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Neuropharmacology. 2016 Sep;108:345-52. doi: 10.1016/j.neuropharm.2016.05.007. Epub 2016 May 11.

MicroRNA let-7d is a target of cannabinoid CB1 receptor and controls cannabinoid signaling.

Author information

1
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.
2
Department of Pharmacology and Toxicology, University of Magdeburg, 39106 Magdeburg, Germany.
3
Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), 28034 Madrid, Spain.
4
Instituto de Investigaciones Biomédicas de Salamanca (IBSAL), 37007 Salamanca, Spain.
5
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.
6
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.

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.

KEYWORDS:

CB(1) receptor; Cannabinoid; Cell signaling; Synaptic transmission; microRNA

[Indexed for MEDLINE]

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