https://m2.mtmt.hu/ eng 2026-10-24 07:56 JournalArticle 35781630 VALIDATED true 0 false 2026-07-24T12:01:53.595+0000 2026-06-05T08:57:24.348+0000 2025-02-24T09:52:21.297+0000 true 10063958 Horváth Eszter /api/admin/10063958 Admin true 10063958 2026-06-05T08:57:24.727+0000 2026-06-05T08:57:24.727+0000 2025-12-18T16:47:19.255+0000 true 521 Szuper Admin /api/admin/521 Admin true Admin 10025544 /api/admin/10025544 Lévayné Deseő Katalin true 10025544 true 2026-05-20T07:50:07.833+0000 true false true 24 24 /api/publicationtype/24 PublicationType 1 true 24 JournalArticle true 10000059 Article true 24 24 /api/publicationtype/24 PublicationType 1 true 24 JournalArticle /api/subtype/10000059 Szakcikk SubType 101 true 10000059 true 1 /api/category/1 Category true 1 Straub, Verena M. The endocannabinoid 2-arachidonoylglycerol is released and transported on demand via extracellular microvesicles true true /api/journal/3547 REVIEWED true false 3547 false 3547 true 0027-8424 1091-6490 Journal FOREIGN 122 8 e2421717122 e2421717122 11 2025 Endocannabinoids (eCB) are lipid neurotransmitters that play a critical role in brain function by activating the cannabinoid CB1 receptor. Unlike classical neurotransmitters, their storage and release mechanisms have remained elusive, leading to major gaps in our understanding of how these signals are regulated. In this study, we developed an experimental system combining genetically encoded fluorescent sensors, electrophysiology, and mathematical modeling to study endocannabinoid signaling with temporal precision. Our findings led us to propose an ?on-demand release? model, where microvesicle formation governs endocannabinoid release. This comprehensive model extends the ?on-demand production? model and reconciliates the three previously proposed hypotheses for eCB trafficking. The model reshapes our understanding of endocannabinoid signaling and addresses key unanswered questions in the field. 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 expressing the fluorescent eCB sensor, G protein-coupled receptor-based (GRAB)eCB2.0, 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 ?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. 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G. true false false AuthorshipType 1 /api/authorshiptype/1 0 true 0 true false true PersonAuthorship 123481060 /api/authorship/123481060 14 0.067 false false false Author 10011502 /api/author/10011502 Katona István true 10011502 true Katona István true false false AuthorshipType 1 /api/authorshiptype/1 0 true 0 true false true PersonAuthorship 123481061 /api/authorship/123481061 15 0.067 false true false van der Stelt Mario true false false AuthorshipType 1 /api/authorshiptype/1 0 true 0 true false true PublicationIdentifier 28459258 /api/publicationidentifier/28459258 PlainSource 6 /api/publicationsource/6 PublicationSourceType 10001 /api/publicationsourcetype/10001 true true true DOI DOI https://doi.org/@@@ true true 6 true GOLD true IDENTICAL 10.1073/pnas.2421717122 https://doi.org/10.1073/pnas.2421717122 false true PublicationIdentifier 28968651 /api/publicationidentifier/28968651 PlainSource 1 /api/publicationsource/1 PublicationSourceType 10003 /api/publicationsourcetype/10003 false true true WoS WoS https://www.webofscience.com/wos/woscc/full-record/@@@ true true 1 true IDENTICAL 001439855800005 https://www.webofscience.com/wos/woscc/full-record/001439855800005 false true PublicationIdentifier 32686254 /api/publicationidentifier/32686254 SwordSource 36 /api/publicationsource/36 PublicationSourceType 10007 /api/publicationsourcetype/10007 true true true REAL REAL https://real.mtak.hu/@@@ true true 36 true