PMID- 29463911 OWN - NLM STAT- MEDLINE DCOM- 20190208 LR - 20221207 IS - 1740-634X (Electronic) IS - 0893-133X (Print) IS - 0893-133X (Linking) VI - 43 IP - 7 DP - 2018 Jun TI - Disruption of lipid-raft localized Galpha(s)/tubulin complexes by antidepressants: a unique feature of HDAC6 inhibitors, SSRI and tricyclic compounds. PG - 1481-1491 LID - 10.1038/s41386-018-0016-x [doi] AB - 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 alpha-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 Galpha(s) from lipid rafts toward increased association with adenylyl cyclase (AC). Concomitant with this is a sustained increase in cAMP production. While Galpha(s) modifies microtubule dynamics, tubulin also acts as an anchor for Galpha(s) in lipid-rafts. Since HDAC-6 inhibitors potentiate alpha-tubulin acetylation, we hypothesize that acetylation of alpha-tubulin disrupts tubulin-Galpha(s) raft-anchoring, rendering Galpha(s) 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 alpha-tubulin acetylation but also translocated Galpha(s) from lipid-rafts, without changing total Galpha(s). Reciprocally, depletion of alpha-tubulin acetyl-transferase-1 ablated this phenomenon. While escitalopram and imipramine also disrupt Galpha(s)/tubulin complexes and translocate Galpha(s) 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 Galpha(s) translocation from lipid-rafts as a biosignature for antidepressant response that may be useful in the development of new antidepressant compounds. FAU - Singh, Harinder AU - Singh H AD - Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL, 60612, USA. FAU - Wray, Nathan AU - Wray N AD - Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL, 60612, USA. FAU - Schappi, Jeffrey M AU - Schappi JM AD - Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL, 60612, USA. FAU - Rasenick, Mark M AU - Rasenick MM AD - Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL, 60612, USA. raz@uic.edu. AD - Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, 60612, USA. raz@uic.edu. AD - Jesse Brown VAMC, Chicago, IL, 60612, USA. raz@uic.edu. LA - eng GR - R01 AT009169/AT/NCCIH NIH HHS/United States GR - P50 AA022538/AA/NIAAA NIH HHS/United States GR - IK6 BX004475/BX/BLRD VA/United States GR - I01 BX001149/BX/BLRD VA/United States GR - T32 MH067631/MH/NIMH NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20180205 PL - England TA - Neuropsychopharmacology JT - Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology JID - 8904907 RN - 0 (Antidepressive Agents, Tricyclic) RN - 0 (Bdnf protein, rat) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Cyclic AMP Response Element-Binding Protein) RN - 0 (Histone Deacetylase Inhibitors) RN - 0 (Hydroxamic Acids) RN - 0 (Indoles) RN - 0 (RNA, Small Interfering) RN - 0 (Serotonin Uptake Inhibitors) RN - 0 (Tubulin) RN - 0DHU5B8D6V (Citalopram) RN - 2XTSOX1NF8 (tubastatin A) RN - E0399OZS9N (Cyclic AMP) RN - EC 2.3.1.- (Acetyltransferases) RN - EC 3.6.5.1 (GTP-Binding Protein alpha Subunits, Gs) RN - OGG85SX4E4 (Imipramine) SB - IM EIN - Neuropsychopharmacology. 2019 Jan 7;:. PMID: 30617260 MH - Acetylation/drug effects MH - Acetyltransferases/antagonists & inhibitors/genetics MH - Animals MH - Antidepressive Agents, Tricyclic/*pharmacology MH - Brain-Derived Neurotrophic Factor/biosynthesis MH - Cell Line, Tumor MH - Citalopram/pharmacology MH - Cyclic AMP/biosynthesis MH - Cyclic AMP Response Element-Binding Protein/metabolism MH - GTP-Binding Protein alpha Subunits, Gs/*metabolism MH - Histone Deacetylase Inhibitors/*pharmacology MH - Hydroxamic Acids/pharmacology MH - Imipramine/pharmacology MH - Indoles/pharmacology MH - Membrane Microdomains/*drug effects MH - RNA, Small Interfering/pharmacology MH - Rats MH - Selective Serotonin Reuptake Inhibitors/*pharmacology MH - Tubulin/*metabolism PMC - PMC5983546 COIS- 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. EDAT- 2018/02/22 06:00 MHDA- 2019/02/09 06:00 PMCR- 2019/06/01 CRDT- 2018/02/22 06:00 PHST- 2017/10/18 00:00 [received] PHST- 2018/01/18 00:00 [accepted] PHST- 2018/01/11 00:00 [revised] PHST- 2018/02/22 06:00 [pubmed] PHST- 2019/02/09 06:00 [medline] PHST- 2018/02/22 06:00 [entrez] PHST- 2019/06/01 00:00 [pmc-release] AID - 10.1038/s41386-018-0016-x [pii] AID - 16 [pii] AID - 10.1038/s41386-018-0016-x [doi] PST - ppublish SO - Neuropsychopharmacology. 2018 Jun;43(7):1481-1491. doi: 10.1038/s41386-018-0016-x. Epub 2018 Feb 5.