A Novel Ca2+/Calmodulin-Dependent Protein Kinase Lacking Autophosphorylation Activity in the Rabbit Heart

Uemura, Arata; Okazaki, Katsuo; Takesue, Hisashi; Hidaka, Hiroyoshi

doi:10.1006/bbrc.1995.1850

Cited by 5 publications

(2 citation statements)

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“…1,2 CaMKII was initially identified in the nervous system, but is found in most tissues, including heart. 3,4 CaMKII␦ is the predominant isoform in heart. 3,5 CaMKII phosphorylates several Ca 2ϩ transport proteins, including ryanodine receptors (RyRs) 6,7 and phospholamban (PLB).…”

Section: Abstract-camentioning

confidence: 99%

Transgenic CaMKIIδ _C Overexpression Uniquely Alters Cardiac Myocyte Ca ²⁺ Handling

Maier

Zhang

Chen

et al. 2003

Circulation Research

406

230

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Abstract-Ca2ϩ /calmodulin-dependent protein kinase II (CaMKII) ␦ is the predominant cardiac isoform, and the ␦ C splice variant is cytoplasmic. We overexpressed CaMKII␦ C in mouse heart and observed dilated heart failure and altered myocyte Ca 2ϩ regulation in 3-month-old CaMKII␦ C transgenic mice (TG) versus wild-type littermates (WT). Heart/body weight ratio and cardiomyocyte size were increased about 2-fold in TG versus WT. At 1 Hz, twitch shortening, [Ca 2ϩ ] i transient amplitude, and diastolic [Ca 2ϩ ] i were all reduced by Ϸ50% in TG versus WT. This is explained by Ͼ50% reduction in SR Ca 2ϩ content in TG versus WT. Peak Ca 2ϩ current (I Ca ) was slightly increased, and action potential duration was prolonged in TG versus WT. CaMKII was initially identified in the nervous system, but is found in most tissues, including heart. 3,4 CaMKII␦ is the predominant isoform in heart. 3,5 CaMKII phosphorylates several Ca 2ϩ transport proteins, including ryanodine receptors (RyRs) 6,7 and phospholamban (PLB). 8,9 CaMKII is involved in L-type Ca 2ϩ current (I Ca ) facilitation 10,11 and frequency-dependent acceleration of relaxation (FDAR; which depends on SR Ca 2ϩ uptake). 12-16 Ramirez et al 17 found that the nuclear CaMKII isoform (␦ B ) caused transcriptional activation and expression of atrial natriuretic peptide (ANF, a hypertrophic signaling marker) in neonatal rat ventricular myocytes. Transgenic overexpression of CaMKII␦ B or expression of CaMKIV (also nuclear) induces cardiac hypertrophy. 18,19 However, in vivo expression of cytoplasmic CaMKII (␦ C ) has not been examined.In human heart failure (HF), CaMK activity is increased 2-to 3-fold, which could be compensatory because it correlated positively with cardiac index and ejection fraction in patients. 20,21 Because phosphatase activity is also enhanced in human HF, 22 the net phosphorylation state of individual targets is unclear. For example, whereas many protein kinase A (PKA) targets are relatively dephosphorylated in HF, RyRs can be hyperphosphorylated due to reduced local phosphatase bound to RyRs. 23 To investigate CaMKII␦ effects on cellular Ca 2ϩ regulation, we overexpressed cytoplasmic CaMKII␦ C in mouse heart. 24 The transgenic line studied here exhibits 3-fold increase in CaMKII activity, profound dilated hypertrophy, and ventricular dysfunction. 24 Materials and Methods Generating CaMKII␦ C Transgenic Mice and Myocyte IsolationTransgenic mice were generated as in Zhang et al. 24 In the present study, Ca 2ϩ handling was assessed using (unless noted) 3-month-old CaMKII␦ C TG mice (nϭ8) exhibiting a 3-fold increase in CaMKII activity (TGM line 24 ), and age-matched WT littermates (nϭ8). Ventricular myocytes were isolated as reported 14 ] i-rest was used. Results were comparable among indo-1, fluo-3, and fluo-4, so results were pooled. Ca 2ϩ sparks were characterized by an algorithm (IDL 5.3) 29 using a threshold of 3.8ϫSD with human verification. We measured Ca 2ϩ spark peak (F/F 0 ), duration (full-duration-half-maximum, FDHM), width, or spa...

