Tip60 and HDAC7 interact with the endothelin receptor a and may be involved in downstream signaling

Endothelins exert their biological effects through G; protein-coupled recep tors. However, the precise mechanism of downstream signaling and traffickin g of the receptors is largely unknown. Here we report that the histone acet yltransferase Tip60 and the histone deacetylase HDAC7 interact with one of the ET receptors, ETA, as determined by yeast two-hybrid analysis, glutathi one S-transferase pull-down assays, and co-immunoprecipitation from transfe cted COS-7 cells. In the absence of ET-1, Tip60 and HDAC7 were localized ma inly in the cell nucleus while ETA was predominantly confined to the plasma membrane. Stimulation with ET-1 resulted in the internalization of ETA to the perinuclear compartment and simultaneously ill the efflux of Tip60 and HDAC7 from the nucleus to the same perinuclear compartment where each prote in co-localized with the receptor. Upon co-transfection with ETA into COS-7 cells, Tip60 strongly increased ET-l-induced ERK1/2 phosphorylation, where as HDAC7 had no significant effect. We thus suggest that protein acetylase and deacetylase interact with ETA in a ligand-dependent fashion and may par ticipate in ET signal transduction.