Activity-Induced SUMOylation of Neuronal Nitric Oxide Synthase Is Associated with Plasticity of Synaptic Transmission and Extracellular Signal-Regulated Kinase 1/2 Signaling

2020 ◽  
Vol 32 (1) ◽  
pp. 18-34 ◽  
Author(s):  
Cai-Ping Du ◽  
Mei Wang ◽  
Chi Geng ◽  
Bin Hu ◽  
Li Meng ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Synaptic Transmission ◽  
Neuronal Nitric Oxide Synthase ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Oxide Synthase

scholarly journals Neuronal nitric oxide synthase-induced S-nitrosylation of H-Ras inhibits calcium ionophore-mediated extracellular-signal-regulated kinase activity

2006 ◽  
Vol 397 (2) ◽  
pp. 329-336 ◽  
Author(s):  
Kimberly W. Raines ◽  
Guan-Liang Cao ◽  
Eun Kyoung Lee ◽  
Gerald M. Rosen ◽  
Paul Shapiro
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Calcium Ionophore ◽  
Neuronal Nitric Oxide Synthase ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Exogenous Expression ◽  
Oxide Synthase ◽  
Constitutively Active

nNOS (neuronal nitric oxide synthase) is a constitutively expressed enzyme responsible for the production of NO• from L-arginine and O2. NO• acts as both an intra- and an inter-cellular messenger that mediates a variety of signalling pathways. Previous studies from our laboratory have demonstrated that nNOS production of NO• blocks Ca2+-ionophore-induced activation of ERK1/2 (extracellular-signal-regulated kinase 1/2) of the mitogen-activated protein kinases through a mechanism involving Ras G-proteins and Raf-1 kinase. Herein we describe a mechanism by which NO• blocks Ca2+-mediated ERK1/2 activity through direct modification of H-Ras. Ca2+-mediated ERK1/2 activation in NO•-producing cells could be restored by exogenous expression of constitutively active mitogen-activated protein kinase kinase 1. In contrast, exogenous expression of constitutively active mutants of Raf-1 and H-Ras only partially restored ERK1/2 activity, by 50% and 10% respectively. On the basis of these findings, we focused on NO•-mediated mechanisms of H-Ras inhibition. Assays for GTP loading and H-Ras interactions with the Ras-binding domain on Raf-1 demonstrated a decrease in H-Ras activity in the presence of NO•. We demonstrate that S-nitrosylation of H-Ras occurs in nNOS-expressing cells activated with Ca2+ ionophore. Mutation of a putative nitrosylation site at Cys118 inhibited S-nitrosylation and restored ERK1/2 activity by constitutively active H-Ras even in the presence of NO•. These findings indicate that intracellular generation of NO• by nNOS leads to S-nitrosylation of H-Ras, which interferes with Raf-1 activation and propagation of signalling through ERK1/2.

scholarly journals Cardiomyocyte overexpression of the α1a-adrenergic receptor in the rat phenocopies second but not first window preconditioning

2012 ◽  
Vol 302 (8) ◽  
pp. H1614-H1624 ◽  
Author(s):  
Xin Zhao ◽  
Jiyeon Park ◽  
David Ho ◽  
Shumin Gao ◽  
Lin Yan ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Heart Rate ◽  
Nitric Oxide Synthase ◽  
Adrenergic Receptor ◽  
Ischemia Reperfusion ◽  
Fold Increase ◽  
Area At Risk ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Oxide Synthase

We examined α1A-adrenergic receptor (AR) mediation of preconditioning in a novel α1A-AR cardiac transgenic (TG) rat model (α1A-TG). Compared with nontransgenic littermates (NTLs), in conscious α1A-TG rats, heart rate was reduced, contractility [left ventricle (LV) +dP/d t, ejection fraction, end-systolic elastance] was significantly enhanced, and triple product (LV systolic wall stress × LV +dP/d t × heart rate) was unchanged. However, infarct size (IS)/area at risk (AAR) in response to ischemia-reperfusion (30 min coronary occlusion/3 h reperfusion) was reduced to 35 ± 4.6% in α1A-TGs vs. 52 ± 2.2% in NTLs ( P < 0.05). Second window preconditioning reduced IS/AAR in NTLs to 29 ± 2.7% but did not afford further protection in α1A-TGs. In contrast, with first window preconditioning, IS/AAR was reduced to similar levels in both α1A-TGs (12 ± 1.4%) and NTLs (10 ± 1.1%). In untreated α1A-TGs, cardioprotection was associated with enhanced myocardial phosphorylated (p)-mitogen/extracellular signal-regulated kinase (MEK), p-extracellular signal-regulated kinase (ERK), and inducible nitric oxide synthase (iNOS) at the protein level, along with a 1.3-fold increase in total nitric oxide synthase activity like in second window preconditioning. Affymetrix microarrays revealed that few genes (4.6% of 3,172 upregulated; 8.8% of 3,498 downregulated) showed directionally similar changes in α1A-TGs vs. NTLs subjected to second window preconditioning. Thus, second, but not first, window cardioprotection is evident in α1A-TGs in the absence of ischemic preconditioning and is mediated by iNOS activation associated with MEK/ERK phosphorylation. Transcriptionally, however, second window preconditioning is considerably more complex than α1A-TG preconditioning, with the alteration of thousands of additional genes affording no further protection than that already available in α1A-TG rats.

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