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CANNABINOID TOLERANCE RELIES ON CB<SUB>1</SUB> RECEPTOR UBIQUITINATION BY NEDD4L
Alicia Álvaro Blázquezand 10 co-authors
Complutense University of Madrid
FENS Forum 2026 (2026)
Barcelona, Spain
Board PS03-08AM-550
Presentation
Date TBA
Board: PS03-08AM-550
Event Information
Poster Board
PS03-08AM-550
Poster
View posterAbstract
Cannabinoids, the active components of Cannabis sativa, exert numerous acute effects in the brain by engaging cannabinoid CB1 receptors (CB1Rs). However, most of these effects undergo rapid tolerance upon repeated cannabinoid intake, which reduces the efficacy of cannabinoid-based medicines and increases the risks of cannabis abuse. While the processes of CB1R short-term desensitization (i.e., receptor uncoupling and internalization) are quite well characterized, the mechanisms underlying CB1R long-term desensitization (i.e., receptor downregulation by protein degradation) remain basically unknown. Here, using a combination of in vitro and in vivo approaches, we show that agonist-evoked CB1R activation triggers the protein kinase C-dependent phosphorylation and activation of the E3 ubiquitin ligase NEDD4L, promoting its recruitment to CB1R. This induces CB1R ubiquitination and subsequent proteasomal degradation, thereby decreasing neuronal receptor protein levels and causing behavioral cannabinoid tolerance in mice. These findings provide a new regulatory mechanism of cannabinoid signaling by ubiquitin-dependent CB1R protein degradation.
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