Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.6.99.3 (diaphorase)
 5,903 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelial nitric-oxide synthase (type III) (eNOS) was reported to form an inhibitory complex with the bradykinin receptor B2 (B2R) from which the enzyme is released in an active form upon receptor activation (Ju, H., Venema, V. J., Marrero, M. B., and Venema, R. C. (1998) J. Biol. Chem. 273, 24025-24029). Using a synthetic peptide derived from the known inhibitory sequence of the B2R (residues 310-329) we studied the interaction of the receptor with purified eNOS and neuronal nitric-oxide synthase (type I) (nNOS). The peptide inhibited formation of L-citrulline by eNOS and nNOS with IC(50) values of 10.6 +/- 0.4 microM and 7.1 +/- 0.6 microM, respectively. Inhibition was not due to an interference of the peptide with L-arginine or tetrahydrobiopterin binding. The NADPH oxidase activity of nNOS measured in the absence of L-arginine was inhibited by the peptide with an IC(50) of 3.7 +/- 0.6 microM, but the cytochrome c reductase activity of the enzyme was much less susceptible to inhibition (IC(50) >0.1 mM). Steady-state absorbance spectra of nNOS recorded during uncoupled NADPH oxidation showed that the heme remained oxidized in the presence of the synthetic peptide consisting of amino acids 310-329 of the B2R, whereas the reduced oxyferrous heme complex was accumulated in its absence. These data suggest that binding of the B2R 310-329 peptide blocks flavin to heme electron transfer. Co-immunoprecipitation of B2R and nNOS from human embryonic kidney cells stably transfected with human nNOS suggests that the B2R may functionally interact with nNOS in vivo. This interaction of nNOS with the B2R may recruit the enzyme to allow for the effective coupling of bradykinin signaling to the nitric oxide pathway.
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PMID:Interaction of endothelial and neuronal nitric-oxide synthases with the bradykinin B2 receptor. Binding of an inhibitory peptide to the oxygenase domain blocks uncoupled NADPH oxidation. 1068 1

Nitric oxide (NO) may subserve different functions in different central neurons subjected to axotomy. The difference may depend on whether the neurons basally express neuronal nitric oxide synthase (nNOS), a biosynthetic enzyme of NO. This is supported by our previous finding that suggests the differential role of NO in neurons of nucleus dorsalis (ND) and red nucleus (RN) which have different basal expression of nNOS. This study aimed to establish firmly the functions of NO, as revealed by nNOS immunoreactivity and nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) histochemistry, by the administration of endogenous NO donor, l-arginine (l-arg), and NOS inhibitor, l-N(G)-nitroarginine methyl ester (l-NAME). To relate the role of NO to glutamate receptors (GluR), the distributions of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) and N-methyl-d-aspartate receptor (NMDAR) in the two nuclei were revealed by immunohistochemical techniques. nNOS immunoreactivity was void in ND neurons, but expressed weakly in the RN normally. It was induced in ipsilateral ND neurons and upregulated on both sides of RN after spinal cord hemisection. Neuronal loss in the ipsilateral ND was augmented by l-arg, but reduced by l-NAME. In the contralateral RN, l-arg attenuated neuronal loss. NMDAR1 was present in most neurons in ND. After axotomy, some NMDAR1 immunoreactive neurons of the ipsilateral ND were induced to express NOS, whereas RN neurons showed strong staining for NMDAR1 and all the AMPA subunits. Most of the NOS-positive neurons in the RN were coexistent with GluR2 in normal rats and those subjected to axotomy. The present data demonstrated that NO exerted neurodestructive function in the non-NOS-containing ND neurons characterized by NMDAR as the predominant glutamate receptor. NO might be beneficial to the NOS-containing RN neurons. This could be attributed to the presence of GluR2. Possible diverse synthesizing pathways of NO in two different central nuclei were suggested from the observation that NOS was colocalized with NADPH-d in ND neurons, but not in RN neurons.
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PMID:Neuroprotective and neurodestructive functions of nitric oxide after spinal cord hemisection. 1068 69

