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CaMKII and PKA-dependent phosphorylation co-regulate nuclear localization of HDAC4 in adult cardiomyocytes

Kathryn G Helmstadter1, Senka Ljubojevic-Holzer2,3,4, Brent M Wood1

  • 1Department of Pharmacology, University of California, Genome Building Rm 3513, Davis, CA, 95616-8636, USA.

Basic Research in Cardiology
|February 16, 2021
PubMed

Insights

Calcium/calmodulin-dependent protein kinase II (CaMKII) limits nuclear localization of histone deacetylase 4 (HDAC4), while protein kinase A (PKA) promotes it, with this balance shifting in heart failure.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Cell Signaling

Background:

  • Nuclear histone deacetylase 4 (HDAC4) plays a role in heart failure by repressing MEF2-mediated transcription.
  • Both CaMKII and PKA are implicated in HDAC4 translocation, but their interplay in adult cardiomyocytes is not fully understood.

Purpose of the Study:

  • To investigate the interplay between PKA and CaMKII in regulating HDAC4 phosphorylation and translocation in adult ventricular myocytes.
  • To determine the roles of CaMKII and PKA in controlling HDAC4 nuclear localization and its implications in cardiac signaling.

Main Methods:

  • Confocal imaging and protein analyses were used to quantify HDAC4 localization in adult mouse, rabbit, and human ventricular myocytes.
  • Pharmacological inhibitors and activators of CaMKII and PKA were employed, alongside genetic manipulation (mutant HDAC4, kinase overexpression).
  • Experiments involved varying extracellular calcium, pacing frequencies, and applying angiotensin II to modulate kinase activity.

Main Results:

  • Baseline CaMKII activity limits HDAC4 nuclear localization; CaMKII inhibition increased nuclear HDAC4.
  • CaMKII activation promoted HDAC4 nuclear export, while PKA activation (via isoproterenol/forskolin) drove HDAC4 nuclear import.
  • PKA-mediated nuclear accumulation of HDAC4 was dependent on specific phosphorylation sites (S265/266) and was predominant in early responses, whereas CaMKII-dependent export prevailed upon prolonged stimulation.
  • In failing cardiomyocytes, CaMKII-dependent effects predominated over PKA-dependent responses.
  • Similar CaMKII- and PKA-dependent HDAC4 shifts were observed in human cardiomyocytes.

Conclusions:

  • CaMKII limits nuclear localization of HDAC4, while PKA favors its nuclear retention in cardiac cells.
  • The phosphorylation sites S265/266 on HDAC4 are crucial for PKA-mediated regulation.
  • These competing pathways dynamically regulate HDAC4 nuclear localization and transcriptional activity in cardiac signaling, with a shift towards CaMKII dominance in heart failure.

Keywords:
Calcium-calmodulin-dependent protein kinase (CaMKII)Cardiac hypertrophyHistone deacetylase 4 (HDAC4)Protein kinase A (PKA)Ventricular remodeling

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