Gβγ binds histone deacetylase 5 (HDAC5) and inhibits its transcriptional co-repression activity

In a yeast two-hybrid screen designed to identify novel effectors of theG beta gamma subunit of heterotrimeric G proteins, we found thatG beta gamma 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 beta(1)gamma(2)-HDAC5 complex in mammalian cells can be blocked by overexpression of G alpha(0), and this inhibition is relieved by activation of alpha(2A)-adrenergic receptor, suggesting that the interaction occurs in a signal-dependent manner. The C-terminal domain of HDAC5 binds directly to G beta gamma through multiple motifs, and overexpression of this domain mimics the C terminus of G protein-coupled receptor kinase 2, a known G beta gamma scavenger, in its ability to inhibit the G beta gamma/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 beta(1)gamma(2) in cultured cells, suggesting that the C-terminal domain of class II HDACs is a general G beta gamma binding motif. Activation of aG(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 beta gamma 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 beta gamma effectors.