Nitric oxide in excitable tissues: physiological roles and disease.

Christopherson, Karen S.; Bredt, David S.

doi:10.1172/jci119783

Cited by 275 publications

(163 citation statements)

References 62 publications

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“…This may allow more efficient modulation of eNOS activity via local changes in flow-induced shear stress and in calcium flux through the plasma membrane, and may also affect rates of NO production by placing eNOS in close apposition to arginine transporters in the plasma membrane [189]. Recent studies have shown that nNOS is primarily associated with the rough endoplasmic reticulum and postsynaptic membranes in brain and with the sarcolemma of skeletal muscle [284,285]. As in the case of eNOS, it is thought that the subcellular localization of nNOS near calcium channels permits highly precise regulation of its activity.…”

Section: Nosmentioning

confidence: 99%

Arginine metabolism: nitric oxide and beyond

Morris

1998

Biochemical Journal

2,424

2,036

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Arginine is one of the most versatile amino acids in animal cells, serving as a precursor for the synthesis not only of proteins but also of nitric oxide, urea, polyamines, proline, glutamate, creatine and agmatine. Of the enzymes that catalyse rate-controlling steps in arginine synthesis and catabolism, argininosuccinate synthase, the two arginase isoenzymes, the three nitric oxide synthase isoenzymes and arginine decarboxylase have been recognized in recent years as key factors in regulating newly identified aspects of arginine metabolism. In particular, changes in the activities of argininosuccinate synthase, the arginases, the inducible isoenzyme of nitric oxide synthase and also cationic amino acid transporters play major roles in determining the metabolic fates of arginine in health and disease, and recent studies have identified

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Section: Nosmentioning

confidence: 99%

Arginine metabolism: nitric oxide and beyond

Morris

1998

Biochemical Journal

2,424

2,036

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“…1 is a gaseous molecule that plays an important role in the central nervous system (1,2). It is produced by the enzyme neuronal nitric-oxide synthase (nNOS), which can be stimulated when glutamate receptors of the N-methyl-D-aspartate receptor family are activated, and calcium enters the neuron (2).…”

Section: Nitric Oxide (No)mentioning

confidence: 99%

Binding of Neuronal Nitric-oxide Synthase (nNOS) to Carboxyl-terminal-binding Protein (CtBP) Changes the Localization of CtBP from the Nucleus to the Cytosol

Riefler

Firestein

2001

Journal of Biological Chemistry

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Recent work suggests a role for PDZ domains in the targeting of binding partners to specific sites in the cell. To identify whether the PDZ domain of neuronal nitricoxide synthase (nNOS) can play such a role, we performed affinity chromatography of brain extract with the nNOS PDZ domain. We identified the carboxyl-terminal-binding protein (CtBP), a phosphoprotein first identified as a binding partner to adenovirus E1A, as a nNOS binding partner. CtBP interacts with the PDZ domain of nNOS, and this interaction can be competed with peptide that binds to the PDZ peptide-binding site. In addition, binding of CtBP to nNOS is dependent on its carboxyl-terminal sequence -DXL, residues conserved between species that fit the canonical sequence for nNOS PDZ binding. Immunoprecipitation studies show that CtBP and nNOS associate in the brain. When CtBP is expressed in Madin-Darby canine kidney cells, its distribution is primarily nuclear; however, when CtBP is co-expressed with nNOS, its localization becomes more cytosolic. This change in CtBP localization does not occur when its carboxyl-terminal nNOS PDZ binding motif is mutated or when CtBP is co-expressed with postsynaptic density 95, another PDZ domain-containing protein. Taken together, our data suggest a new function for nNOS as a regulator of CtBP nuclear localization. Nitric oxide (NO)1 is a gaseous molecule that plays an important role in the central nervous system (1, 2). It is produced by the enzyme neuronal nitric-oxide synthase (nNOS), which can be stimulated when glutamate receptors of the N-methyl-D-aspartate receptor family are activated, and calcium enters the neuron (2). Calcium binds to calmodulin, and the complex then activates nNOS. Furthermore, the NO produced can increase the production of 3Ј,5Ј-cyclic guanosine monophosphate levels, which can activate other enzymes including protein kinases (3, 4). Recent evidence supports a role for NO in synaptic plasticity (5), long-term potentiation (6), and aspects of learning and memory (7).nNOS contains a PDZ (PSD-95, discs-large and zona occludens-1) domain, a consensus sequence of approximately 90 amino acids that has been shown to mediate protein-protein interactions (8). In neurons, nNOS is targeted to synaptic sites via its interaction with the PDZ domains of PSD-95 and PSD-93 (9). In fact, PSD-95 also interacts with N-methyl-Daspartate receptors via one of its PDZ domains. Through its concurrent interaction with nNOS, PSD-95 serves as a physical tether to allow nNOS signaling by N-methyl-D-aspartate receptor activity (10, 11). By abolishing expression of PSD-95 protein either by knockout technology in mice or by antisense technology in tissue culture, it has been shown that the presence of PSD-95 is essential for NO production by glutamate stimulation (12, 13). Thus, the PDZ domain of nNOS plays an important role in helping to localize nNOS to appropriate sites in the neuron.Subcellular fractionation shows that roughly half of nNOS is soluble, and half is particulate (14). As such, binding partners of t...

