Inducible NO synthase II and neuronal NO synthase I are constitutively expressed in different structures of guinea pig skeletal muscle: implications for contractile function

Gath, Ingolf; Closs, Ellen I.; Gödtel-Armbrust, Ute; Schmitt, Sandra; Nakane, Masaki; Wessler, Ignaz; Förstermann, Ulrich

doi:10.1096/fasebj.10.14.9002553

Cited by 127 publications

(127 citation statements)

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“…35 In skeletal muscle, iNOS was found mostly in a particulate fraction. 33 None of these studies, however, associated the increase of particulate iNOS with any effect on other cellular proteins.…”

Section: Discussionmentioning

confidence: 94%

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Peroxisomal localization of inducible nitric oxide synthase in hepatocytes

et al. 2002

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Shock states induce the expression of inducible nitric oxide synthase (iNOS) in both Kupffer cells and hepatocytes in the liver, but little is known about its subcellular localization in these cells. Studies were undertaken to characterize the subcellular location of iNOS in hepatocytes in response to sepsis. By immunofluorescence analysis, intraperitoneal challenge with bacterial lipopolysaccharide induced cytosolic iNOS in Kupffer cells but punctate labeling in hepatocytes. Cultured rat hepatocytes exposed to interferon gamma, interleukin 1, and tumor necrosis factor ␣ showed iNOS protein expression within peroxisomes as early as 4 hours after stimulation, as determined by colabeling for catalase or PMP70. To a lesser extent, iNOS was also observed associated with the plasma membrane and in undefined intracellular aggregates. S tudies in the past decade have shown that all nitric oxide synthases (NOS), whether constitutive or inducible, are regulated at transcriptional, posttranscriptional, translational, and posttranslational levels. 1 One important aspect of NOS regulation is its subcellular localization. For example, endothelial NOS is localized to the caveolae of endothelial cells, where direct association with caveolin I regulates enzyme activity. 2 Such localization may enhance NO function by concentrating NO release close to the cell surface. The inducible NOS (iNOS; NOS2) isoform, which contributes to inflammatory processes through high NO output, is regulated positively and negatively by cytokines but can also be controlled posttranslationally by NO and/or its reaction products. 1,3,4 Furthermore, this enzyme is found in both particulate and cytosolic cellular pools. 5 Our interest has focused on the regulation and function of iNOS in the liver. This enzyme is readily upregulated in hepatocytes, 6 and human iNOS expression was first detected in hepatocytes. 7 In vivo studies have shown that the consequences of iNOS up-regulation in liver are dependent on the physiologic or pathologic circumstances. Following conditions associated with severe redox stress, iNOS contributes to hepatocellular damage during hemorrhagic shock or hepatic ischemia/reperfusion. 8,9 In contrast, iNOS-generated NO suppresses hepatocyte apoptosis in endotoxemia 10 and following cytokine exposure. 11 To better understand how iNOS functions within hepatocytes as well as factors that might determine the fate of NO in the liver, we undertook a study to characterize its subcellular localization. We show that iNOS localizes to the peroxisome, plasma membrane, and cytoplasm. Interestingly, increased expression of iNOS is associated with decreased catalase expression.

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Section: Discussionmentioning

confidence: 94%

“…32 Furthermore, nNOS was found predominantly in a particulate fraction in skeletal muscle. 33 Likewise, iNOS also exists in a particulate pool. Previous studies have shown a membranous subcellular location for as much as 50% of total cellular iNOS, 5 and a recent study showed that an iNOS-like enzyme is present in mitochondria.…”

Section: Discussionmentioning

confidence: 99%

Peroxisomal localization of inducible nitric oxide synthase in hepatocytes

et al. 2002

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“…A 5-HT 2B -dependent transcriptional regulation of iNOS activity can be excluded because the steady state level of iNOS transcripts is found constant during the cell response. Therefore the possibility that, upon DOI-mediated induction, iNOS is turned on from an inactive state by post-translational controls only, has to be considered (44,45).…”

