Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.5.1.19 (NOS)
7,285 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The gaseous radical nitric oxide (NO) is catalyzed by conversion of L-arginine to L-citrulline by one cytokine inducible form (iNOS), which becomes active only within hours after the inducing event, and by two constitutively expressed forms, endothelial (eNOS) and neuronal (nNOS), which are regulated by the cytosolic concentration of free Ca2+. Brain nNOS is physiologically present in discrete populations of neurons, which are all excited by glutamate via the ionotropic N-methyl-D-aspartate (NMDA) receptor, which controls a Ca2+ channel. After its diffusion into the extraneuronal space, NO may activate in neurons, which as a rule do not stain for NOS, soluble guanylyl cyclase and formation of cGMP as an intracellular messenger. Beyond that, NO is important as a feedback regulator of glutamatergic excitation. NO as a nitrosylating agent enhances disulfide bonding of vicinal sulfhydryl (thiol) groups of the redox modulatory site of the NMDA receptor complex and thereby down-regulates its Ca2+ channel activity. Histochemical studies have revealed the presence of a large number of NOS containing neurons in the magnocellular and parvocellular subdivisions of hypothalamic nuclei. Numerous studies conform to the view that NO participates in the control of many different neurosecretory processes, especially of the corticotropin-releasing hormone (CRH) neurosecretory system. The redox-modulatory site of the NMDA receptor appears, therefore, as a critical structure in the control of the hypothalamic-pituitary-adrenocortical (HPA) axis. Moreover, glucocorticoids augment neuronal excitotoxicity by increasing the expression of glutamate receptors and inhibition of glutamate reuptake. In attempting to explain the many conflicting results obtained in studies with NO, it may be worthwhile to consider that the actual redox-environment of distinct loci of the brain may determine the final function of NO, acting either as a transmitter or neuromodulator or, in the worst case, causing neurodestruction. It seems likely that any kind of stress by altering the ratio of reduced vs oxidized thiols within the central nervous system influences neuronal excitability, with NO working either as an amplifier or as a feedback regulator of neuronal excitation or inhibition, which may alter acutely or chronically, among others, the homeostasis of a given neurosecretory system.
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PMID:Role of nitric oxide in the control of the hypothalamic-pituitary-adrenocortical axis. 1115 2

In addition to their ionotropic role, neuronal nicotinic acetylcholine receptors (nAChRs) can influence second messenger levels, transmitter release and gene transcription. In this study, we show that nAChRs in an insect CNS control cGMP levels by coupling to NO production. In conditions that inhibit spiking, nicotine induced cGMP synthesis. This increase in cGMP was blocked by nicotinic antagonists, and by inhibitors of both nitric oxide synthase and soluble guanylyl cyclase. The nicotinic-evoked increase in cGMP was localized to specific NO-sensitive neurons in the CNS, several of which are identified motoneurons. Because NO production requires Ca2+, we investigated the effect of nicotinic stimulation on [Ca2+]i in cultured neurons. We found that activation of nAChRs increased [Ca2+]i, which was blocked by nAChR antagonists. Nicotinic stimulation of neurons in the isolated CNS in low-Na+, also evoked increases in [Ca2+]i independent of fast changes in voltage. In addition, approximately 10% of the nicotinic-evoked [Ca2+]i increase in cultured neurons persisted when voltage-gated Ca2+ channels were blocked by Ni2+. Under the same conditions, nicotinic stimulation of cGMP in the CNS was unaffected. These combined results suggest that nicotinic stimulation is coupled to NOS potentially by directly gating Ca2+.
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PMID:Nicotinic-acetylcholine receptors are functionally coupled to the nitric oxide/cGMP-pathway in insect neurons. 1242 52

