Cocaine-induced endocannabinoid signaling mediated by sigma-1 receptors and extracellular vesicle secretion
PublishereLife Sciences Publications Ltd
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AbstractCocaine is an addictive drug that acts in brain reward areas. Recent evidence suggests that cocaine stimulates synthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG) in midbrain, increasing dopamine neuron activity via disinhibition. Although a mechanism for cocaine-stimulated 2-AG synthesis is known, our understanding of 2-AG release is limited. In NG108 cells and mouse midbrain tissue we find that 2-AG is localized in non-synaptic extracellular vesicles (EVs) that are secreted in the presence of cocaine via interaction with the chaperone protein sigma-1 receptor (Sig-1R). The release of EVs occurs when cocaine causes dissociation of the Sig-1R from ADP-ribosylation factor (ARF6), a G-protein regulating EV trafficking, leading to activation of myosin light chain kinase (MLCK). Blockade of Sig-1R function, or inhibition of ARF6 or MLCK also prevented cocaine-induced EV release and cocaine-stimulated 2-AG-modulation of inhibitory synapses in DA neurons. Our results implicate the Sig-1R-ARF6 complex in control of EV release and demonstrate that cocaine-mediated 2-AG release can occur via EVs.
SponsorsThis work is supported by the U.S. Department of Health and Human Services, National Institutes of Health, and National Institute on Drug Abuse, Intramural Research Program. Y.N. , and in part by the Japanese Society for Promotion of Sciences.
KeywordADP-ribosylation factor 6
Guanine nucleotide exchange factor
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85074457618&doi=10.7554%2feLife.47209&partnerID=40&md5=59d8a67e02c6465d7260cdc88fe0f574; http://hdl.handle.net/10713/11394
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