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Increased α‐tubulin Acetylation Translocates Gα s out of Lipid‐rafts: a Novel Mechanism for Antidepressant Effects of HDAC‐6 Inhibitors
Author(s) -
Singh Harinder M,
Schappi Jeffrey,
Rasenick Mark M
Publication year - 2017
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.31.1_supplement.990.5
Subject(s) - lipid raft , tubulin , acetylation , microtubule , hdac6 , chemistry , microbiology and biotechnology , adenylyl cyclase , histone deacetylase , biology , biochemistry , histone , cell , enzyme , gene
Histone deacetylase‐6 (HDAC‐6) enzymes deacetylate α‐tubulin and have been shown to be upregulated during neuropsychiatric disorders. HDAC6 knockout or HDAC6 inhibitors displayed an antidepressant profile in animal models. While, a possible role for HDAC6 inhibitors in treatment of depression exists, the potential mechanism for this remains elusive. Previously, our group has shown that treatment of rats or C6 glioma cells with several classes of antidepressants result in facilitation of the G‐protein, Gα s , activity by translocating it from lipid‐rafts inducing a sustained elevation in cAMP production. Studies have also demonstrated interplay between tubulin and Gα s in lipid‐rafts. Once freed from lipid‐raft domains, Gα s , couples with adenylyl cyclase (AC). Although Gα s interacts directly with tubulin to modify microtubule dynamics, tubulin also acts as an anchor for Gα s in lipid rafts. Based on HDAC‐6 roles in tubulin deacetylation and our data showing Gα s complexes with tubulin in lipid‐rafts, we hypothesized that acetylation of α‐tubulin disrupts tubulin‐Gα s anchoring, rendering Gα s free to activate AC. To test this, C6 glial cells were treated with the HDAC‐6 inhibitor, tubastatin‐A. Three‐day treatment with tubastatin‐A not only increased acetylation of α‐tubulin but also caused translocation of Gα s out of lipid‐rafts. Fluorescence Recovery After Photobleaching (FRAP) on C6 cells stably expressing GFP‐Gα s , was conducted and cells treated for three days with tubastatin‐A showed an “antidepressant signature”. Finally, sustained elevation of cAMP was revealed by increased cAMP response element binding protein (CREB) phosphorylation and increased expression of brain derived neurotrophic factor (BDNF). An increase in acetylated α‐tubulin prevented the formation of tubulin‐Gα s ‐complexes in lipid rafts. This did not appear to be a mechanism shared with other classes of antidepressants. These findings suggest HDAC6 inhibition shows incomplete commonality with traditional antidepressants. Nonetheless, it is possible that compounds that decrease tubulin‐Gα s interactions by increasing acetylation of a α‐tubulin may show promise for antidepressant therapy. Support or Funding Information NIH R01 AT 009169 (MMR) VA BX 001149 (MMR) AHA Postdoctoral Fellowship (HS) NIH T32 MH0667631 (JS)