Alternative splicing introduces a nuclear localization signal that targets multifunctional CaM kinase to the nucleus

Srinivasan, Mallika; Edman, C.F.; Schulman, Howard

doi:10.1016/0962-8924(94)90047-7

Cited by 17 publications

(22 citation statements)

References 13 publications

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“…We also used myocytes from InsP 3 R2 knock out mice (29) to show that CaMKII was not activated by ET-1 in the absence of InsP 3 R2 (28). We further demonstrated that CaMKII activation by localized InsP 3 dependent increases in Ca 2+ led to HDAC export from the nucleus whereas a more global increase in Ca 2+ did not (26). Class II HDACs including HDAC regulate activity of the transcription factor MEF2 thereby affecting hypertrophic gene expression (30;31).…”

Section: Involvement Of Camkii In Cardiac Hypertrophymentioning

confidence: 87%

“…We recently addressed the question of whether localized, rather than global increases in Ca 2+ induced by the Gq receptor coupled hypertrophic agonist ET-1 might lead to activation of CaMKII and elicit hypertrophic responses. This possibility was suggested by the observation that in cardiomyocytes, type 2 InsP 3 (InsP 3 R2) receptors are concentrated in the nucleus (25) and that a splice variant of the predominant cardiac CaMKII isoform, CaMKII δ B , contains a nuclear localization sequence which targets it to the nucleus (26;27). We determined in this study that CaMKII can be activated through an InsP 3 receptor dependent mechanism by demonstrating that either ET-1 or the InsP 3 receptor agonist adenophostin increased CaMKII autophosphorylation and that this response was attenuated by inhibition of InsP 3 receptor signaling using 2-APB (28).…”

Section: Involvement Of Camkii In Cardiac Hypertrophymentioning

confidence: 99%

“…Both CaMKII δ B and δ C TG mice were generated. The CaMKII δ B splice variant differs from δ C by the inclusion of a nuclear localization sequence (26). Immunohistochemical analysis indicated that CaMKII δ B was largely limited to the nucleus, while CaMKII δ C was primarily cytosolic (27;33;35).…”

Section: Role Of Camkii In In Vivo Hypertrophymentioning

confidence: 99%

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Cardiac Hypertrophy and Heart Failure Development Through Gq and CaM Kinase II Signaling

Mishra

Ling

Grimm

et al. 2010

Journal of Cardiovascular Pharmacology

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The molecular events associated with the development of pathological hypertrophy have been shown to be stimulated through G-protein coupled receptors (GPCRs) that activate Gq signaling pathways in neonatal cardiomyocytes and in transgenic (TG) and knockout (KO) mice. We demonstrated that CaMKII, a multifunctional Ca 2+ regulated protein kinase, was activated through GPCR and InsP 3 mediated Ca 2+ release and suggested that CaMKII was a downstream mediator of Gq -coupled hypertrophic signaling. This was supported by the demonstration of CaMKII activation by pressure overload (TAC) and induction of hypertrophy by transgenic (TG) CaMKII expression. CaMKII also phosphorylates Ca 2+ handling proteins including the ryanodine receptor (RyR2), phosphorylation of which markedly increases sarcoplasmic reticulum (SR) Ca 2+ leak. Increased RyR2 phosphorylation is associated with heart failure development in CaMKII TG mice, and mice genetically deleted for CaMKII (KO) have attenuated RyR2 phosphorylation, SR Ca 2+ leak and heart failure development following long term TAC. Genetic ablation of CaMKII also decreases development of heart failure in Gq TG mice, and decreases infarct size, while improving functional recovery in mice subject to ischemia/reperfusion and preventing adverse remodeling following coronary artery occlusion. The underlying mechanisms are currently under study.

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Section: Involvement Of Camkii In Cardiac Hypertrophymentioning

confidence: 87%

Section: Involvement Of Camkii In Cardiac Hypertrophymentioning

confidence: 99%

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Cardiac Hypertrophy and Heart Failure Development Through Gq and CaM Kinase II Signaling

Mishra

Ling

Grimm

et al. 2010

Journal of Cardiovascular Pharmacology

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“…Two primary splicing variants of the ␦ isoform, CaMKII ␦B and CaMKII ␦C , have been cloned from rat heart (2). Compared with CaMKII ␦C , CaMKII ␦B has an additional 11-amino acid sequence that contains a nuclear targeting signal (6). Thus, CaMKII ␦B and CaMKII ␦C localize to the nuclear and the cytosolic compartments, respectively, in cardiac myocytes (6).…”

Section: Ca 2ϩmentioning

confidence: 99%

Activation of CaMKIIδC Is a Common Intermediate of Diverse Death Stimuli-induced Heart Muscle Cell Apoptosis