Protein inhibitor of neuronal nitric oxide synthase (PIN) is reported as the protein inhibiting neuronal nitric oxide synthase (nNOS) activity by preventing dimerization of nNOS. It was also reported that PIN inhibits the activity of all nitric oxide synthase (NOS) isozymes. We examined the effects of facial nerve transection on PIN mRNA and NOS expression by in situ hybridization for PIN mRNA and nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) staining. PIN mRNA was initially expressed and transiently increased from 3 to 5 days and returned to the basal level at 7 days after axotomy in the motoneurons of the facial nucleus. NADPH-d-positive motoneurons were found from 7 days post-operation in the facial nucleus. These results suggest that PIN may interact with NOS from 7 days post-operation.
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PMID:Changes in mRNA of protein inhibitor of neuronal nitric oxide synthase following facial nerve transection. 1069 46

When the axon of motoneurons is transected, the number of synaptic boutons contacting the cell body is decreased, and the recovery of synapses depends on muscle reinnervation. Post-synaptic density-95 (PSD-95) is a protein which is located at the post-synaptic density (PSD) and it plays a pivotal role in regulating synaptic plasticity and synaptogenesis. In addition, PSD-95 binds with neuronal nitric oxide synthase (nNOS), which is competitively inhibited by carboxy-terminal PDZ ligand of nNOS (CAPON) and, thereby, nNOS activity is thought to be regulated by PSD-95 and CAPON. We investigated the changes in mRNA for PSD-95, CAPON and nNOS in the facial motor nucleus of adult rats following axotomy, by in situ hybridization, in combination with the time course of muscle reinnervation, by retrograde tracing and nNOS protein expression, by examining nicotinamide adenine nucleotide phosphate diaphorase (NADPH-d) activity. Signals of mRNA for PSD-95 and CAPON were initially expressed in the facial motoneurons, transiently decreased following axotomy and gradually recovered to the control level. When reinnervation of the axotomized nerve into muscle was observed, mRNA expression of PSD-95 and CAPON started to recover in the facial motoneurons. It was also found that mRNA and protein expression of nNOS started to increase in the axotomized facial motoneurons just prior to the recovery of mRNA expression of PSD-95 and CAPON. These results suggest that PSD-95 and CAPON are involved in synaptogenesis and/or recovery of synaptic function in motoneurons after axotomy.
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PMID:Changes in mRNA for post-synaptic density-95 (PSD-95) and carboxy-terminal PDZ ligand of neuronal nitric oxide synthase following facial nerve transection. 1076 8

Nitric oxide and acetylcholine are important neuromodulators implicated in brain plasticity and disease. We have examined the cellular and fiber localization of nitric oxide in the cat superior colliculus (SC) and its degree of co-localization with ACh using nicotinamide adenine dinucleotide phosphate diaphorase (NADPHd) histochemistry and an antibody to neuronal nitric oxide synthase. ACh was localized using an antibody against choline acetyltransferase. We also made injections of biocytin into the region of the parabrachial brainstem to confirm that this region is a source of nitric oxide containing fibers in SC. NADPHd labeled neurons within the superficial layers of the superior colliculus included pyriform, vertical fusiform, and horizontal morphologies. Labeled neurons in the intermediate gray layer were small to medium in size, and mostly of stellate morphology. Neurons in the deepest layers had mostly vertical or stellate morphologies. NADPHd labeled fibers formed dense patches of terminal boutons within the intermediate gray layer and streams of fibers within the deepest layers of SC. Choline acetyltransferase antibody labeling in adjacent sections indicated that many fibers must contain both labels. Over 94% of neurons in the pedunculopontine tegmental and lateral dorsal tegmental nuclei were also labeled by both NADPHd and choline acetyltransferase. In addition, biocytin labeled fibers from this region were localized in the NADPHd labeled patches. We conclude that nitric oxide is contained in a variety of cell types in SC and that both nitric oxide and ACh likely serve as co-modulators in this midbrain structure.
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PMID:Nitric oxide synthase distribution in the cat superior colliculus and co-localization with choline acetyltransferase. 1078 33

