Cardiac CaMKII activation promotes rapid translocation to its extra-dyadic targets

Wood, Brian D.; Simon, Mitchell; Galice, Samuel; Alim, Chidera C.; Ferrero, Maura; Pinna, Natalie N.; Bers, Donald M.; Bossuyt, Julie

doi:10.1016/j.yjmcc.2018.10.010

Cited by 24 publications

(38 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To test how the relative dominance of the opposing effects of agonist-induced PKA activity (nuclear retention) or CaMKII activity (nuclear depletion), we first overexpressed CaMKIIδC in cardiomyocytes and treated them with PKA and CaMKII agonists. Under the same experimental conditions we previously found exogenous CaMKIIδ to be 63.2 ± 33% of endogenous CaMKII [ 68 ], which is comparable to the increase seen in heart failure [ 41 ]. The overexpression of CaMKIIδC (as occurs in HF) by itself led to significant nuclear export of HDAC4 (F Nuc /F Cyto decreased from 1 ± 0.02, n = 84 to 0.83 ± 0.02, n = 70; Fig.…”

Section: Resultssupporting

confidence: 71%

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

et al. 2021

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Resultssupporting

confidence: 71%

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

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…Therefore, the physiological significance of these residues in CAPN1 function warrants further investigation. CaMKII possesses several properties, such as mobility 43 , and serves as a carrier or structural component for substrate transmission 26,27 . Our data showed that self-phosphorylated CaMKII translocated to membrane upon ischemia/ reperfusion challenge, and that CaMKII T287A mutation did not increase the level of CaMKII in the plasma membrane.…”

Section: Discussionmentioning

confidence: 99%

CaMKII/calpain interaction mediates ischemia/reperfusion injury in isolated rat hearts

Feng

Tang

et al. 2020

Cell Death Dis

View full text Add to dashboard Cite

Previous studies indicated that Ca 2+ /calmodulin-dependent kinase II (CaMKII), a kinase involved in the modulation of ryanodine receptor activity, activates Ca 2+-regulated protease μ-calpain to promote myocardial ischemia/ reperfusion injury. This study was performed to explore the underlying mechanisms in CaMKII-induced calpain activation to better understand heart injury. To examine the Ca 2+ paradox and ischemia/reperfusion injury, isolated rat hearts were subjected to a Ca 2+-free solution for 3 min, or left coronary artery occlusion for 40 min, prior to restoration of normal perfusion. Blockade of trans-sarcoplasmic reticulum Ca 2+ flux using ryanodine and thapsigargin failed to prevent Ca 2+ paradox-induced heart injury. In contrast, the Ca 2+ paradox increased CaMKII auto-phosphorylation at Thr 287 , while the CaMKII inhibitor KN-62 and the Na + /Ca 2+ exchanger inhibitor KB-R7943 alleviated heart injury and calpain activity. Intriguingly, the binding of μ-calpain large subunit calpain-1 (CAPN1) to phospho-CaMKII was blunted by both inhibitors. Thus, a Ca 2+ leak via the ryanodine receptor is not an essential element in CaMKII-elicited calpain activation. In hearts receiving vector injection, ischemia/reperfusion caused elevated calpain activity and α-fodrin degradation, along with membrane integrity damage, similar to the effects noted in control hearts. Importantly, all these alterations were diminished with delivery of adeno-associated virus expressing mutant CaMKIIδC T287A. Ischemia/reperfusion increased CaMKII auto-phosphorylation and binding of CAPN1 to phospho-CaMKII, and facilitated the translocation of phospho-CaMKII and CAPN1 to the plasma membrane, all of which were reversed by injecting CaMKII mutant. Furthermore, the relocation capacity and the interaction of CaMKII with CAPN1 appeared to be dependent upon CaMKII autophosphorylation, as its mutant delivery increased the level of CaMKII, but did not increase membrane content of CaMKII and CAPN1, or their interactions. Together, CaMKII/calpain interaction represents a new avenue for mediating myocardial ischemia/ reperfusion injury, and CaMKII likely serves as both a kinase and a carrier, thereby promoting calpain membrane translocation and activation.

show abstract

“…January (University of Wisconsin–Madison, Madison, WI) and maintained in minimum essential medium supplemented with 10% FBS and 400 µg/ml G418 (Axenia Biologix) as previously described (Zhou et al, 1998). Ventricular myocytes were enzymatically isolated from the rabbit ventricles on the day of electrophysiological experiments as previously described (Wood et al, 2018). HEK cells or cardiac myocytes used for electrophysiological study were adhered to the poly- l -lysine–coated (MW 30,000–70,000; Sigma-Aldrich; 0.1 mg/ml for 2 h at 37°C) coverslips in 12-well plates and transferred to a small recording chamber mounted on the stage of an inverted microscope (Axiovert S100; Carl Zeiss) and were continuously superfused with HEPES-buffered Tyrode’s solution containing (in mM) 137 NaCl, 4 KCl, 1.8 CaCl 2 , 1 MgCl 2 , 10 glucose, and 10 HEPES, pH 7.4 with NaOH.…”

Section: Methodsmentioning

confidence: 99%

Facilitation of IKr current by some hERG channel blockers suppresses early afterdepolarizations

Furutani

Tsumoto

Chen

et al. 2019

Journal of General Physiology

View full text Add to dashboard Cite

Drug-induced block of the cardiac rapid delayed rectifying potassium current (IKr), carried by the human ether-a-go-go-related gene (hERG) channel, is the most common cause of acquired long QT syndrome. Indeed, some, but not all, drugs that block hERG channels cause fatal cardiac arrhythmias. However, there is no clear method to distinguish between drugs that cause deadly arrhythmias and those that are clinically safe. Here we propose a mechanism that could explain why certain clinically used hERG blockers are less proarrhythmic than others. We demonstrate that several drugs that block hERG channels, but have favorable cardiac safety profiles, also evoke another effect; they facilitate the hERG current amplitude in response to low-voltage depolarization. To investigate how hERG facilitation impacts cardiac safety, we develop computational models of IKr block with and without this facilitation. We constrain the models using data from voltage clamp recordings of hERG block and facilitation by nifekalant, a safe class III antiarrhythmic agent. Human ventricular action potential simulations demonstrate the ability of nifekalant to suppress ectopic excitations, with or without facilitation. Without facilitation, excessive IKr block evokes early afterdepolarizations, which cause lethal arrhythmias. When facilitation is introduced, early afterdepolarizations are prevented at the same degree of block. Facilitation appears to prevent early afterdepolarizations by increasing IKr during the repolarization phase of action potentials. We empirically test this prediction in isolated rabbit ventricular myocytes and find that action potential prolongation with nifekalant is less likely to induce early afterdepolarization than action potential prolongation with dofetilide, a hERG channel blocker that does not induce facilitation. Our data suggest that hERG channel blockers that induce facilitation increase the repolarization reserve of cardiac myocytes, rendering them less likely to trigger lethal ventricular arrhythmias.

show abstract

Cardiac CaMKII activation promotes rapid translocation to its extra-dyadic targets

Cited by 24 publications

References 55 publications

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

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

CaMKII/calpain interaction mediates ischemia/reperfusion injury in isolated rat hearts

Facilitation of IKr current by some hERG channel blockers suppresses early afterdepolarizations

Contact Info

Product

Resources

About