Glutamate can induce neuronal cell death by activating ionotropic glutamate receptors (iGluRs) as well as metabotropic glutamate receptors (mGluRs). In the present study, we investigated whether glutamate induces apoptosis of cultured anterior pituitary cells from female rats. Glutamate (1 mm) significantly reduced the metabolic activity of viable cells and increased the percentage of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL)-positive cells and caspase-3 activity in anterior pituitary cells. The inhibitory effect of glutamate on the viability of anterior pituitary cells was not observed in the presence of [2S]-alpha-ethylglutamic acid (0.75 mm), a specific group II mGluR antagonist. Also, (2S,1'S,2'S)-2-(carboxycyclopropyl)glycine (LCCG-I; 0.75 mm), a specific group II mGluR agonist, reduced viability and increased the percentage of TUNEL-positive anterior pituitary cells. Group I and III mGluRs and iGluRs agonists failed to modify the metabolic activity of anterior pituitary cells. Glutamate and LCCG-I increased the percentage of TUNEL-positive lactotropes and somatotropes. The subunit mGluR2/3, belonging to group II mGluR, was localized in these cell types. Glutamate increased nitric oxide (NO) synthase (NOS) activity and inducible NOS expression in anterior pituitary cells. N-methyl-l-arginine (NMMA, 0.5 mm), a NOS inhibitor, potentiated the apoptotic effect of glutamate in anterior pituitary cells, indicating that NO may restrain glutamate-induced apoptosis. Incubation of anterior pituitary cells with a cAMP analog (N6, 2'-o-dibutyryladenosine 3', 5'-cyclic monophosphate; 1 mm) attenuated the apoptosis induced by glutamate. Glutamate and LCCG-I decreased prolactin release from anterior pituitary cells. N6, 2'-o-dibutyryladenosine 3', 5'-cyclic monophosphate reversed the inhibitory effect of glutamate on prolactin release, but NMMA failed to modify it. Our data show that glutamate induces apoptosis of lactotropes and somatotropes through group II mGluR activation, probably by decreasing cAMP synthesis.
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PMID:Glutamate induces apoptosis in anterior pituitary cells through group II metabotropic glutamate receptor activation. 1520 12

In this work, the involvement of ionotropic glutamatergic receptors and nitric oxide on striatal dopamine release induced by anatoxin-a was investigated in conscious and freely-moving rats. To study the participation of glutamatergic receptors, the effects of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate receptors antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), and N-methyl-D-aspartate (NMDA) receptor antagonists, dizocilpine (MK-801) and d(-)-2-amino-5-phosphonopentanoic acid (APV), were examined. The perfusion of 3.5 mM anatoxin-a increased the extracellular dopamine levels to 701% relative to the basal. When CNQX was administered with 3.5 mM anatoxin-a, the increase of dopamine levels was 29% smaller than that observed with anatoxin-a alone. When MK-801 and APV were administered, the effect of anatoxin-a was attenuated 26% and 25% respectively in terms of that observed with anatoxin-a alone. And with CNQX plus MK-801, the effect of anatoxin-a was 53% inhibited in terms of the effect of anatoxin-a alone. These results suggest that the striatal dopamine release induced by anatoxin-a is partly mediated by activation of both ionotropic glutamatergic receptors. Since the neuronal form of nitric oxide synthase (nNOS) produces nitric oxide (NO) primarily in response to activation of NMDA receptors, it was tested if NO could play any role in the effect of anatoxin-a. Treatment with NOS inhibitors, L-nitro-arginine methyl ester (L-NAME) and d(-)-2-amino-5-phosphonopentanoic acid (7-NI), induced decreased anatoxin-a effects of 22% and 26% respectively. In conclusion, the present in vivo results demonstrate that anatoxin-a induced an indirect activation of ionotropic glutamatergic receptors (NMDA and AMPA/kainite receptors), which stimulate striatal dopamine release. On the other hand, activation of NMDA receptors may elicit NO increased levels enhancing dopamine release.
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PMID:Mediation of glutamatergic receptors and nitric oxide on striatal dopamine release evoked by anatoxin-a. An in vivo microdialysis study. 1696 20

Glutamatergic transmission through metabotropic and ionotropic receptors, including kainate receptors, plays an important role in the nucleus of the solitary tract (NTS) functions. Glutamate system may interact with several other neurotransmitter systems which might also be influenced by steroid hormones. In the present study we analyzed the ability of systemic kainate to stimulate rat NTS neurons, which was evaluated by c-Fos as a marker of neuronal activation, and also to change the levels of NTS neurotransmitters such as GABA, NPY, CGRP, GAL, NT and NO by means of quantitative immunohistichemistry combined with image analysis. The analysis was also performed in adrenalectomized and kainate stimulated rats in order to evaluate a possible role of adrenal hormones on NTS neurotransmission. Male Wistar rats (3 month-old) were used in the present study. A group of 15 rats was submitted either to bilateral adrenalectomy or sham operation. Forty-eight hours after the surgeries, adrenalectomized rats received a single intraperitoneal injection of kainate (12 mg/kg) and the sham-operated rats were injected either with saline or kainate and sacrificed 8 hours later. The same experimental design was applied in a group of rats in order to register the arterial blood pressure. Systemic kainate decreased the basal values of mean arterial blood pressure (35%) and heart rate (22%) of sham-operated rats, reduction that were maintained in adrenalectomized rats. Kainate triggered a marked elevation of c-Fos positive neurons in the NTS which was 54% counteracted by adrenalectomy. The kainate activated NTS showed changes in the immunoreactive levels of GABA (143% of elevation) and NPY (36% of decrease), which were not modified by previous ablation of adrenal glands. Modulation in the levels of CGRP, GAL and NT immunoreactivities were only observed after kainate in the adrenalectomized rats. Treatments did not alter NOS labeling. It is possible that modulatory function among neurotransmitter systems in the NTS might be influenced by steroid hormones and the implications for central regulation of blood pressure or other visceral regulatory mechanisms control should be further investigated.
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PMID:Effects of bilateral adrenalectomy on systemic kainate-induced activation of the nucleus of the solitary tract. Regulation of blood pressure and local neurotransmitters. 1819 66

