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G betagamma binds histone deacetylase 5 (HDAC5) and inhibits its transcriptional co-repression activity.

In a yeast two-hybrid screen designed to identify novel effectors of the G betagamma subunit of heterotrimeric G proteins, we found that G betagamma binds to histone deacetylase 5 (HDAC5), an enzyme involved in a pathway not previously recognized to be directly impacted by G proteins. Formation of the G beta1gamma2-HDAC5 complex in mammalian cells can be blocked by overexpression of G alpha(o), and this inhibition is relieved by activation of alpha2A-adrenergic receptor, suggesting that the interaction occurs in a signal-dependent manner. The C-terminal domain of HDAC5 binds directly to G betagamma through multiple motifs, and overexpression of this domain mimics the C terminus of G protein-coupled receptor kinase 2, a known G betagamma scavenger, in its ability to inhibit the G betagamma/HDAC5 interaction. The C terminus of HDAC4 shares significant similarity with that of HDAC5, and accordingly, HDAC4 is also able to form complexes with G beta1gamma2 in cultured cells, suggesting that the C-terminal domain of class II HDACs is a general G betagamma binding motif. Activation of a G(i/o)-coupled receptor results in a time-dependent activation of MEF2C, an HDAC5-regulated transcription factor, whereas inhibition of the interaction with a G betagamma scavenger inhibits MEF2C activity, suggesting a reduced potency of HDAC5-mediated inhibition. Taken together, these data imply that HDAC5 and possibly other class II HDACs can be added to the growing list of G betagamma effectors.

Pubmed ID: 16221676 RIS Download

Mesh terms: Amino Acid Motifs | Animals | Blotting, Western | Cattle | Cell Line | GTP-Binding Protein beta Subunits | GTP-Binding Protein gamma Subunits | Genes, Reporter | Histone Deacetylases | Humans | Immunoprecipitation | Mice | Plasmids | Protein Binding | Protein Structure, Tertiary | Rats | Rats, Sprague-Dawley | Receptors, Adrenergic, alpha-2 | Repressor Proteins | Signal Transduction | Time Factors | Transcription, Genetic | Transfection | Two-Hybrid System Techniques

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Associated grants

  • Agency: NEI NIH HHS, Id: EY010291
  • Agency: NIMH NIH HHS, Id: T32 MH65215-02

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