Disruption of lipid-raft localized Gαs/tubulin complexes by antidepressants: a unique feature of HDAC6 inhibitors, SSRI and tricyclic compounds

  • Neuropsychopharmacologyvolume 43pages14811491 (2018)
  • doi:10.1038/s41386-018-0016-x
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Current antidepressant therapies meet with variable therapeutic success and there is increasing interest in therapeutic approaches not based on monoamine signaling. Histone deacetylase 6 (HDAC6), which also deacetylates α-tubulin shows altered expression in mood disorders and HDAC6 knockout mice mimic traditional antidepressant treatments. Nonetheless, a mechanistic understanding for HDAC6 inhibitors in the treatment of depression remains elusive. Previously, we have shown that sustained treatment of rats or glioma cells with several antidepressants translocates Gαs from lipid rafts toward increased association with adenylyl cyclase (AC). Concomitant with this is a sustained increase in cAMP production. While Gαs modifies microtubule dynamics, tubulin also acts as an anchor for Gαs in lipid-rafts. Since HDAC-6 inhibitors potentiate α-tubulin acetylation, we hypothesize that acetylation of α-tubulin disrupts tubulin-Gαs raft-anchoring, rendering Gαs free to activate AC. To test this, C6 Glioma (C6) cells were treated with the HDAC-6 inhibitor, tubastatin-A. Chronic treatment with tubastatin-A not only increased α-tubulin acetylation but also translocated Gαs from lipid-rafts, without changing total Gαs. Reciprocally, depletion of α-tubulin acetyl-transferase-1 ablated this phenomenon. While escitalopram and imipramine also disrupt Gαs/tubulin complexes and translocate Gαs from rafts, they evoke no change in tubulin acetylation. Finally, two indicators of downstream cAMP signaling, cAMP response element binding protein phosphorylation (pCREB) and expression of brain-derived-neurotrophic-factor (BDNF) were both elevated by tubastatin-A. These findings suggest HDAC6 inhibitors show a cellular profile resembling traditional antidepressants, but have a distinct mode of action. They also reinforce the validity of antidepressant-induced Gαs translocation from lipid-rafts as a biosignature for antidepressant response that may be useful in the development of new antidepressant compounds.

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H.S. designed and conducted experiments, analyzed and wrote the paper. N.W., J.S. conducted the experiments in Fig. 3. ACY-738 compound was a gift from Matthew Jarpe, Acetylon Pharmaceutics. Authors would like to thank Prof. Mark Brodie for advice with statistical analysis.


VA Merit award-BX001149 (M.M.R.); NIH RO1AT009169 (M.M.R.); NIH P50AA022538 and NIH T32 067631.HS was supported by AHA 16POST27770113

Author information


  1. Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL, 60612, USA

    • Harinder Singh
    • , Nathan Wray
    • , Jeffrey M. Schappi
    •  & Mark M. Rasenick
  2. Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, 60612, USA

    • Mark M. Rasenick
  3. Jesse Brown VAMC, Chicago, IL, 60612, USA

    • Mark M. Rasenick


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Conflict of interest

M.M.R. has received research support from Eli Lilly and Lundbeck, Inc. and is consultant to Otsuka Pharmaceuticals. He also has ownership in Pax Neuroscience. The remaining authors have nothing to disclose. H.S., N.W. and J.S. declare no conflicts of interest.

Corresponding author

Correspondence to Mark M. Rasenick.

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