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“…1 In contrast to the restricted endothelial cell-specific expression of the endothelial NOS (eNOS), 2 the nNOS isoform is constitutively expressed in a series of diverse cell types and tissues. 3 For instance, nNOS plays a fundamental role in the regulation of male sexual function. Lines of evidence have indicated the involvement of nNOS in penile erection, 4 in testosterone synthesis in the Leydig cells of the testis, 5,6 in sexual behavior, [7][8][9] and in egg activation at fertilization, 10 among others.…”

mentioning

confidence: 99%

An Alternative Promoter of the Human Neuronal Nitric Oxide Synthase Gene Is Expressed Specifically in Leydig Cells

Wang¹,

Newton²,

Miller³

et al. 2002

The American Journal of Pathology

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Neuronal nitric oxide synthase (nNOS) plays a modulatory role in the biology of a variety of neuroendocrine tissues and is especially relevant to gonadal function. We have previously reported the cloning and characterization of a variant of the nNOS protein, termed testis nNOS (TnNOS), the mRNA for which was restricted in expression to male gonadal tissues. To examine the cell-specificity of the testis-specific NOS regulatory regions we defined patterns of ␤-galactosidase expression of an insertional transgene in which the reporter gene lacZ was under the transcriptional control of the human TnNOS promoter. ␤-galactosidase activity was detected exclusively in the interstitial cells of the testis in transgenic mice. These cells also evidenced positive staining for nNOS protein and were identified as androgen-producing Leydig cells by staining with the Leydig cell marker, P 450 scc. Expression of the promoter was absent in cells of the seminiferous tubules, specifically germline cells of different stages and Sertoli cells. In contrast to the male gonad, ␤-galactosidase activity was not detected in ovaries of adult female mice. Activity was also not evident in organs known to express full-length nNOS, such as skeletal muscle, kidney, or cerebellum. The same pattern of ␤-galactosidase staining was observed in independent transgenic founders and was distinct from that observed for an endothelial NOS promoter/reporter transgene. In the testis of male adult eNOS promoter-reporter transgenic mice, ␤-galactosidase activity was expressed only in endothelial cells of large-and medium-sized arterial blood vessels. Transcriptional activity of the Of the three known human nitric oxide synthases (NOS) isoforms, the neuronal nitric oxide synthase (nNOS) has unique properties. The nNOS (NOS1) isoform is expressed from a very complex human genomic locus spanning 240 kb at 12q24.2.

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Nitric oxide in excitable tissues: physiological roles and disease.

Cited by 275 publications

References 62 publications

Arginine metabolism: nitric oxide and beyond

Arginine metabolism: nitric oxide and beyond

Binding of Neuronal Nitric-oxide Synthase (nNOS) to Carboxyl-terminal-binding Protein (CtBP) Changes the Localization of CtBP from the Nucleus to the Cytosol

An Alternative Promoter of the Human Neuronal Nitric Oxide Synthase Gene Is Expressed Specifically in Leydig Cells

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