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

Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology
Harinder SinghM M Rasenick

Abstract

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 o...Continue Reading

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Jul 31, 2018·The World Journal of Biological Psychiatry : the Official Journal of the World Federation of Societies of Biological Psychiatry·Alessandra MalleiMaurizio Popoli
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Jun 3, 2021·International Journal of Molecular Sciences·Hyun-Sun ParkHong-Yeoul Ryu
Jan 1, 2022·Molecular Psychiatry·Steven D TargumMark M Rasenick

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Methods Mentioned

BETA
acetylation
immunoprecipitation
transfection
fluorescence-activated cell sorting
density gradient centrifugation
co-immunoprecipitation
fluorescence recovery after photobleaching

Software Mentioned

Zeiss Zen
ImageLab
GraphPad
Prism
Image

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