The KN-93 Molecule Inhibits Calcium/Calmodulin-Dependent Protein Kinase II (CaMKII) Activity by Binding to Ca2+/CaM

Wong, Melanie; Samal, Alexandra B.; Lee, Mike; Vlach, Jiří; Novikov, Nikolai; Niedziela-Majka, Anita; Feng, Joy Y.; Koltun, Dmitry O.; Brendza, Katherine M.; Kwon, Ho-Keun; Schultz, Brian E.; Sakowicz, Roman; Saad, Jamil S.; Papalia, Giuseppe A.

doi:10.1016/j.jmb.2019.02.001

Cited by 82 publications

(68 citation statements)

References 73 publications

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“…In the presence of ATP, the pseudo-substrate section of the intermediate regulatory region of CaMKII can inhibit the func-tion of the N-terminal catalytic region, resulting in the inactivation of CaMKII (23). When Ca 2+ content increases, Ca 2+ combines with CaM (a ubiquitous intracellular Ca 2+ binding protein) to form Ca 2+ /CaM (24). The intermediate regulatory region binds to Ca 2+ /CaM, which causes conformational changes in the pseudosubstrate region and releases the catalytic domain, exposing the substrate and ATP binding sites, further resulting in CaMKII activation (Fig.…”

Section: Camkii Activation Mechanismmentioning

confidence: 99%

Regulatory mechanism of calcium/calmodulin‑dependent protein kinase II in the occurrence and development of ventricular arrhythmia (Review)

Guo

et al. 2021

Exp Ther Med

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Ventricular arrhythmia (VA) is a highly fatal arrhythmia that involves multiple ion channels. Of all sudden cardiac death events, ~85% result from VAs, including ventricular tachycardia and ventricular fibrillation. Calcium/calmodulin-dependent pro-tein kinase II (CaMKII) is an important ion channel regulator that participates in the excitation-contraction coupling of the heart, and as such is important for regulating its electrophysiological function. CaMKII can be activated in a Ca 2+ /calmodulin (CaM)-dependent or Ca 2+ /CaM-independent manner, serving a key role in the occurrence and development of VA. The present review aimed to determine whether activated CaMKII induces early afterdepolarizations and delayed afterdepolarizations that result in VA by regulating sodium, potassium and calcium ions. Assessing VA mechanisms based on the CaMKII pathway is of great significance to the clinical treatment of VA and the de-velopment of effective drugs for use in clinical practice.

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Section: Camkii Activation Mechanismmentioning

confidence: 99%

Regulatory mechanism of calcium/calmodulin‑dependent protein kinase II in the occurrence and development of ventricular arrhythmia (Review)

Guo

et al. 2021

Exp Ther Med

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“…An important item to bring up is that KN-62/93 binds to the holoenzyme and directly steps in the interaction of Ca 2+ /CaM but does not directly bind to CaM (Sumi et al, 1991). Besides belonging to a family of CaM antagonists, KN-93 cannot avoid the activity of autophosphorylation of CaMKII (Wong et al, 2019).…”

Section: Camkii Inhibition Displays Cardioprotectionmentioning

confidence: 99%

An Overview of the Role of Calcium/Calmodulin-Dependent Protein Kinase in Cardiorenal Syndrome

et al. 2020

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Calcium/calmodulin-dependent protein kinases (CaMKs) are key regulators of calcium signaling in health and disease. CaMKII is the most abundant isoform in the heart; although classically described as a regulator of excitation-contraction coupling, recent studies show that it can also mediate inflammation in cardiovascular diseases (CVDs). Among CVDs, cardiorenal syndrome (CRS) represents a pressing issue to be addressed, considering the growing incidence of kidney diseases worldwide. In this review, we aimed to discuss the role of CaMK as an inflammatory mediator in heart and kidney interaction by conducting an extensive literature review using the database PubMed. Here, we summarize the role and regulating mechanisms of CaMKII present in several quality studies, providing a better understanding for future investigations of CamKII in CVDs. Surprisingly, despite the obvious importance of CaMKII in the heart, very little is known about CaMKII in CRS. In conclusion, more studies are necessary to further understand the role of CaMKII in CRS.

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“…Since dopamine can also activate CaMKII signaling (Hasbi et al, 2009;Adaikkan et al, 2018), we examined the role of the pathway in D1 receptor-dependent eEF2 dephosphorylation. Surprisingly, treatment of cultures with SKF38393 in the presence of the CaMKII specific inhibitor TatCN21 peptide (Wong et al, 2019) demonstrated a mild contribution of CaMKII to the D1 receptor-dependent dephosphorylation of eEF2 (Supplementary Figure S2B).…”

Section: D1 But Not D2 Receptor Activation Induces Eef2 Dephosphorylamentioning

confidence: 99%

D1 Dopamine Receptor Activation Induces Neuronal eEF2 Pathway-Dependent Protein Synthesis

David

Barrera

Gould

et al. 2020

Front. Mol. Neurosci.

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Dopamine, alongside other neuromodulators, defines brain and neuronal states, inter alia through regulation of global and local mRNA translation. Yet, the signaling pathways underlying the effects of dopamine on mRNA translation and psychiatric disorders are not clear. In order to examine the molecular pathways downstream of dopamine receptors, we used genetic, pharmacologic, biochemical, and imaging methods, and found that activation of dopamine receptor D1 but not D2 leads to rapid dephosphorylation of eEF2 at Thr 56 but not eIF2α in cortical primary neuronal culture in a time-dependent manner. NMDA receptor, mTOR, and ERK pathways are upstream of the D1 receptor-dependent eEF2 dephosphorylation and essential for it. Furthermore, D1 receptor activation resulted in a major reduction in dendritic eEF2 phosphorylation levels. D1-dependent eEF2 dephosphorylation results in an increase of BDNF and synapsin2b expression which was followed by a small yet significant increase in general protein synthesis. These results reveal the role of dopamine D1 receptor in the regulation of eEF2 pathway translation in neurons and present eEF2 as a promising therapeutic target for addiction and depression as well as other psychiatric disorders.

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The KN-93 Molecule Inhibits Calcium/Calmodulin-Dependent Protein Kinase II (CaMKII) Activity by Binding to Ca2+/CaM

Cited by 82 publications

References 73 publications

Regulatory mechanism of calcium/calmodulin‑dependent protein kinase II in the occurrence and development of ventricular arrhythmia (Review)

Regulatory mechanism of calcium/calmodulin‑dependent protein kinase II in the occurrence and development of ventricular arrhythmia (Review)

An Overview of the Role of Calcium/Calmodulin-Dependent Protein Kinase in Cardiorenal Syndrome

D1 Dopamine Receptor Activation Induces Neuronal eEF2 Pathway-Dependent Protein Synthesis

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