it is known that endocannabinoids (eCB) modulate multiple neuronal functions, the molecular mechanism governing their release and transport remains elusive. Here, we propose an "<i>on-demand release</i>" model, wherein the formation of microvesicles, a specific group of extracellular vesicles (EVs) containing the eCB, 2-arachidonoylglycerol (2-AG), is an important step. A coculture model system that combines a reporter cell line expressing the fluorescent eCB sensor, G protein-coupled receptor-based (GRAB)<sub>eCB2.0</sub>, and neuronal cells revealed that neurons release EVs containing 2-AG, but not anandamide, in a stimulus-dependent process regulated by protein kinase C, Diacylglycerol lipase, Adenosinediphosphate (ADP) ribosylation factor 6 (Arf6), and which was sensitive to inhibitors of eCB facilitated diffusion. A vesicle contained approximately 2,000 2-AG molecules. Accordingly, hippocampal eCB-mediated synaptic plasticity was modulated by Arf6 and transport inhibitors. The "<i>on-demand release</i>" model, supported by mathematical analysis, offers a cohesive framework for understanding eCB trafficking at the molecular level and suggests that microvesicles carrying signaling lipids in their membrane regulate neuronal functions in parallel to canonical synaptic vesicles.

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Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2025-02-20
DOI
https://doi.org/10.1073/pnas.2421717122
Citations
12
Primary Topic
Cannabis and Cannabinoid Research
Type
article
Field-Weighted Citation Impact
16.73

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article

The endocannabinoid 2-arachidonoylglycerol is released and transported on demand via extracellular microvesicles

Laura H. Heitman, Benjámin Barti, Sebastian T. Tandar, Anna F. Stevens et al.
12 citations
Proceedings of the National Academy of Sciences
Cannabis and Cannabinoid Research
16.73
article

The endocannabinoid 2-arachidonoylglycerol is released and transported on demand via extracellular microvesicles

Laura H. Heitman, Benjámin Barti, Sebastian T. Tandar, Anna F. Stevens, István Katona, Nephi Stella, Noëlle van Egmond, Cas van der Horst, J. G. Coen van Hasselt, Tom van der Wel, Mario van der Stelt, Na Zhu, Yulong Li, Joel Rüegger, Verena M. Straub
article en
12 citations

Abstract

While it is known that endocannabinoids (eCB) modulate multiple neuronal functions, the molecular mechanism governing their release and transport remains elusive. Here, we propose an "<i>on-demand release</i>" model, wherein the formation of microvesicles, a specific group of extracellular vesicles (EVs) containing the eCB, 2-arachidonoylglycerol (2-AG), is an important step. A coculture model system that combines a reporter cell line expressing the fluorescent eCB sensor, G protein-coupled receptor-based (GRAB)<sub>eCB2.0</sub>, and neuronal cells revealed that neurons release EVs containing 2-AG, but not anandamide, in a stimulus-dependent process regulated by protein kinase C, Diacylglycerol lipase, Adenosinediphosphate (ADP) ribosylation factor 6 (Arf6), and which was sensitive to inhibitors of eCB facilitated diffusion. A vesicle contained approximately 2,000 2-AG molecules. Accordingly, hippocampal eCB-mediated synaptic plasticity was modulated by Arf6 and transport inhibitors. The "<i>on-demand release</i>" model, supported by mathematical analysis, offers a cohesive framework for understanding eCB trafficking at the molecular level and suggests that microvesicles carrying signaling lipids in their membrane regulate neuronal functions in parallel to canonical synaptic vesicles.

Proceedings of the National Academy of SciencesVol. 122(8)
King University (US), Leiden University (NL), McGovern Institute for Brain Research (US), University of Washington (US), Peking University (CN), Oncode Institute (NL), Indiana University Bloomington (US), Centre for Human Drug Research (NL), Research Network (United States) (US), Center for Life Sciences (CN)
National Institutes of Health
Openalex Percentile: Top 1%
Cannabis and Cannabinoid Research
16.73
DOIOpen Access PDFOpenAlex
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