C(3)-tris-malonyl-C(60)-fullerene and D(3)-tris-malonyl-C(60)-fullerene derivatives inhibit citrulline and NO formation by all three nitric oxide synthase isoforms in a manner fully reversible by dilution. The inhibition of citrulline formation by C(3)-tris-malonyl-C(60)-fullerene occurs with IC(50) values of 24, 17, and 123 microM for the neuronal, endothelial, and inducible nitric oxide synthase (NOS) isoforms, respectively. As measured at 100 microM l-arginine, neuronal NOS-catalyzed nitric oxide formation was inhibited 50% at a concentration of 25 microM C(3)-tris-malonyl-C(60)-fullerene. This inhibition was a multisite, positively cooperative inhibition with a Hill coefficient of 2.0. C(3)-tris-malonyl-C(60)-fullerene inhibited the arginine-independent NADPH-oxidase activity of nNOS with an IC(50) value of 22 microM but had no effects on its cytochrome c reductase activity at concentrations as high as 300 microM. The inhibition of nNOS activity by C(3)-tris-malonyl-C(60)-fullerene reduced the maximal velocity of product formation but did not alter the EC(50) value for activation by calmodulin. C(3)-tris-malonyl-C(60)-fullerene reduced the maximal velocity of citrulline formation by inducible NOS without altering the K(m) for l-arginine substrate or the EC(50) value for tetrahydrobiopterin cofactor. As measured by sucrose density gradient centrifugation, fully inhibitory concentrations of C(3)-tris-malonyl-C(60)-fullerene did not produce a dissociation of nNOS dimers into monomers. These observations are consistent with the proposal that C(3)-tris-malonyl-C(60)-fullerene inhibits the inter-subunit transfer of electrons, presumably by a reversible distortion of the dimer interface.
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PMID:Inhibition of nitric oxide synthase isoforms by tris-malonyl-C(60)-fullerene adducts. 1086 May 39

Using nicotinamide-adenine-dinucleotide-phosphate-diaphorase (NADPHd) histochemistry, we analyzed the effects of an intracerebroventricular injection of colchicine on the activity of neuronal nitric oxide synthase in the hypothalamic nuclei of intact and ovariectomized estradiol-primed guinea pigs. We also examined the effects of colchicine on the immunocytochemical colocalization of nitric oxide synthase with the progesterone receptor in the ventrolateral nucleus, a key region in the control of sexual behavior. Treatment with colchicine resulted in a significant increase in the number of NADPHd-positive neurons in the ventrolateral nucleus in intact as well as in ovariectomized estradiol-primed animals, whereas in the other hypothalamic regions analyzed (preoptic area, paraventricular nucleus and posterior arcuate nucleus), the enzymatic activity remained unchanged. Quantitative analysis showed a significantly greater number of NADPHd-positive cells in the medial and the posterior aspects of the ventrolateral nucleus of colchicine-treated guinea pigs compared to the control group. In the caudal subdivision of this nucleus, colchicine induced nitric oxide synthase in the target cells for progesterone. These results suggest that neuronal nitric oxide synthase activity in the hypothalamus is affected by colchicine in a region-specific manner and especially in the ventrolateral nucleus, which is involved in progesterone-facilitated lordosis.
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PMID:Differential effects of colchicine on the induction of nitric oxide synthase in neurons containing progesterone receptors of the guinea pig hypothalamus. 1092 24

