Functional processing of nuclear Ca2+/calmodulin-dependent protein kinase phosphatase (CaMKP-N): Evidence for a critical role of proteolytic processing in the regulation of its catalytic activity, subcellular localization and substrate targeting in vivo

2012 ◽  
Vol 517 (1) ◽  
pp. 43-52 ◽  
Author(s):  
Noriyuki Sueyoshi ◽  
Takaki Nimura ◽  
Takashi Onouchi ◽  
Hiromi Baba ◽  
Shinobu Takenaka ◽  
...  
Keyword(s):  
Catalytic Activity ◽  
Protein Kinase ◽  
Subcellular Localization ◽  
Critical Role ◽  
Proteolytic Processing ◽  
Dependent Protein Kinase ◽  
Dependent Protein

scholarly journals Ablation of 3-Phosphoinositide-Dependent Protein Kinase 1 (PDK1) in Vascular Endothelial Cells Enhances Insulin Sensitivity by Reducing Visceral Fat and Suppressing Angiogenesis

2012 ◽  
Vol 26 (1) ◽  
pp. 95-109 ◽  
Author(s):  
Kazuhito Tawaramoto ◽  
Ko Kotani ◽  
Mitsuru Hashiramoto ◽  
Yukiko Kanda ◽  
Tomoki Nagare ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Insulin Sensitivity ◽  
Protein Kinase ◽  
Vascular Endothelial Cells ◽  
Whole Body ◽  
Vascular Endothelial ◽  
Dependent Protein Kinase ◽  
Dependent Protein

Abstract The phosphatidylinositol 3-kinase signaling pathway in vascular endothelial cells is important for systemic angiogenesis and glucose metabolism. In this study, we addressed the precise role of the 3-phosphoinositide-dependent protein kinase 1 (PDK1)-regulated signaling network in endothelial cells in vivo, using vascular endothelial PDK1 knockout (VEPDK1KO) mice. Surprisingly, VEPDK1KO mice manifested enhanced glucose tolerance and whole-body insulin sensitivity due to suppression of their hepatic glucose production with no change in either peripheral glucose disposal or even impaired vascular endothelial function at 6 months of age. When mice were fed a standard diet at 6 months of age and a high-fat diet at 3 months of age, hypertrophy of epididymal adipose tissues was inhibited, adiponectin mRNA was significantly increased, and mRNA of MCP1, leptin, and TNFα was decreased in the white adipose tissue of VEPDK1KO mice in comparison with controls. Consequently, both the circulating adiponectin levels and the activity of hepatic AMP-activated protein kinase were significantly increased, subsequently enhancing whole-body insulin sensitivity and energy expenditure with increased hepatic fatty acid oxidation in VEPDK1KO mice. These results provide the first in vivo evidence that lowered angiogenesis through the deletion of PDK1 signaling not only interferes with the growth of adipose tissue but also induces increased energy expenditure due to amelioration of the adipocytokine profile. This demonstrates an unexpected role of PDK1 signaling in endothelial cells on the maintenance of proper glucose homeostasis through the regulation of adipocyte development.

scholarly journals In Vivo Selection of Kinase-responsive RNA Elements Controlling Alternative Splicing

2009 ◽  
Vol 284 (24) ◽  
pp. 16191-16201 ◽  
Author(s):  
Hongzhao Li ◽  
Guodong Liu ◽  
Jiankun Yu ◽  
Wenguang Cao ◽  
Vincent G. Lobo ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Protein Kinase ◽  
Cultured Cells ◽  
Feedback Regulation ◽  
Dependent Protein Kinase ◽  
Dependent Protein ◽  
Rna Elements ◽  
Cell Signals

