scholarly journals Inhibition of Neuronal Nitric-oxide Synthase by Calcium/ Calmodulin-dependent Protein Kinase IIα through Ser847 Phosphorylation in NG108-15 Neuronal Cells

2000 ◽  
Vol 275 (36) ◽  
pp. 28139-28143 ◽  
Author(s):  
Keiichi Komeima ◽  
Yuji Hayashi ◽  
Yasuhito Naito ◽  
Yasuo Watanabe
Keyword(s):  
Nitric Oxide ◽  
Protein Kinase ◽  
Nitric Oxide Synthase ◽  
Neuronal Cells ◽  
Neuronal Nitric Oxide Synthase ◽  
Dependent Protein Kinase ◽  
Calcium Calmodulin Dependent ◽  
Dependent Protein ◽  
Oxide Synthase

scholarly journals Neuronal Nitric Oxide Synthase and Calmodulin-Dependent Protein Kinase IIα Undergo Neurotoxin-Induced Proteolysis

2002 ◽  
Vol 69 (3) ◽  
pp. 1006-1013 ◽  
Author(s):  
Iradj Hajimohammadreza ◽  
Kadee J. Raser ◽  
Rathna Nath ◽  
Ravi Nadimpalli ◽  
Michele Scott ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Protein Kinase ◽  
Nitric Oxide Synthase ◽  
Neuronal Nitric Oxide Synthase ◽  
Dependent Protein Kinase ◽  
Dependent Protein ◽  
Oxide Synthase

Abstract P076: Essential Role of Neuronal Nitric Oxide Synthase in Ca 2+ /Calmodulin-Dependent Protein Kinase II Activation in Cardiac Myocytes During β-Adrenergic Stimulation

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Lifei Tang ◽  
Steve Roof ◽  
Mark Ziolo
Keyword(s):  
Nitric Oxide ◽  
Protein Kinase ◽  
Nitric Oxide Synthase ◽  
Neuronal Nitric Oxide Synthase ◽  
Dependent Protein Kinase ◽  
Positive Inotropy ◽  
Cell Shortening ◽  
Protein Kinase Ii ◽  
Dependent Protein ◽  
Oxide Synthase

RATIONALE: Stimulation of the beta-adrenergic (beta-AR) pathway leads to positive inotropy, and is the major regulator of heart function. In addition to the traditional PKA pathway, activation of Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) and neuronal nitric oxide synthase (NOS1) signaling also play important roles in the positive inotropy by modulating ryanodine receptor (RyR) activity. OBJECTIVE: The upstream activators of CaMKII during beta-AR stimulation are not well defined. The purpose of this study is to investigate if there is any cross-talk between the CaMKII and NOS1 signaling pathways. METHODS AND RESULTS: Myocytes were isolated from wildtype (WT, C57Bl/6) and NOS1 −/− mice. Ca 2+ transients (Fluo-4) and cell shortening (edge detection) were simultaneously measured. RyR activity was measured using the SR Ca 2+ leak/load relationship. CaMKII was acutely inhibited by KN93. In WT myocytes, KN93 decreased beta-AR stimulated contraction (Ca2+ transients (Fluo-4) and cell shortening). In NOS1 −/− myocytes, beta-AR stimulated contraction was blunted compared to WT, and KN93 had no further effect on contraction. Furthermore, beta-AR stimulated RyR activity was blunted in NOS1 −/− compared to WT myocytes. As with contraction, KN93 decreased beta-AR stimulated RyR activity in WT myocytes, but had no effect in NOS1 −/− myocytes. CONCLUSION: These data suggest that NOS1 is required for CaMKII-mediated RyR activation which contributes to positive inotropy during beta-AR stimulation. Further study of this pathway is warranted since CAMKII expression and activity are increased in cardiac hypertrophy and heart failure. A better understanding of the NOS1/CaMKII pathway during beta-AR stimulation has beneficial therapeutic potential for heart diseases.

