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Modulation of CB1R expression, trafficking and signaling by HSP90 isoforms
Author(s) -
Filipeanu Catalin,
Bailey Evangeline M
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.837.4
Subject(s) - hsp90 , endosome , microbiology and biotechnology , downregulation and upregulation , cannabinoid receptor , hek 293 cells , receptor , g protein coupled receptor , signal transduction , subcellular localization , chemistry , biology , biochemistry , intracellular , heat shock protein , gene , agonist , cytoplasm
We recently demonstrated that the levels of AHA1, a HSP90 cochaperone, were increased by chronic Δ9‐THC in female rat cerebellum (Filipeanu et al., J. Neurochem., 2011). In turn, AHA1 overexpression upregulated the plasma membrane levels and signaling of CB1 cannabinoid receptor (CB1R) in HEK293T and Neuro2A cell lines. To precisely define the roles of HSP90 chaperone machinery in the regulation of cannabinoid receptors expression levels and signaling, we generated stable HEK293T cells with specific reduction of HSP90α or β cellular levels. Downregulation of HSP90α was accompanied by an increase in the total CB1R cellular levels, whereas the receptor plasma membrane levels were increased in both HSP90α and β deficient cells. Similar results were obtained after pharmacological inhibition of HSP90 activity using 17‐DMAG (0.5 μM, 18h). Fluorescent microscopy analysis of CB1R subcellular localization indicated that in basal conditions this receptor is present not only at the plasma membrane, but also in the early endosomes. Reduction of the HSP90 levels decreased the CB1R pool present in the endosomes. These changes in the CB1R total cellular levels and subcellular localization determined alterations in the P‐ERK 1/2 activation by acute Δ9‐THC treatment. In conclusion, these results together with our previous publications (Filipeanu et al., BBA., 2011), indicate that HSP90 chaperone machinery is a novel modulator of G protein‐coupled receptors trafficking and signaling. Supported by NIH Grant1R03DA031596‐01 .