Section: Figmentioning

confidence: 99%

PDZ-dependent Activation of Nitric-oxide Synthases by the Serotonin 2B Receptor

Manivet

Mouillet-Richard

Crinon

et al. 2000

Journal of Biological Chemistry

115

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Taking advantage of three cellular systems, we established that 5-HT 2B receptors are coupled with NO signaling pathways. In the 1C11 serotonergic cell line and Mastomys natalensis carcinoid cells, which naturally express the 5-HT 2B receptor, as well as in transfected LMTK ؊ fibroblasts, stimulation of the 5-HT 2B receptor triggers intracellular cGMP production through dual activation of constitutive nitric-oxide synthase (cNOS) and inducible NOS (iNOS). The group I PDZ motif at the C terminus of the 5-HT 2B receptor is required for recruitment of the cNOS and iNOS transduction pathways. Indeed, the 5-HT 2B receptor-mediated NO coupling is abolished not only upon introduction of a competitor C-terminal 5-HT 2B peptide in the three cell types but also in LMTK ؊ fibroblasts expressing a receptor C-terminally truncated or harboring a point mutation within the PDZ domain. The occurrence of a direct functional coupling between the receptor and cNOS activity is supported by highly significant correlations between the binding constants of drugs on the receptor and their effects on cNOS activity. The 5-HT 2B /iNOS coupling mechanisms appear more complex because neutralization of endogenous G␣ 13 by specific antibodies cancels the cellular iNOS response while not interfering with cNOS activities. These findings may shed light on physiological links between the 5-HT 2B receptor and NO and constitute the first demonstration that PDZ interactions participate in downstream transductional pathways of a G protein-coupled receptor.The monoamine serotonin (5-hydroxytryptamine; 5-HT) 1 modulates a wide variety of human behavioral and physiological processes, such as sleep, anxiety, and cognition, as well as memory, perception, cardiovascular function, smooth muscle response, and gastrointestinal contraction (1, 2). So far, the diversity of 5-HT receptors and the lack of specific pharmacological tools have impaired the investigation of the precise roles of these proteins in the signaling networks that mediate 5-HT physiological functions. This is particularly true in the case of the 5-HT 2B receptor, which, like all the 15 known mammalian 5-HT receptor subtypes but one (5-HT 3 ), belongs to the G protein-coupled receptors (GPCRs). 5-HT 2B receptors cDNA were cloned from the rat stomach fundus, mouse brain, human liver, and neuroblastoma cell lines (see Ref. 3 for review). The 5-HT 2B receptor could be expressed either by transfection or endogeneously during the serotonergic neuronal differentiation of 1C11 cells, referred to as 1C11* /5HT cells (4, 5). In both cases, the receptor couples with PIP 2 hydrolysis, similarly to the two other members (5-HT 2A and 5-HT 2C ) of the 5-HT 2 receptor family. In contrast, the 5-HT 2B receptor stimulation fails to stimulate PIP 2 hydrolysis in rat fundus (6) and in rat vasculature (7). Signaling processes involving 5-HT 2B receptors and distinct from PIP 2 hydrolysis might thus occur. Accordingly, 5-HT 2B -dependent activations of both the ras-mitogen-activated protein kinase cascade (8) and ...

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“…27 There are 3 types of NOS: neuronal (nNOS/NOS1), endothelial (eNOS/NOS3), and inducible (iNOS/NOS2). 2 Neuronal NOS is mainly expressed in neurons of the central 31 and peripheral nervous systems, but can also be found in other cells such as skeletal muscle myocytes, 10 lung epithelial cells, 3 and skin mast cells. 36 Endothelial NOS is mainly expressed by endothelial cells and can be found in neurons, 7 dermal fibroblasts, 40 epidermal keratinocytes, 36 thyroid follicular cells, 5 hepatocytes, and smooth muscle cells.…”

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confidence: 99%

The relationships between endothelial nitric oxide synthase polymorphisms and the formation of intracranial aneurysms in the Korean population

Kim

Baek

et al. 2011

FOC

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Object Some genetic factors are known to be associated with the formation of cerebral aneurysms in the Caucasian population. One of these factors is endothelial nitric oxide synthase (eNOS) gene polymorphisms. Endothelial nitric oxide synthase genes encode eNOS, which synthesizes NO from l-arginine. There continues to be controversy about the relationships between eNOS gene polymorphisms and the formation of intracranial aneurysms. In this study, the authors evaluated these relationships in the Korean population. Methods Three eNOS polymorphisms (eNOS 27VNTR, T786C, and G894T) were genotyped in 96 patients with ruptured aneurysms, 53 patients with unruptured aneurysms, and in 121 volunteers via polymerase chain reaction–restriction fragment length polymorphism analysis. Results The mean ages of the patients and healthy volunteers were 52.9 ± 12.3 years and 55.2 ± 9.1 years, respectively. The patient group was composed of 56 men and 93 women, and the healthy volunteer group was composed of 46 men and 75 women. Only the incidence of smoking history was significantly higher in the patient group than in the control group (p = 0.001). The genotypic frequencies for the 3 eNOS gene polymorphisms were in agreement with those predicted by Hardy-Weinberg equilibrium. There were no significant associations between the eNOS recessive models and the formation of an aneurysm. The authors found no genotypic differences between similar races among patients with aneurysms. Conclusions The present study shows that eNOS 27VNTR, T786C, and G894T polymorphisms cannot be used as indicators of the formation of intracranial aneurysms in Korean patients. To confirm these findings an additional analyses might need to be performed using a larger sample size. There were no differences in the genotypic distributions and allelic frequencies between similar races among patients with aneurysms, which were the same in previously reported normal populations.

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Inducible NO synthase II and neuronal NO synthase I are constitutively expressed in different structures of guinea pig skeletal muscle: implications for contractile function

Cited by 127 publications

References 5 publications

Peroxisomal localization of inducible nitric oxide synthase in hepatocytes

Peroxisomal localization of inducible nitric oxide synthase in hepatocytes

PDZ-dependent Activation of Nitric-oxide Synthases by the Serotonin 2B Receptor

The relationships between endothelial nitric oxide synthase polymorphisms and the formation of intracranial aneurysms in the Korean population

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