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

Abstract

Nuclear histone deacetylase 4 (HDAC4) represses MEF2-mediated transcription, implicated in the development of heart failure. CaMKII-dependent phosphorylation drives nucleus-to-cytoplasm HDAC4 shuttling, but protein kinase A (PKA) is also linked to HDAC4 translocation. However, the interplay of CaMKII and PKA in regulating adult cardiomyocyte HDAC4 translocation is unclear. Here we sought to determine the interplay of PKA- and CaMKII-dependent HDAC4 phosphorylation and translocation in adult mouse, rabbit and human ventricular myocytes. Confocal imaging and protein analyses revealed that inhibition of CaMKII—but not PKA, PKC or PKD—raised nucleo-to-cytoplasmic HDAC4 fluorescence ratio (FNuc/FCyto) by ~ 50%, indicating baseline CaMKII activity that limits HDAC4 nuclear localization. Further CaMKII activation (via increased extracellular [Ca2+], high pacing frequencies, angiotensin II or overexpression of CaM or CaMKIIδC) led to significant HDAC4 nuclear export. In contrast, PKA activation by isoproterenol or forskolin drove HDAC4 into the nucleus (raising FNuc/FCyto by > 60%). These PKA-mediated effects were abolished in cells pretreated with PKA inhibitors and in cells expressing mutant HDAC4 in S265/266A mutant. In physiological conditions where both kinases are active, PKA-dependent nuclear accumulation of HDAC4 was predominant in the very early response, while CaMKII-dependent HDAC4 export prevailed upon prolonged stimuli. This orchestrated co-regulation was shifted in failing cardiomyocytes, where CaMKII-dependent effects predominated over PKA-dependent response. Importantly, human cardiomyocytes showed similar CaMKII- and PKA-dependent HDAC4 shifts. Collectively, CaMKII limits nuclear localization of HDAC4, while PKA favors HDAC4 nuclear retention and S265/266 is essential for PKA-mediated regulation. These pathways thus compete in HDAC4 nuclear localization and transcriptional regulation in cardiac signaling.

Activation of transient receptor potential vanilloid 4 is involved in pressure overload-induced cardiac hypertrophy

“…Furthermore, AngII/PE-induced [Ca 2+ ] i rise, as well as the phosphorylation of CaMKII in NRVMs, was significantly reduced by the TRPV4 antagonist. Previous studies have also shown that Ang II/PE promotes the phosphorylation of CaMKII, increases CaMKII activity, and subsequently mediates cardiac hypertrophy ( Helmstadter et al, 2021 ; Nakamura and Sadoshima, 2018 ; Tonegawa et al, 2017 ). However, the calcineurin/NFAT pathway may play a more important role in AngII-induced cardiac hypertrophy ( Yu et al, 2021 ).…”

β-Adrenergic Receptor Stimulation Maintains NCX-CaMKII Axis and Prevents Overactivation of IL6R-Signaling in Cardiomyocytes upon Increased Workload

“…Although chronic β-adrenergic tone is readily implicated in the development of cardiac pathologies, while acute effects are known for instantaneous regulation of cellular Ca 2+ cycling and contractility, little is known about the role of β-adrenergic signaling in preventing gene reprograming under short-term physiological stress. We previously showed that ISO keeps histone deacetylase 4 (HDAC4) localized in the nucleus in the very early response to physiological challenge [ 37 ]. Maccari et al showed that β-adrenergic signaling also prevents the upregulation of β-myosin heavy chain (β-MHC), and both effects are associated with preventing cardiac dysfunction [ 37 , 38 ].…”

“…We previously showed that ISO keeps histone deacetylase 4 (HDAC4) localized in the nucleus in the very early response to physiological challenge [ 37 ]. Maccari et al showed that β-adrenergic signaling also prevents the upregulation of β-myosin heavy chain (β-MHC), and both effects are associated with preventing cardiac dysfunction [ 37 , 38 ]. Our present data identify a novel β-adrenergic-signaling-dependent mechanism for controlling transcriptional reprograming during short-term increase in workload demands of the heart.…”

FKN/NR Signaling Pathway Regulates Hippocampal Inflammatory Responses: the Survival of Hippocampal Neurons in Diabetic Rats with Chronic Unpredictable Mild Stress

“…The binding of FKN to its receptor CX3CR1 increases intracellular secretion of adenosine, which binds to its receptor and presents key biological activities and pharmacological characteristics in the hippocampus [ 42 ]. We inferred that, under diabetic condition, (a) abnormal increase in A2AR density promotes the release of a large amount of D-serine, an endogenous ligand for NR, resulting in excessive activation of NR on neurons [ 43 ]; (b) adenosine binds to the A1R, which leads to decreased BDNF secretion and neurotrophic deficiency [ 44 ]; and (c) inhibition of the A3R on neuronal membrane induces NMDA channel opening and increases intracellular Ca 2+ concentration, resulting in Ca 2+ /CaMKII-dependent inhibition [ 45 ]. Therefore, FKN can regulate the density changes of NR receptor subtypes NR2A and NR2B through the FKN/CX3CR1 signaling pathway, leading to NR activation and thus mediating the abnormal change of hippocampal neurons.…”