Autophagy activation by novel inducers prevents BECN2-mediated drug tolerance to cannabinoids.
Cannabinoids and related drugs generate profound behavioral effects (such as analgesic effects) through activating CNR1 (cannabinoid receptor 1 [brain]). However, repeated cannabinoid administration triggers lysosomal degradation of the receptor and rapid development of drug tolerance, limiting the medical use of marijuana in chronic diseases. The pathogenic mechanisms of cannabinoid tolerance are not fully understood, and little is known about its prevention. Here we show that a protein involved in macroautophagy/autophagy (a conserved lysosomal degradation pathway), BECN2 (beclin 2), mediates cannabinoid tolerance by preventing CNR1 recycling and resensitization after prolonged agonist exposure, and deletion of Becn2 rescues CNR1 activity in mouse brain and conveys resistance to analgesic tolerance to chronic cannabinoids. To target BECN2 therapeutically, we established a competitive recruitment model of BECN2 and identified novel synthetic, natural or physiological stimuli of autophagy that sequester BECN2 from its binding with GPRASP1, a receptor protein for CNR1 degradation. Co-administration of these autophagy inducers effectively restores the level and signaling of brain CNR1 and protects mice from developing tolerance to repeated cannabinoid usage. Overall, our findings demonstrate the functional link among autophagy, receptor signaling and animal behavior regulated by psychoactive drugs, and develop a new strategy to prevent tolerance and improve medical efficacy of cannabinoids by modulating the BECN2 interactome and autophagy activity.
a Department of Cell and Molecular Biology , Feinberg School of Medicine, Northwestern University , Chicago , IL , USA.
Kenta
K
Kuramoto
a Department of Cell and Molecular Biology , Feinberg School of Medicine, Northwestern University , Chicago , IL , USA.|b Key Laboratory of Industrial Microbiology, Ministry of Education and Tianjin City, College of Biotechnology, Tianjin University of Science and Technology , Tianjin , China.
Nan
N
Wang
a Department of Cell and Molecular Biology , Feinberg School of Medicine, Northwestern University , Chicago , IL , USA.|c School of Life Sciences, Northeast Normal University , Changchun , Jilin , China.
Yuying
Y
Fan
a Department of Cell and Molecular Biology , Feinberg School of Medicine, Northwestern University , Chicago , IL , USA.
Weiran
W
Zhang
d Higuchi Biosciences Center, University of Kansas , Lawrence , KS , USA.
Frank J
FJ
Schoenen
e UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill , Chapel Hill , NC , USA.
Kevin J
KJ
Frankowski
f Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health , Bethesda , MD , USA.
Juan
J
Marugan
c School of Life Sciences, Northeast Normal University , Changchun , Jilin , China.
Yifa
Y
Zhou
a Department of Cell and Molecular Biology , Feinberg School of Medicine, Northwestern University , Chicago , IL , USA.
Sui
S
Huang
a Department of Cell and Molecular Biology , Feinberg School of Medicine, Northwestern University , Chicago , IL , USA.
Congcong
C
He
D000700:Analgesics / Q000737:chemistry; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism; D002186:Cannabinoids / Q000378:metabolism*; D004361:Drug Tolerance; D017353:Gene Deletion; D057809:HEK293 Cells; D006367:HeLa Cells; D006579:Heterozygote; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D059408:Pain Management; D021381:Protein Transport; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D015398:Signal Transduction
D000700:Analgesics; C584110:BECN2 protein, human; C584111:Becn2 protein, mouse; C571130:CNR1 protein, human; C578453:CNR1 protein, mouse; D002186:Cannabinoids; D047908:Intracellular Signaling Peptides and Proteins; D043884:Receptor, Cannabinoid, CB1
BECN2; analgesia; autophagy inducer; behavior; cannabinoid; cannabinoid receptor 1; drug tolerance; intracellular trafficking