Nuclear factor-kB (NF-kB) is a family of DNA-binding proteins that are important regulators involved in immune and inflammatory responses, as well as in cell survival and apoptosis. In the nervous system NF-kB is activated under physiological and pathological conditions including learning and memory mechanisms and neurodegenerative diseases. NF-kB is activated in neurons in response to excitotoxic, metabolic and oxidative stress and there is a body of evidence to suggest that glutamate induces NF-kB by the main ionotropic glutamate receptors. In the present study, 3 nitroproprionic acid (3NP), an irreversible inhibitor of succinate dehydrogenase (SD, complex II) has been employed to provide an experimental model of Huntington's disease (HD). Specifically, we described 3NP-induced activation of NF-kB and of iNOS and nNOS genes in striatal treated slices. To aim to better understand the relationship between these identified dysregulated genes and mitochondrial dysfunction, we investigated in SK-N-MC human neuroblastoma cells following 3NP treatment, whether NF-kB nuclear translocation and activation might be involved in the mechanisms by which 3NP leads to transcriptional activation of NOS genes. These results are relevant to more precisely define the role of NF-kB in neuronal cells and better understand its putative involvement in neurodegeneration.
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PMID:NF-kB/NOS cross-talk induced by mitochondrial complex II inhibition: implications for Huntington's disease. 1832 71

In vitro, nitric oxide (NO) inhibits the firing rate of magnocellular neurosecretory cells (MNCs) of hypothalamic supraoptic and paraventricular nuclei and this effect has been attributed to GABAergic activation. However, little is known about the direct effects of NO in MNCs. We used the patch-clamp technique to verify the effect of L-arginine, a precursor for NO synthesis, and N(omega)-nitro-L-arginine methyl ester hydrochloride (L-NAME), an inhibitor of NOS, on spontaneous electrical activity of MNCs after glutamatergic and GABAergic blockade in Wistar rat brain slices. 6-Cyano-7-nitroquinoxaline-2,3-dione (CNQX) (10 microM) and dl-2-amino-5-phosphonovaleric acid (dl-AP5) (30 microM) were used to block postsynaptic glutamatergic currents, and picrotoxin (30 microM) and saclofen (30 microM) to block ionotropic and metabotropic postsynaptic GABAergic currents. Under these conditions, 500 microM L-arginine decreased the firing rate from 3.7+/-0.6 Hz to 1.3+/-0.3 Hz. Conversely, 100 microM L-NAME increased the firing rate from 3.0+/-0.3 Hz to 5.8+/-0.4 Hz. All points histogram analysis showed changes in resting potential from -58.1+/-0.8 mV to -62.2+/-1.1 mV in the presence of L-arginine and from -59.8+/-0.7 mV to -56.9+/-0.8 mV by L-NAME. Despite the nitrergic modulator effect on firing rate, some MNCs had no significant changes in their resting potential. In those neurons, hyperpolarizing after-potential (HAP) amplitude increased from 12.4+/-1.2 mV to 16.8+/-0.7 mV by L-arginine, but without significant changes by L-NAME treatment. To our knowledge, this is the first demonstration that NO can inhibit MNCs independent of GABAergic inputs. Further, our results point to HAP as a potential site for nitrergic modulation.
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PMID:Nitric oxide modulates the firing rate of the rat supraoptic magnocellular neurons. 1858 43

In several species of cephalopod molluscs there is good evidence for the presence of L-glutamate in the central and peripheral nervous system and evidence for both classes of ionotropic receptor, AMPA/kainate and NMDA.The best evidence for glutamate being a transmitter in cephalopods comes from pharmacological, immunohistochemical and molecular investigations on the giant fibre system in the squid stellate ganglion. These studies confirm there are AMPA/kainate-like receptors on the third-order giant axon. In the (glial) Schwann cells associated with the giant axons both classes of glutamate receptor occur.Glutamate is an excitatory transmitter in the chromatophores and in certain somatic muscles and its action is mediated primarily via AMPA/kainate-like receptors, but at some chromatophores there are NMDA-like receptors.In the statocysts the afferent crista fibres are also glutamatergic, acting at non-NMDA receptors.In the brain (of Sepia) a neuronal NOS is activated by glutamate with subsequent production of nitric oxide and elevation of cGMP levels. This signal transduction pathway is blocked by D-AP-5, a specific antagonist of the NMDA receptor.Recently immunohistochemical analysis has demonstrated (in Sepia and Octopus) the presence of NMDAR2A /B - like receptors in motor centres, in the visual and olfactory systems and in the learning system. Physiological experiments have shown that glutamatergic transmission is involved in long term potentation (LTP) in the vertical lobe of Octopus, a brain area involved in learning. This effect seems to be mediated by non-NMDA receptors. Finally in the CNS of Sepia NMDA-mediated nitration of tyrosine residues of cytoskeletal protein such as alpha-tubulin, has been demonstrated.
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PMID:L-glutamate and its ionotropic receptors in the nervous system of cephalopods. 1865 36