GOLD true 243216 https://real.mtak.hu/243216 false true PublicationIdentifier 30368488 /api/publicationidentifier/30368488 PlainSource 3 /api/publicationsource/3 PublicationSourceType 10003 /api/publicationsourcetype/10003 false true true Scopus Scopus http://www.scopus.com/record/display.url?origin=inward&eid=2-s2.0-@@@ true true 3 true IDENTICAL 85219344488 http://www.scopus.com/record/display.url?origin=inward&eid=2-s2.0-85219344488 false true PublicationIdentifier 30368489 /api/publicationidentifier/30368489 PlainSource 17 /api/publicationsource/17 PublicationSourceType 10003 /api/publicationsourcetype/10003 false true true PubMed PubMed http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=@@@&dopt=Abstract true true 17 true IDENTICAL 39977325 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=39977325&dopt=Abstract false true MtaRating 11435140 /api/mtarating/11435140 RatingType 10031 /api/ratingtype/10031 X. 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Földtudományok Osztálya HAS Section of Earth Sciences (X.) true 70 true true true A true true MtaRating 11551102 /api/mtarating/11551102 RatingType 10010 /api/ratingtype/10010 RegTB Institute 14100 /api/institute/14100 0 false true false Regionális Tudományok Bizottsága Committee on Regional Studies true 14100 true true true A nemzetközi false true MtaRating 519088 /api/mtarating/519088 RatingType 10007 /api/ratingtype/10007 SZTB Institute 14102 /api/institute/14102 0 false true false Szociológiai Tudományos Bizottság Committee on Sociology true 14102 true true true A nemzetközi true 19088 true SjrRating 11736298 /api/sjrrating/11736298 7 0.1 journal RatingType 10002 /api/ratingtype/10002 sjr true true ClassificationExternal 1000 /api/classificationexternal/1000 true 1000 true D1 DIRECT true true /api/publication/35781630 <div class="JournalArticle Publication long-list"> <div class="authors"> <img title="Forrásközlemény" style="float: left" src="/frontend/resources/grid/publication-core-icon.png"> <img title="Idézőközlemény" style="float: left" src="/frontend/resources/grid/publication-citation-icon.png"> <div class="autype autype0"> <span class="author-name" >Straub Verena M. </span> ;&nbsp;&nbsp;&nbsp; <span class="author-name" mtid="10053132"><a href="/gui2/?type=authors&mode=browse&sel=10053132" target="_blank">Barti Benjamin (<span class="authorship-author-name">Barti Benjámin</span> <span class="authorAux-mtmt"> idegtudomány</span>) </a> </span> <span class="author-affil">HUN-REN Institute of Experimental Medicine</span> ;&nbsp;&nbsp;&nbsp; <span class="author-name" >Tandar Sebastian T. </span> ;&nbsp;&nbsp;&nbsp; <span class="author-name" >Stevens A. Floor </span> ;&nbsp;&nbsp;&nbsp; <span class="author-name" >van Egmond Noëlle </span> ;&nbsp;&nbsp;&nbsp; <span class="author-name" >van der Wel Tom </span> ;&nbsp;&nbsp;&nbsp; <span class="author-name" >Zhu Na </span> ;&nbsp;&nbsp;&nbsp; <span class="author-name" >Rüegger Joel </span> ;&nbsp;&nbsp;&nbsp; <span class="author-name" >van der Horst Cas </span> ;&nbsp;&nbsp;&nbsp; <span class="author-name" >Heitman Laura H. </span> ;&nbsp;&nbsp;&nbsp; <span class="author-name" >Li Yulong </span> ;&nbsp;&nbsp;&nbsp; <span class="author-name" >Stella Nephi </span> ;&nbsp;&nbsp;&nbsp; <span class="author-name" >Coen van Hasselt J. G. </span> ;&nbsp;&nbsp;&nbsp; <span class="author-name" mtid="10011502"><a href="/gui2/?type=authors&mode=browse&sel=10011502" target="_blank">Katona István (<span class="authorship-author-name">Katona István</span> <span class="authorAux-mtmt"> Neurobiológia</span>) </a> </span> <span class="author-affil"><span title="HUN-REN Institute of Experimental Medicine">HUN-REN