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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\u2014but not PKA, PKC or PKD\u2014raised nucleo-to-cytoplasmic HDAC4 fluorescence ratio (F<jats:sub>Nuc<\/jats:sub>\/F<jats:sub>Cyto<\/jats:sub>) by\u2009~\u200950%, indicating baseline CaMKII activity that limits HDAC4 nuclear localization. Further CaMKII activation (via increased extracellular [Ca<jats:sup>2+<\/jats:sup>], high pacing frequencies, angiotensin II or overexpression of CaM or CaMKII\u03b4C) led to significant HDAC4 nuclear export. In contrast, PKA activation by isoproterenol or forskolin drove HDAC4 into the nucleus (raising F<jats:sub>Nuc<\/jats:sub>\/F<jats:sub>Cyto<\/jats:sub> by\u2009&gt;\u200960%). 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.<\/jats:p>","DOI":"10.1007\/s00395-021-00850-2","type":"journal-article","created":{"date-parts":[[2021,2,18]],"date-time":"2021-02-18T21:14:20Z","timestamp":1613682860000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":45,"title":["CaMKII and PKA-dependent phosphorylation co-regulate nuclear localization of HDAC4 in adult cardiomyocytes"],"prefix":"10.1007","volume":"116","author":[{"given":"Kathryn G.","family":"Helmstadter","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6994-9976","authenticated-orcid":false,"given":"Senka","family":"Ljubojevic-Holzer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brent M.","family":"Wood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khanha D.","family":"Taheri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Sedej","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey R.","family":"Erickson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Bossuyt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2237-9483","authenticated-orcid":false,"given":"Donald M.","family":"Bers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,2,15]]},"reference":[{"key":"850_CR1","doi-asserted-by":"publisher","first-page":"468","DOI":"10.1016\/j.yjmcc.2011.01.012","volume":"51","author":"ME Anderson","year":"2011","unstructured":"Anderson ME, Brown JH, Bers DM (2011) CaMKII in myocardial hypertrophy and heart failure. 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Human hearts (from patients and organ donors whose hearts could not be used for transplantation) were acquired via the California Transplant Donor Network (UC Davis) or collaboration with the Division of Cardiac Surgery (Medical University of Graz). Human sample use was approved by the Ethical Committee of the University of California, San Francisco and Davis and the Medical University of Graz and all experimental procedures were carried out in accordance with the Declaration of Helsinki<b>.<\/b>","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"Not applicable.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"Not applicable.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}}],"article-number":"11"}}