Acute β-adrenergic activation triggers nuclear import of histone deacetylase 5 and delays Gq-induced transcriptional activation

Chia Wei Jenny Chang, Linda Lee, David Yu, Khanha Dao, Julie B C Bossuyt, Donald M Bers

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

During hemodynamic stress, catecholamines and neurohumoral stimuli may induce co-activation of Gq-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 Gq 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 Gq-mediated nuclear HDAC5 export. Intriguingly, the attenuation of Gq-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 Gq-agonist mediated export is preserved. Acute β-AR/PKA activation protects against hypertrophic signaling by delaying Gq-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.

Original languageEnglish (US)
Pages (from-to)192-204
Number of pages13
JournalJournal of Biological Chemistry
Volume288
Issue number1
DOIs
StatePublished - Jan 4 2013

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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