title: Acute β-adrenergic activation triggers nuclear import of histone deacetylase 5 and delays G(q)-induced transcriptional activation.
abstract: During hemodynamic stress, catecholamines and neurohumoral stimuli may induce co-activation of G(q)-coupled receptors and β-adrenergic receptors (β-AR), leading to cardiac remodeling. Dynamic regulation of histone deacetylase 5 (HDAC5), a transcriptional repressor, is crucial during stress signaling due to its role in epigenetic control of fetal gene markers. Little is known about its regulation during acute and chronic β-AR stimulation and its cross-interaction with G(q) signaling in adult cardiac myocytes. Here, we evaluate the potential cross-talk between G(q)-driven and β-AR mediated signaling at the level of nucleocytoplasmic shuttling of HDAC5. We show the translocation of GFP-tagged wild type HDAC5 or mutants (S279A and S279D) in response to β-AR or G(q) agonists. Isoproterenol (ISO) or PKA activation results in strong nuclear accumulation of HDAC5 in contrast to nuclear export driven by Ca(2+)-calmodulin protein kinase II and protein kinase D. Moreover, nuclear accumulation of HDAC5 under acute ISO/PKA signaling is dependent on phosphorylation of Ser-279 and can block subsequent G(q)-mediated nuclear HDAC5 export. Intriguingly, the attenuation of G(q)-induced export is abolished after chronic PKA activation, yet nuclear HDAC5 remains elevated. Last, the effect of chronic β-AR signaling on HDAC5 translocation was examined in adult myocytes from a rabbit model of heart failure, where ISO-induced nuclear import is ablated, but G(q)-agonist mediated export is preserved. Acute β-AR/PKA activation protects against hypertrophic signaling by delaying G(q)-mediated transcriptional activation. This serves as a key physiological control switch before allowing genetic reprogramming via HDAC5 nuclear export during more severe stress, such as heart failure.
authors.affiliation: Department of Pharmacology, University of California, Davis, California 95616-8636, USA.
authors.forename: Chia-Wei Jenny
authors.initials: CW
authors.lastname: Chang
authors.forename: Linda
authors.initials: L
authors.lastname: Lee
authors.forename: David
authors.initials: D
authors.lastname: Yu
authors.forename: Khanha
authors.initials: K
authors.lastname: Dao
authors.forename: Julie
authors.initials: J
authors.lastname: Bossuyt
authors.forename: Donald M
authors.initials: DM
authors.lastname: Bers
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism*; D005786:Gene Expression Regulation; D006439:Hemodynamics; D006655:Histone Deacetylases / Q000378:metabolism*; D008297:Male; D018613:Microscopy, Confocal / Q000379:methods; D008954:Models, Biological; D032342:Muscle Cells / Q000378:metabolism; D009154:Mutation; D010766:Phosphorylation; D011485:Protein Binding; D011493:Protein Kinase C / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation
chemical_list: D011943:Receptors, Adrenergic, beta; C089212:protein kinase D; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C517675:Camk2a protein, rat; C498619:Hdac5 protein, rat; D006655:Histone Deacetylases; D043802:GTP-Binding Protein alpha Subunits, Gq-G11