Zhu

Woo

Yang

et al. 2007

Journal of Biological Chemistry

129

105

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Ca2؉ -calmodulin-dependent protein kinase II (CaMKII) is expressed in many mammalian cells, with the ␦ isoform predominantly expressed in cardiomyocytes. Previous studies have shown that inhibition of CaMKII protects cardiomyocytes against ␤ 1 -adrenergic receptor-mediated apoptosis. However, it is unclear whether activation of CaMKII is sufficient to cause cardiomyocyte apoptosis and whether CaMKII signaling is important in heart muscle cell apoptosis mediated by other stimuli. Here, we specifically enhanced or suppressed CaMKII activity using adenoviral gene transfer of constitutively active (CA-CaMKII ␦C ) or dominant negative (DN-CaMKII ␦C ) mutants of CaMKII ␦C in cultured adult rat cardiomyocytes. Expression of CA-CaMKII ␦C promoted cardiomyocyte apoptosis that was associated with increased mitochondrial cytochrome c release and attenuated by co-expression of Bcl-X L . Importantly, isoform-specific suppression of CaMKII ␦C with the DN-CaMKII ␦C mutant similar to nonselective CaMKII inhibition by the pharmacological inhibitors (KN-93 or AIP) not only prevented CA-CaMKII ␦C -mediated apoptosis but also protected cells from multiple death-inducing stimuli. Thus, activation of CaMKII ␦C constitutes a common intermediate by which various death-inducing stimuli trigger cardiomyocyte apoptosis via the primary mitochondrial death pathway. Ca 2ϩ

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“…Two primary splicing variants of the δ isoform, CaMKII-δB and CaMKII-δC, have been cloned from rat heart 1. The only difference between these isoforms is the additional 11-amino acids conferring a nuclear targeting signal of CaMKII-δB 5. As a result, CaMKII-δB and CaMKII-δC localize to the nucleus and the cytoplasm, respectively, although they share many common biochemical properties 5.…”

mentioning

confidence: 99%

Cardioprotection by CaMKII-δB Is Mediated by Phosphorylation of Heat Shock Factor 1 and Subsequent Expression of Inducible Heat Shock Protein 70

Peng

Zhang

Zheng

et al. 2010

Circulation Research

115

134

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Rationale: Ca 2؉ /calmodulin-dependent protein kinase (CaMK)II is a multifunctional kinase involved in vital cellular processes such as Ca 2؉ handling and cell fate regulation. In mammalian heart, 2 primary CaMKII isoforms, ␦B and ␦C, localize in nuclear and cytosolic compartments, respectively. Although previous studies have established an essential role of CaMKII-␦C in cardiomyocyte apoptosis, the functional role of the more abundant isoform, CaMKII-␦B, remains elusive. Objective: Here, we determined the potential role of CaMKII-␦B in regulating cardiomyocyte viability and explored the underlying mechanism. Methods and Results: In cultured neonatal rat cardiomyocytes, the expression of CaMKII-␦B and CaMKII-␦C was inversely regulated in response to H 2 O 2 -induced oxidative stress with a profound reduction of the former and an increase of the later. Similarly, in vivo ischemia/reperfusion (IR) led to an opposite regulation of these CaMKII isoforms in a rat myocardial IR model. Notably, overexpression of CaMKII-␦B protected cardiomyocytes against oxidative stress-, hypoxia-, and angiotensin II-induced apoptosis, whereas overexpression of its cytosolic counterpart promoted apoptosis. Using cDNA microarray, real-time PCR and Western blotting, we demonstrated that overexpression of CaMKII-␦B but not CaMKII-␦C elevated expression of heat shock protein (HSP)70 family members, including inducible (i)HSP70 and its homolog (Hst70). Moreover, overexpression of CaMKII-␦B led to phosphorylation and activation of heat shock factor (HSF)1, the primary transcription factor responsible for HSP70 gene regulation. Importantly, gene silencing of iHSP70, but not Hst70, abolished CaMKII-␦B-mediated protective effect, indicating that only iHSP70 was required for CaMKII-␦B elicited antiapoptotic signaling. Conclusions: We conclude that cardiac CaMKII-␦B and CaMKII-␦C were inversely regulated in response to oxidative stress and IR injury, and that in contrast to CaMKII-␦C, CaMKII-␦B serves as a potent suppressor of cardiomyocyte apoptosis triggered by multiple death-inducing stimuli via phosphorylation of HSF1 and subsequent induction of iHSP70, marking both CaMKII-␦ isoforms as promising therapeutic targets for the treatment of ischemic heart disease. (Circ Res. 2010;106:102-110.)Key Words: CaMKII isoforms Ⅲ CaMKII-␦B Ⅲ oxidative stress Ⅲ hypoxia Ⅲ cardiomyocyte apoptosis Ⅲ iHSP70 Ⅲ HSF1 C a 2ϩ /calmodulin-dependent protein kinase (CaMK)II is a ubiquitous and multifunctional serine/threonine protein kinase family, which consists of 30 distinct members encoded by 4 different genes (␣, ␤, ␦, and ␥). The ␦ isoform of CaMKII is predominantly expressed in the heart of many mammalian species, including rat, mouse and human. [1][2][3][4] Two primary splicing variants of the ␦ isoform, CaMKII-␦B and CaMKII-␦C, have been cloned from rat heart. 1 The only difference between these isoforms is the additional 11 amino acids, conferring a nuclear targeting signal of CaMKII-␦B. 5 As a result, CaMKII-␦B and CaMKII-␦C localize to the nucleus and ...

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Alternative splicing introduces a nuclear localization signal that targets multifunctional CaM kinase to the nucleus

Cited by 17 publications

References 13 publications

Cardiac Hypertrophy and Heart Failure Development Through Gq and CaM Kinase II Signaling

Cardiac Hypertrophy and Heart Failure Development Through Gq and CaM Kinase II Signaling

Activation of CaMKIIδC Is a Common Intermediate of Diverse Death Stimuli-induced Heart Muscle Cell Apoptosis

Cardioprotection by CaMKII-δB Is Mediated by Phosphorylation of Heat Shock Factor 1 and Subsequent Expression of Inducible Heat Shock Protein 70

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