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

• 成果类型: Article
• 署名作者: Straub, Verena M.; Barti, Benjamin; Tandar, Sebastian T.; Stevens, A. Floor; van Egmond, Noelle; van der Wel, Tom; Zhu, Na; Rueegger, Joel; van der Horst, Cas; Heitman, Laura H.; Li, Yulong; Stella, Nephi; van Hasselt, J. G. Coen; Katona, Istvan; van der Stelt, Mario
• 署名单位: Leiden University - Excl LUMC; Leiden University; Indiana University System; Indiana University Bloomington; Leiden University - Excl LUMC; Leiden University; Leiden University; Leiden University - Excl LUMC; Peking University; Peking University; University of Washington; University of Washington Seattle; HUN-REN; HUN-REN Institute of Experimental Medicine
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13166
• DOI: 10.1073/pnas.2421717122
• 发表日期: 2025-02-25
• 关键词: diacylglycerol-lipase-alpha; endogenous cannabinoids; monoacylglycerol lipase; key role; anandamide; membrane; cells; TRAFFICKING; inhibition; mechanism

摘要

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 on- demand release 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 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 tive to inhibitors of eCB facilitated diffusion. A vesicle contained approximately 2,000 ulated by Arf6 and transport inhibitors. The on- demand release 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.