title: MicroRNA let-7d is a target of cannabinoid CB1 receptor and controls cannabinoid signaling.
abstract: Cannabinoid CB1 receptor, the molecular target of endocannabinoids and cannabis active components, is one of the most abundant metabotropic receptors in the brain. Cannabis is widely used for both recreational and medicinal purposes. Despite the ever-growing fundamental roles of microRNAs in the brain, the possible molecular connections between the CB1 receptor and microRNAs are surprisingly unknown. Here, by using reporter gene constructs that express interaction sequences for microRNAs in human SH-SY5Y neuroblastoma cells, we show that CB1 receptor activation enhances the expression of several microRNAs, including let-7d. This was confirmed by measuring hsa-let-7d expression levels. Accordingly, knocking-down CB1 receptor in zebrafish reduced dre-let-7d levels, and knocking-out CB1 receptor in mice decreased mmu-let-7d levels in the cortex, striatum and hippocampus. Conversely, knocking-down let-7d increased CB1 receptor mRNA expression in zebrafish, SH-SY5Y cells and primary striatal neurons. Likewise, in primary striatal neurons chronically exposed to a cannabinoid or opioid agonist, a let-7d-inhibiting sequence facilitated not only cannabinoid or opioid signaling but also cannabinoid/opioid cross-signaling. Taken together, these findings provide the first evidence for a bidirectional link between the CB1 receptor and a microRNA, namely let-7d, and thus unveil a new player in the complex process of cannabinoid action.
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) and Instituto Universitario de Investigación Neuroquímica (IUIN), Department of Biochemistry and Molecular Biology I, Complutense University, 28040 Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), 28034 Madrid, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Chiarlone
authors.affiliation: Department of Pharmacology and Toxicology, University of Magdeburg, 39106 Magdeburg, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Börner
authors.affiliation: Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), 28034 Madrid, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Martín-Gómez
authors.affiliation: Instituto de Investigaciones Biomédicas de Salamanca (IBSAL), 37007 Salamanca, Spain.
authors.forename: Ada
authors.initials: A
authors.lastname: Jiménez-González
authors.affiliation: Instituto de Investigaciones Biomédicas de Salamanca (IBSAL), 37007 Salamanca, Spain.
authors.forename: Adrián
authors.initials: A
authors.lastname: García-Concejo
authors.affiliation: Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), 28034 Madrid, Spain.
authors.forename: María L
authors.initials: ML
authors.lastname: García-Bermejo
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) and Instituto Universitario de Investigación Neuroquímica (IUIN), Department of Biochemistry and Molecular Biology I, Complutense University, 28040 Madrid, Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: Lorente
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) and Instituto Universitario de Investigación Neuroquímica (IUIN), Department of Biochemistry and Molecular Biology I, Complutense University, 28040 Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), 28034 Madrid, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Blázquez
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) and Instituto Universitario de Investigación Neuroquímica (IUIN), Department of Biochemistry and Molecular Biology I, Complutense University, 28040 Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), 28034 Madrid, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: García-Taboada
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) and Instituto Universitario de Investigación Neuroquímica (IUIN), Department of Biochemistry and Molecular Biology I, Complutense University, 28040 Madrid, Spain.
authors.forename: Amador
authors.initials: A
authors.lastname: de Haro
authors.affiliation: Department of Pharmacology and Toxicology, University of Magdeburg, 39106 Magdeburg, Germany.
authors.forename: Elisa
authors.initials: E
authors.lastname: Martella
authors.affiliation: Department of Pharmacology and Toxicology, University of Magdeburg, 39106 Magdeburg, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Höllt
authors.affiliation: Instituto de Investigaciones Biomédicas de Salamanca (IBSAL), 37007 Salamanca, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Rodríguez
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) and Instituto Universitario de Investigación Neuroquímica (IUIN), Department of Biochemistry and Molecular Biology I, Complutense University, 28040 Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), 28034 Madrid, Spain.
authors.forename: Ismael
authors.initials: I
authors.lastname: Galve-Roperh
authors.affiliation: Department of Pharmacology and Toxicology, University of Magdeburg, 39106 Magdeburg, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Kraus
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) and Instituto Universitario de Investigación Neuroquímica (IUIN), Department of Biochemistry and Molecular Biology I, Complutense University, 28040 Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), 28034 Madrid, Spain. Electronic address: mguzman@quim.ucm.es.
authors.forename: Manuel
authors.initials: M
authors.lastname: Guzmán
mesh_terms: D000818:Animals; D001892:Camphanes / Q000494:pharmacology; D002186:Cannabinoids / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000096:biosynthesis*; D011720:Pyrazoles / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D015027:Zebrafish
chemical_list: D001892:Camphanes; D002186:Cannabinoids; D035683:MicroRNAs; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C110630:SR 144528; C487931:mirnlet7 microRNA, human
keywords: CB(1) receptor; Cannabinoid; Cell signaling; Synaptic transmission; microRNA