Alternative pre-mRNA splicing is often controlled by cell signals, for example, those activating the cAMP-dependent protein kinase (PKA) or the Ca2+/calmodulin-dependent protein kinase IV (CaMKIV). We have shown that CaMKIV regulates alternative splicing through short CA repeats and hnRNP L. Here we use a splicing reporter that shows PKA/CaMKIV promotion of exon inclusion to select from exons containing random 13-nt sequences for RNA elements responsive to the kinases in cultured cells. This selection not only identified both PKA- and CaMKIV-responsive elements that are similar to the CaMKIV-responsive RNA element 1 (CaRRE1) or CA repeats, but also A-rich elements not previously known to respond to these kinases. Consistently, hnRNP L is identified as a factor binding the CA-rich elements. Analyses of the motifs in the highly responsive elements indicate that they are indeed critical for the kinase effect and are enriched in alternative exons. Interestingly, a CAAAAAA motif is sufficient for the PKA/CaMKIV-regulated splicing of the exon 16 of the CaMK kinase β1 (CaMKK2) transcripts, implying a role of this motif in signaling cross-talk or feedback regulation between these kinases through alternative splicing. Therefore, these experiments identified a group of RNA elements responsive to PKA and CaMKIV from in vivo selection. This also provides an approach for selecting RNA elements similarly responsive to other cell signals controlling alternative splicing.

Abstract 438: Downregulation of Ca 2+ /calmodulin-dependent Protein Kinase Type II Delta in the Heart by Antisense Oligonucleotides Mitigates Development of Post-infarct Ventricular Arrhythmias

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Ting-yuan T Yeh ◽  
Xin Yi Yeap ◽  
Adam E Mullick
Keyword(s):  
Protein Kinase ◽  
Antisense Oligonucleotides ◽  
Ventricular Arrhythmias ◽  
Cardiac Mechanics ◽  
Type Ii ◽  
Dependent Protein Kinase ◽  
Dependent Protein ◽  
To Receive

Pathological activation of Ca2+/calmodulin-dependent protein kinase type II delta (CaMK2d) has been implicated in the development of heart failure (HF) and arrhythmia. In preclinical models, inhibition or deletion of cardiac CaMK2d has shown a benefit to prevent HF progression or arrhythmia occurrence. We hypothesized that reduction of CaMK2d in the heart by antisense oligonucleotides (ASO) can mitigate the inducibility of MI-associated ventricular arrhythmias. Eight-week-old female C57BL6/N mice, which received permanent ligation of the left anterior descending coronary artery, were randomized to receive PBS, control ASO or two different mouse CaMK2d ASOs five days after the surgery. The ASOs were administered subcutaneously at 50 mg/kg weekly for four weeks. At the end of study, programmed electrical stimulation (PES) was performed to evaluate ventricular effective refractory period (VERP) and inducibility of ventricular arrhythmias (VA). PCR results showed 70% reduction of cardiac CaMK2d in the CaMK2d ASO groups and no changes of other CaMK2 isoforms. There is no significant change of VERP (VERP expressed as mean±SEM, PBS: 35.2±3.0 ms, control ASO: 36.2±3.8 ms, CaMK2d ASO1: 35.7±2.3 ms and CaMK2d ASO2: 33.8±1.4 ms) while the inducible arrhythmias by PES are declined after CaMK2d ASO treatment (VA inducibility index expressed as mean±SEM, PBS: 1.21±0.27, control ASO: 1.21±0.52, CaMK2d ASO1: 0.54±0.22, CaMK2d ASO2: 0.47±0.22). Echocardiography and invasive hemodynamic studies were unable to demonstrate significant functional improvements in the CaMK2d ASO treated groups, suggesting that the anti-arrhythmia effects of CaMK2d ASO treatment were not secondary to improved cardiac mechanics. In conclusion, ASO-mediated reduction of cardiac CaMK2d in a murine MI model ameliorates MI-associated ventricular arrhythmias, providing in vivo proof-of-concept support of the pathological role of CaMK2d activity in MI-related arrhythmia.

scholarly journals Studies of mice with cyclic AMP-dependent protein kinase (PKA) defects reveal the critical role of PKA’s catalytic subunits in anxiety

2016 ◽  
Vol 307 ◽  
pp. 1-10 ◽  
Author(s):  
George Briassoulis ◽  
Margaret F. Keil ◽  
Bilal Naved ◽  
Sophie Liu ◽  
Matthew F. Starost ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Cyclic Amp ◽  
Critical Role ◽  
Dependent Protein Kinase ◽  
Catalytic Subunits ◽  
Dependent Protein