IEM</span>/Molekuláris Neurobiológiai Kutatócsoport</span> ;&nbsp;&nbsp;&nbsp; <span class="author-name" >van der Stelt Mario </span> </div> </div> <div class="title"><a href="/gui2/?mode=browse&params=publication;35781630" target="_blank">The endocannabinoid 2-arachidonoylglycerol is released and transported on demand via extracellular microvesicles</a></div> <div> <span class="journal-title">PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA</span> <span class="journal-issn">(<a target="_blank" href="https://portal.issn.org/resource/ISSN/0027-8424">0027-8424</a> <a target="_blank" href="https://portal.issn.org/resource/ISSN/1091-6490">1091-6490</a>)</span>: <span class="journal-volume">122</span> <span class="journal-issue">8</span> <span class="page"> Paper e2421717122. 11 p. </span> <span class="year">(2025)</span> </div> <div class="pub-footer"> <span class="language" xmlns="http://www.w3.org/1999/html">Language: English | </span> <span class="identifiers"> <span class="id identifier oa_GOLD" title=" Gold "> <a style="color:blue" title="10.1073/pnas.2421717122" target="_blank" href="https://doi.org/10.1073/pnas.2421717122"> DOI </a> </span> <span class="id identifier oa_none" title="none"> <a style="color:blue" title="001439855800005" target="_blank" href="https://www.webofscience.com/wos/woscc/full-record/001439855800005"> WoS </a> </span> <span class="id identifier oa_GOLD" title=" Gold "> <a style="color:black" title="243216" target="_blank" href="https://real.mtak.hu/243216"> REAL </a> </span> <span class="id identifier oa_none" title="none"> <a style="color:blue" title="85219344488" target="_blank" href="http://www.scopus.com/record/display.url?origin=inward&eid=2-s2.0-85219344488"> Scopus </a> </span> <span class="id identifier oa_none" title="none"> <a style="color:blue" title="39977325" target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=39977325&dopt=Abstract"> PubMed </a> </span> </span> <OnlyViewableByAuthor><div class="ratings"> <div class="journal-subject">Journal subject: Scopus - Multidisciplinary&nbsp;&nbsp;&nbsp;Rank:&nbsp;D1</div> <div class="journal-subject">HAS Section of Earth Sciences (X.) HASSESX&nbsp;&nbsp;&nbsp;A</div> <div class="journal-subject">Committee on Regional Studies HASSELIX RTB [1901-]&nbsp;&nbsp;&nbsp;A nemzetközi</div> <div class="journal-subject">Committee on Sociology HASSELIX SZTB [1901-]&nbsp;&nbsp;&nbsp;A nemzetközi</div> </div></OnlyViewableByAuthor> <div class="publication-citation" style="margin-left: 0.5cm;"> <span title="" class="citingPub-count">Citing papers: 14</span> | Independent citation: 11 | Self citation: 3 | Unknown citation: 0 | Number of citations in WoS: 13 | Number of citations in Scopus:&nbsp;13 | WoS/Scopus assigned:&nbsp;14 | Number of citations with DOI:&nbsp;14 </div> <div class="publication-citation"> <a target="_blank" href="/api/publication?cond=citations.related;eq;35781630&sort=publishedYear,desc&sort=title"> Number of cited publications: 2 </a> </div> <div class="mtid"><span class="long-pub-mtid">Publication: 35781630</span> | <span class="status-data status-VALIDATED"> Validated </span> Core Citing | <span class="type-subtype">Journal Article ( Article ) </span> | <span class="pub-category">Scientific</span> | <span class="publication-sourceOfData">RIS-Egyéb</span> </div> <div class="funder"> Netherlands Organization for Scientific Research(724.017.002), Frontier Program(KKP129961), NIH grant(P30DA056410) </div> <div class="lastModified">Last Modified: 2026.06.05. 10:57 Marcell Kovács (MTMT Közp., admin) </div> <div class="lockedBy">Centrally managed 2026.05.20. 09:50 Katalin Lévayné Deseő (MTMT Központi admin) </div> </div></div>