title: Δ9-THC increases endogenous AHA1 expression in rat cerebellum and may modulate CB1 receptor function during chronic use.
abstract: To characterize the long-term effects of adolescent marijuana abuse, we performed a proteomic analysis of cerebellar extracts from adult female rats with and without ovariectomy that were treated with Δ9-THC for 40 days during adolescence. Six proteins were found to significantly differ among the four treatment groups, with Δ9-THC and ovariectomy (OVX) decreasing the mitochondrial proteins, pyruvate carboxylase and NADH dehydrogenase, whereas the levels of putative cytosolic molecular chaperones NM23B, translationally controlled tumor protein, DJ-1 and activator of heat-shock 90kDa protein ATPase homolog 1 (AHA1) were increased. We further analyzed the effects of AHA1, a HSP90 co-chaperone, on CB1R and CB2R trafficking and signaling in transfected HEK293T and Neuro-2A cells. In HEK293T cells, AHA1 over-expression enhanced plasma membrane levels of CB1R and increased CB1R-mediated effects on cAMP levels and on MAPK phosphorylation. AHA1 over-expression also enhanced cell surface levels of endogenous CB1R and the effects of Δ9-THC on the cAMP levels in Neuro-2A cells. In contrast, over-expression of AHA1 did not affect the subcellular localization and signaling of CB2R. Our data indicate that chronic Δ9-THC administration in adolescence altered the endogenous levels of specialized proteins in the cerebellum, such as AHA1, and that this protein can change CB1R cell surface levels and signaling.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA. cfilip@lsuhsc.edu
authors.forename: Catalin M
authors.initials: CM
authors.lastname: Filipeanu
authors.forename: Jesse J
authors.initials: JJ
authors.lastname: Guidry
authors.forename: Stuart T
authors.initials: ST
authors.lastname: Leonard
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Winsauer
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D000242:Cyclic AMP / Q000378:metabolism; D013759:Dronabinol / Q000494:pharmacology*; D015180:Electrophoresis, Gel, Two-Dimensional; D005260:Female; D006801:Humans; D047468:Immunoprecipitation; D002189:Marijuana Abuse / Q000378:metabolism*; D013058:Mass Spectrometry; D008856:Microscopy, Fluorescence; D018832:Molecular Chaperones / Q000096:biosynthesis* / Q000235:genetics; D010052:Ovariectomy; D040901:Proteomics; D051381:Rats; D020318:Rats, Long-Evans; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects*; D043885:Receptor, Cannabinoid, CB2 / Q000187:drug effects; D011956:Receptors, Cell Surface / Q000187:drug effects; D014162:Transfection
chemical_list: D018832:Molecular Chaperones; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D011956:Receptors, Cell Surface; D013759:Dronabinol; D000242:Cyclic AMP