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J. Biol. Chem., Vol. 280, Issue 50, 41769-41776, December 16, 2005

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G Binds Histone Deacetylase 5 (HDAC5) and Inhibits Its Transcriptional Co-repression Activity^*

From the Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232

In a yeast two-hybrid screen designed to identify novel effectors of the G subunit of heterotrimeric G proteins, we found that G 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 G₁₂-HDAC5 complex in mammalian cells can be blocked by overexpression of G_o, and this inhibition is relieved by activation of _2A-adrenergic receptor, suggesting that the interaction occurs in a signal-dependent manner. The C-terminal domain of HDAC5 binds directly to G through multiple motifs, and overexpression of this domain mimics the C terminus of G protein-coupled receptor kinase 2, a known G scavenger, in its ability to inhibit the G/HDAC5 interaction. The C terminus of HDAC4 shares significant similarity with that of HDAC5, and accordingly, HDAC4 is also able to form complexes with G₁₂ in cultured cells, suggesting that the C-terminal domain of class II HDACs is a general G 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 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 effectors.

Received for publication, April 14, 2005 , and in revised form, October 12, 2005.

^* This work was supported in part by Grant EY010291 (to H. E. H.) from the National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported in part by National Institutes of Health Neurogenomics Training Grant T32 MH65215-02.

² To whom correspondence should be addressed: Dept. of Pharmacology, Vanderbilt University Medical Center, 2200 Pierce Ave., RRB 442, Nashville, TN 37232. Tel.: 615-343-3533; Fax: 615-322-5117; E-mail: heidi.hamm{at}vanderbilt.edu.

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