scholarly journals Post-synaptic density-95 promotes calcium/calmodulin-dependent protein kinase II-mediated Ser847 phosphorylation of neuronal nitric oxide synthase

2003 ◽  
Vol 372 (2) ◽  
pp. 465-471 ◽  
Author(s):  
Yasuo WATANABE ◽  
Tao SONG ◽  
Katsuyoshi SUGIMOTO ◽  
Mariko HORII ◽  
Nobukazu ARAKI ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Protein Kinase ◽  
Nitric Oxide Synthase ◽  
Neuronal Nitric Oxide Synthase ◽  
Dependent Protein Kinase ◽  
Synaptic Density ◽  
Transfected Cells ◽  
Dependent Protein ◽  
Oxide Synthase ◽  
Post Synaptic Density

Post-synaptic density-95 (PSD-95) is a neuronal scaffolding protein that associates with N-methyl-d-aspartate (NMDA) receptors and links them to intracellular signalling molecules. In neurons, neuronal nitric oxide synthase (nNOS) binds selectively to the second PDZ domain (PDZ2) of PSD-95, thereby exhibiting physiological activation triggered via NMDA receptors. We have demonstrated previously that Ca2+/calmodulin-dependent protein kinase IIα (CaM-K IIα) directly phosphorylates nNOS at residue Ser847, and can attenuate the catalytic activity of the enzyme in neuronal cells [Komeima, Hayashi, Naito and Watanabe (2000) J. Biol. Chem. 275, 28139–28143]. In the present study, we examined how CaM-K II participates in the phosphorylation by analysing the functional interaction between nNOS and PSD-95 in cells. The results showed that PSD-95 directly promotes the nNOS phosphorylation at Ser847 induced by endogenous CaM-K II. In transfected cells, this effect of PSD-95 required its dual palmitoylation and the PDZ2 domain, but did not rely on its guanylate kinase domain. CaM-K Iα and CaM-K IV failed to phosphorylate nNOS at Ser847 in transfected cells. Thus PSD-95 mediates cellular trafficking of nNOS, and may be required for the efficient phosphorylation of nNOS at Ser847 by CaM-K II in neuronal cells.

scholarly journals Coordination between Calcium/Calmodulin-Dependent Protein Kinase II and Neuronal Nitric Oxide Synthase in Neurons

2020 ◽  
Vol 21 (21) ◽  
pp. 7997
Author(s):  
Shoma Araki ◽  
Koji Osuka ◽  
Tsuyoshi Takata ◽  
Yukihiro Tsuchiya ◽  
Yasuo Watanabe
Keyword(s):  
Nitric Oxide ◽  
Protein Kinase ◽  
Cell Injury ◽  
Dependent Protein Kinase ◽  
Calcium Calmodulin Dependent ◽  
Pathophysiological Role ◽  
Protein Kinase Ii ◽  
Mutual Regulation ◽  
Dependent Protein ◽  
Oxide Synthase

Ca2+/calmodulin (CaM)-dependent protein kinase II (CaMKII) is highly abundant in the brain and exhibits broad substrate specificity, thereby it is thought to participate in the regulation of neuronal death and survival. Nitric oxide (NO), produced by neuronal NO synthase (nNOS), is an important neurotransmitter and plays a role in neuronal activity including learning and memory processes. However, high levels of NO can contribute to excitotoxicity following a stroke and neurodegenerative disease. Aside from NO, nNOS also generates superoxide which is involved in both cell injury and signaling. CaMKII is known to activate and translocate from the cytoplasm to the post-synaptic density in response to neuronal activation where nNOS is predominantly located. Phosphorylation of nNOS at Ser847 by CaMKII decreases NO generation and increases superoxide generation. Conversely, NO-induced S-nitrosylation of CaMKII at Cys6 is a prominent determinant of the CaMKII inhibition in ATP competitive fashion. Thus, the “cross-talk” between CaMKII and NO/superoxide may represent important signal transduction pathways in brain. In this review, we introduce the molecular mechanism of and pathophysiological role of mutual regulation between CaMKII and nNOS in neurons.

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