Critical Role of cAMP-Dependent Protein Kinase Anchoring to the L-Type Calcium Channel Cav1.2 via A-Kinase Anchor Protein 150 in Neurons†

Biochemistry ◽  
2007 ◽  
Vol 46 (6) ◽  
pp. 1635-1646 ◽  
Author(s):  
Duane D. Hall ◽  
Monika A. Davare ◽  
Mei Shi ◽  
Margaret L. Allen ◽  
Michael Weisenhaus ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Calcium Channel ◽  
Critical Role ◽  
Dependent Protein Kinase ◽  
Anchor Protein ◽  
Camp Dependent Protein Kinase ◽  
Dependent Protein

Abstract 72: Ca 2+ and Calmodulin-Dependent Protein Kinase II Mediate a Temporal Switch Between Cardiotoxic and Cardioprotective Signaling by β2-Adrenergic Receptors

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Viswanathan Rajagopalan ◽  
Giovanni Fajardo ◽  
Mingming Zhao ◽  
Takashi Urashima ◽  
Daniel Bernstein
Keyword(s):  
Protein Kinase ◽  
Adrenergic Receptors ◽  
Time Course ◽  
Critical Role ◽  
Dependent Protein Kinase ◽  
Protein Kinase Ii ◽  
Adverse Remodeling ◽  
Dependent Protein ◽  
And Function

Background: ß-adrenergic receptors (AR) play a critical role in cardiac function but also mediate adverse remodeling associated with chronic sympathetic stimulation in heart failure. Some studies have suggested cardiotoxic signaling through ß1-AR and cardioprotective through ß2-AR. However, ß2-AR can signal through both Gs & Gi, partially dictated by the time course of activation. We sought to determine whether this temporal effect influenced the differential roles of ß1- & ß2-AR in the pathogenesis of cardiomyopathy. Methods: We compared two models of oxidative stress-induced cardiomyopathy: acute doxorubicin (AD) 15 mg/kg in a single dose vs. chronic doxorubicin (CD) 2 mg/kg/wk x 8 wks in WT, ß1-AR-/- & ß2-AR-/- mice. Endpoints were survival and cardiac size and function. Activation of AR signaling pathways was assessed by Western blot. Results: With AD, 100% of ß2-/- die within 20 min, an effect not seen in ß1-/- or WT. With CD, in contrast, ß2-/- were protected: WT survival t½ 42 d, 100% mortality 70 d, n=33; ß2-/- t½ 56 d, 100% mortality 109 d, n=44; ß1-/- t½ 54 d, 100% mortality 99 d, n=31 (log rank p<0.0001). Fractional shortening declined and LV diastolic dimension increased by 2 wks in WT (13.9±2.5, 10.3±2.2%) whereas both were preserved in ß2-/- (5.0±1.7, p<0.01; 4.8±1.5%) and ß1-/- (2±1.6, p<0.001; 0.8±1.8, p<0.01) at least until 4 wks. Total Ca2+ and calmodulin-dependent protein kinase II (CaMKII) was increased at baseline in both ß1-/- & ß2-/- vs. WT. However, in ß2-/-, CaMKII was decreased with AD (0.74±0.1; p<0.01), and increased with CD (1.3±0.05; p<0.01). Similarly, CaMKII phosphorylation was decreased with AD (1.27±0.16) vs. baseline (1.95±0.19) and increased with CD (2.35±0.18, p<0.001). With AD, p-p38 increased 20-fold in ß2-/-, but was normal in CD. In contrast, p-JNK was increased in CD in both ß2-/- (0.34±0.09) and ß1-/- vs. WT (0.1±0.04; p<0.001). Conclusion: The differential role of ß2-AR in mediating cardioprotection/cardiotoxicity are more complex than initially thought. ß2-AR signaling exhibits a temporal switch depending on whether a stress is acute (cardioprotective) vs. chronic (cardiotoxic). This switch is mediated by differential activation of CaMKII and JNK (mediating cardioprotection) and p38 (mediating cardiotoxicity).

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