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Section: Abstract-camentioning

confidence: 99%

Transgenic CaMKIIδ _C Overexpression Uniquely Alters Cardiac Myocyte Ca ²⁺ Handling

Maier

Zhang

Chen

et al. 2003

Circulation Research

406

230

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“…CaMK II can phosphorylate and alter the function of many substrates [65,66] . CaMK II, the predominant isoform in the heart [67,68] and initially identified in the nervous system, is found in most tissues [67,69] . Our study demonstrated that GSSG could activate the CaM kinase II in rat ventricular myocytes.…”

Section: Discussionmentioning

confidence: 99%

Modulation of KATP currents in rat ventricular myocytes by hypoxia and a redox reaction

Yan

Zhang

2009

Acta Pharmacol Sin

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Aim: The present study investigated the possible regulatory mechanisms of redox agents and hypoxia on the K ATP current (I KATP ) in acutely isolated rat ventricular myocytes. Methods: Single-channel and whole-cell patch-clamp techniques were used to record the K ATP current (I KATP ) in acutely isolated rat ventricular myocytes. Results: Oxidized glutathione (GSSG, 1 mmol/L) increased the I KATP , while reduced glutathione (GSH, 1 mmol/L) could reverse the increased I KATP during normoxia. To further corroborate the effect of the redox agent on the K ATP channel, we employed the redox couple DTT (1 mmol/L)/H 2 O 2 (0.3, 0.6, and 1 mmol/L) and repeated the previous processes, which produced results similar to the previous redox couple GSH/GSSG during normoxia. H 2 O 2 increased the I KATP in a concentration dependent manner, which was reversed by DTT (1 mmol/L). In addition, our results have shown that 15 min of hypoxia increased the I KATP , while GSH (1 mmol/L) could reverse the increased I KATP . Furthermore, in order to study the signaling pathways of the I KATP augmented by hypoxia and the redox agent, we applied a protein kinase C(PKC) inhibitor bisindolylmaleimide VI (BIM), a protein kinase G(PKG) inhibitor KT5823, a protein kinase A (PKA) inhibitor H-89, and Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) inhibitors KN-62 and KN-93. The results indicated that BIM, KT5823, KN-62, and KN-93, but not H-89, inhibited the I KATP augmented by hypoxia and GSSG; in addition, these results suggest that the effects of both GSSG and hypoxia on K ATP channels involve the activation of the PKC, PKG, and CaMK II pathways, but not the PKA pathway. Conclusion: The present study provides electrophysiological evidence that hypoxia and the oxidizing reaction are closely related to the modulation of I KATP .

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Calcium, Calmodulin, and Calcium-Calmodulin Kinase II: Heartbeat to Heartbeat and Beyond

Maier¹,

Bers²

2002

Journal of Molecular and Cellular Cardiology

248

244

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A Novel Ca2+/Calmodulin-Dependent Protein Kinase Lacking Autophosphorylation Activity in the Rabbit Heart

Cited by 5 publications

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Transgenic CaMKIIδ _C Overexpression Uniquely Alters Cardiac Myocyte Ca ²⁺ Handling

Transgenic CaMKIIδ _C Overexpression Uniquely Alters Cardiac Myocyte Ca ²⁺ Handling

Modulation of KATP currents in rat ventricular myocytes by hypoxia and a redox reaction

Calcium, Calmodulin, and Calcium-Calmodulin Kinase II: Heartbeat to Heartbeat and Beyond

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A Novel Ca2+/Calmodulin-Dependent Protein Kinase Lacking Autophosphorylation Activity in the Rabbit Heart

Cited by 5 publications

References 0 publications

Transgenic CaMKIIδ C Overexpression Uniquely Alters Cardiac Myocyte Ca 2+ Handling

Transgenic CaMKIIδ C Overexpression Uniquely Alters Cardiac Myocyte Ca 2+ Handling

Modulation of KATP currents in rat ventricular myocytes by hypoxia and a redox reaction

Calcium, Calmodulin, and Calcium-Calmodulin Kinase II: Heartbeat to Heartbeat and Beyond

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Transgenic CaMKIIδ _C Overexpression Uniquely Alters Cardiac Myocyte Ca ²⁺ Handling

Transgenic CaMKIIδ _C Overexpression Uniquely Alters Cardiac Myocyte Ca ²⁺ Handling