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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,8,26]]},"abstract":"<jats:p>\n                    Neuromodulators control mood, arousal, and behavior by inducing synaptic plasticity via G-protein-coupled receptors. While long-term presynaptic potentiation requires structural changes, mechanisms enabling potentiation within minutes remain unclear. Using the\n                    <jats:italic toggle=\"yes\">Drosophila<\/jats:italic>\n                    neuromuscular junction, we show that octopamine, the invertebrate analog of norepinephrine, potentiates evoked neurotransmitter release on the timescale of one minute via a G-protein-coupled pathway involving presynaptic OAMB receptors and phospholipase C. This fast potentiation correlates with elevated signals of the release factor Unc13A and the scaffolding protein Bruchpilot. Live, single-molecule imaging of endogenously tagged Unc13 revealed its instantly reduced motility and increased concentration in synaptic nanoclusters with potentiation. Presynaptic knockdown of Unc13A fully blocked fast potentiation. Moreover, deleting its N-terminal localization sequence mislocalized the protein fragment to the cytosol, but still allowed for rapid plasma membrane recruitment by diacylglycerol (DAG) analog phorbol esters and octopamine, implicating a role of more C-terminal domains. A point mutation of endogenous Unc13 in its DAG-binding C1 domain blocked plasticity-induced nanoscopic enrichment and synaptic potentiation. The mutation increased basal neurotransmission but reduced Unc13 levels, revealing a gain of function and potential homeostatic compensation. The mutation also blocked phorbol ester\u2013induced potentiation, decreased the calcium sensitivity of neurotransmission, and caused short-term synaptic depression. Homeostatic potentiation induced by postsynaptic receptor block mirrored octopamine-induced Unc13 recruitment and required presynaptic OAMB receptors, indicating overlapping machinery. Thus, rapid Unc13 immobilization and nanoscale compaction are salient features of fast presynaptic potentiation.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2514151122","type":"journal-article","created":{"date-parts":[[2025,8,20]],"date-time":"2025-08-20T14:49:18Z","timestamp":1755701358000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":7,"title":["Monoamine-induced diacylglycerol signaling rapidly accumulates Unc13 in nanoclusters for fast presynaptic potentiation"],"prefix":"10.1073","volume":"122","author":[{"given":"Natalie","family":"Blaum","sequence":"first","affiliation":[{"name":"Molecular and Theoretical Neuroscience, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen","place":["Copenhagen, Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tina","family":"Ghelani","sequence":"additional","affiliation":[{"name":"Molecular and Theoretical Neuroscience, Leibniz-Forschungsinstitut f\u00fcr Molekulare Pharmakologie","place":["Berlin, Germany"]},{"name":"Institute for Biology and Genetics, Freie Universit\u00e4t Berlin","place":["Berlin, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Torsten W. 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