Oxidative stress and massive production of nitric oxide (NO) have been implicated in the neuropathogenesis following peripheral nerve injury. This study was aimed to ascertain whether melatonin would exert its neuroprotective effect on the lesioned hypoglossal neurons after peripheral axotomy, since it is known to reduce the oxidative damage in a variety of experimental neuropathologies in which NO is involved. Right-sided hypoglossal nerve transection was performed in adult rats following which the animals were given two different doses of melatonin administered intraperitoneally for 3, 7, 14, 21 and 30 successive days. Nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) histochemistry and neuronal nitric oxide synthase (nNOS) immunohistochemistry were carried out to detect the neuronal NADPH-d/NOS expression in the hypoglossal nucleus (HN). At various time intervals following axotomy, the neurons in the affected HN were induced to express NADPH-d/NOS reactivity on the lesioned side peaking at 14 days. However, the enzyme expression was markedly depressed by melatonin treatment in a dose-dependent manner in terms of frequency of labelled neurons and staining intensity. It is suggested that the suppressive effect of melatonin on NADPH-d/NOS expression may be attributed to its antioxidant properties. Hence, in consideration of therapeutic strategies for reducing the oxidative stress following peripheral nerve injury, melatonin may prove to be beneficial.
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PMID:Melatonin attenuates neuronal NADPH-d/NOS expression in the hypoglossal nucleus of adult rats following peripheral nerve injury. 1093 May 50

The distribution and changes of catalytic nitric oxid synthase (cNOS) activity in the dorsal, lateral and ventral white matter columns at midthoracic level of the rabbit's spinal cord were studied in a model of surgically-induced spinal cord constriction performed at Th7 segment level and compared with the occurrence of nicotinamide adenine dinucleotide phosphate diaphorase expressing and neuronal nitric oxide synthase immunoreactive axons in the white matter of the control thoracic segments. Segmental and white-column dependent differences of cNOS activity were found in the dorsal (141.5 +/- 4.2 dpm/microm protein), lateral (87.3 +/- 11.5 dpm/microm protein) and ventral (117.1 +/- 7.6 dpm/microm protein) white matter columns in the Th5-Th6 segments and in the dorsal (103.3 +/- 15.5 dpm/microm protein), lateral (54.9 +/- 4.9 dpm/microm protein), and ventral (86.1 +/- 6.8 dpm/microm protein) white matter columns in the Th8-Th9 segments. A surgically-induced constriction of Th7 segment caused a disproportionate response of cNOS activity in the rostrally (Th5-Th6) and caudally (Th8-Th9) located segments in both lateral and ventral white matter columns. While a statistically significant decrease of cNOS activity was detected above the constriction site in the ventral columns, a considerable, statistically significant increase of cNOS activity was noted in the white lateral columns below the site of constriction. It is reasoned that the changes of cNOS activity may have adverse effects on nitric oxide (NO) production in the white matter close to the site of constriction injury, thus broadening the scope of the secondary mechanisms that play a role in neuronal trauma.
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PMID:Effect of midthoracic spinal cord constriction on catalytic nitric oxide synthase activity in the white matter columns of rabbit. 1105 53

Since nitric oxide has a role in the refinement of the retinal projection to the superior colliculus (SC), we studied the onset of neuronal nitric oxide synthase (nNOS) expression in the mouse SC in order to compare its development with that of the refinement process. Sections from animals at ages P1, P5, P8, P11, P15, and P21 and adults were examined with nicotinamide adenine dinucleotide phosphate diaphorase (NADPHd) histochemistry or immunocytochemistry using an antibody directed against nNOS. At all ages there was a wedge of labeled neurons in the dorsolateral periaqueductal gray extending into the deep layers of the SC. At P1 there was also a single superficial band of labeled neurons within the region that will become the intermediate gray layer (IGL). By P5, labeled neurons were also seen in what will become the superficial gray layer. There was a ventral to dorsal progression in nNOS expression with substantial changes in the numbers of labeled neurons in the different laminae between P5 and adulthood. The number of labeled neurons in the IGL peaked at P15, whereas in the superficial layers the numbers continued to increase through P21 and then declined in adults. At all ages these neurons represented a variety of morphological cell types. The onset of nNOS expression in the different laminae is earlier than has been reported in studies using NADPHd as a marker for nNOS. The temporal and spatial patterns of nNOS expression reported here match more closely the time course of pathway refinement in the SC, providing additional evidence for the involvement of nitric oxide in this process.
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PMID:Postnatal development of nitric oxide synthase expression in the mouse superior colliculus. 1105 65


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