The major aim of this study was to elucidate the relationship between nitric oxide (NO) and generalized epilepsy. Mice lacking the neuronal nitric oxide synthase (nNOS) gene (nNOS(-/-)) were used in this study to determine the relationship between nNOS alpha and NO in pentylentetrazole (PTZ)-induced convulsions. nNOS(-/-) mice exhibited severe convulsions following injection with a subconvulsive dose of PTZ (40 mg/kg i.p.) and convulsive doses were lethal in all of the mice (60 mg/kg i.p.) following tonic convulsions. The results were confirmed by using selective nNOS inhibitors in wild-type (nNOS(+/+)) mice. The higher doses of the nNOS inhibitors 1-[2-(trifluoromethyl)phenyl] imidazole (TRIM) and 3-bromo-7-nitroindazole (3Br7NI) inhibited clonic-tonic convulsions induced by a convulsive dose of PTZ (60 mg/kg) in nNOS(+/+) mice. In contrast, either TRIM or 3Br7NI at lower doses enhanced convulsions following injection with a subconvulsive dose of PTZ (40 mg/kg) in nNOS(+/+) mice similar to nNOS(-/-) mice treated with PTZ. Such a proconvulsant effect was observed in nNOS(+/+) mice pretreated with nNOS inhibitors but not other NOS inhibitors. These results indicate that NO may be regarded as an anticonvulsant or a proconvulsant substance in relation to convulsions induced by PTZ in mice. Pretreatment with N-methyl-d-aspartate (NMDA) receptor antagonists (5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine maleate (MK-801), (E)-(+/-)-2-amino-4-methyl-5-phospho no-3-pentenoic acid ethyl ester, CGP39551) and DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist (2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide, NBQX) inhibited a subconvulsive dose of PTZ-induced convulsions in nNOS(-/-) mice, demonstrating that convulsions induced by PTZ are modulated by endogenous NO production and ionotropic glutamate receptor-mediated stimulation. These results suggest a negative or positive modulation of neuronal interactions by basal or enhanced NO production, respectively.
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PMID:Paradoxical facilitation of pentylenetetrazole-induced convulsion susceptibility in mice lacking neuronal nitric oxide synthase. 1916 39

Nitric oxide (NO) in NTS plays an important role in regulating autonomic function to the cardiovascular system. Using the fluorescent dye DAF-2 DA, we evaluated the NO concentration in NTS. Brainstem slices of rats were loaded with DAF-2 DA, washed, fixed in paraformaldehyde and examined under fluorescent light. In different experimental groups, NTS slices were pre-incubated with 1 mM l-NAME (a non-selective NOS inhibitor), 1 mM d-NAME (an inactive enantiomere of l-NAME), 1 mM kynurenic acid (a non-selective ionotropic receptors antagonist) or 20 microM bicuculline (a selective GABAA receptors antagonist) before and during DAF-2 DA loading. Images were acquired using a confocal microscope and the intensity of fluorescence was quantified in three antero-posterior NTS regions. In addition, slices previously loaded with DAF-2 DA were incubated with NeuN or GFAP antibody. A semi-quantitative analysis of the fluorescence intensity showed that the basal NO concentration was similar in all antero-posterior aspects of the NTS (rostral intermediate, 15.5 +/- 0.8 AU; caudal intermediate, 13.2 +/- 1.4 AU; caudal commissural, 13.8 +/- 1.4 AU, n = 10). In addition, the inhibition of NOS and the antagonism of glutamatergic receptors decreased the NO fluorescence in the NTS. On the other hand, d-NAME did not affect the NO fluorescence and the antagonism of GABAA receptors increased the NO fluorescence in the NTS. It is important to note that the fluorescence for NO was detected mainly in neurons. These data show that the fluorescence observed after NTS loading with DAF-2 DA is a result of NO present in the NTS and support the concept that NTS neurons have basal NO production which is modulated by l-glutamate and GABA.
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PMID:Fluorescent indication that nitric oxide formation in NTS neurons is modulated by glutamate and GABA. 1929 38


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