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:4.6.1.2 (guanylate cyclase)
8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nitric oxide synthase (NOS) positive neurons are located in most brain areas related to defensive reactions, including the dorsolateral periaqueductal grey (dlPAG). NOS inhibitors injected into this structure induce anxiolytic-like responses whereas NO donors promote flight reactions. Intra-dlPAG administration of carboxy-PTIO, a NO scavenger, or ODQ, a soluble guanylate cyclase inhibitor, produced anxiolytic-like effects on rats exposed to the elevated plus-maze (EPM). A double-staining experiment using NADPHd histochemistry and c-Fos immunohistochemistry in rats exposed to a cat or to the EPM showed increased activation of NO producing neurons in the dlPAG, paraventricular and lateral nuclei of hypothalamus and dorsal raphe nucleus. Cat exposure also increased activation of NOS neurons in the medial amygdala, dorsal pre-mammillary nucleus and bed nucleus of stria terminalis. Local infusion into the dlPAG of a glutamate NMDA-receptor antagonist (AP7) or a benzodiazepine agonist (midazolam) completely prevented the flight reactions induced by intra-dlPAG administration of SIN-1, a NO donor. The responses were also inhibited by the 5-HT2A/C agonist DOI but not by a 5-HT1A agonist. These results suggest a modulatory role for NO on brain areas related to defensive reactions, probably by interacting with glutamate, serotonin and/or GABA-mediated neurotransmission.
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PMID:Role of nitric oxide in brain regions related to defensive reactions. 1609 96

Melatonin is involved in a variety of physiological functions through activating specific receptors coupled to GTP-binding protein. Melatonin and its receptors are abundant in the retina. Here we show for the first time that melatonin modulates glutamatergic synaptic transmission from cones to horizontal cells (HCs) in carp retina. Immunocytochemical data revealed the expression of the MT1 receptor on carp HCs. Whole-cell recordings further showed that melatonin of physiological concentrations potentiated glutamate-induced currents from isolated cone-driven HCs (H1 cells) in a dose-dependent manner, by increasing the efficacy and apparent affinity of the glutamate receptor. The effects of melatonin were reversed by luzindole, but not by K 185, indicating the involvement of the MT1 receptor. Like melatonin, methylene blue (MB), a guanylate cyclase inhibitor, also potentiated the glutamate currents, but internal infusion of cGMP suppressed them. The effects of melatonin were not observed in cGMP-filled and MB-incubated HCs. These results suggest that the melatonin effects may be mediated by decreasing the intracellular concentration of cGMP. Consistent with these observations, melatonin depolarized the membrane potential of H1 cells and reduced their light responses, which could also be blocked by luzindole. These effects of melatonin persisted in the presence of the antagonists of receptors for dopamine, GABA and glycine, indicating a direct action of melatonin on H1 cells. Such modulation by melatonin of glutamatergic transmission from cones to HCs is thought to be in part responsible for circadian changes in light responsiveness of cone HCs in teleost retina.
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PMID:Modulation by melatonin of glutamatergic synaptic transmission in the carp retina. 1623 69

Recent evidence indicates that sildenafil may exert some central effects through enhancement of nitric oxide (NO)-mediated effects. NO is known to have modulatory effects on seizure threshold, raising the possibility that sildenafil may alter seizure susceptibility through NO-mediated mechanisms. This study was performed to examine whether sildenafil influences the threshold of clonic and/or generalized tonic seizures through modulation of nitric oxide (NO)-cGMP pathway. The effect of sildenafil (1-40 mg kg(-1)) was investigated on clonic seizures induced by intravenous administration of GABA antagonists pentylenetetrazole (PTZ) and bicuculine and on generalized tonic seizures induced by intraperitoneal administration of high dose PTZ in male Swiss mice. The interaction of sildenafil-induced effects with NO-cGMP pathway was examined using nitric oxide synthase (NOS) inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), NOS substrate L-arginine, NO donor, sodium nitroprusside (SNP) and guanylyl cyclase inhibitor methylene blue (MB). Sildenafil induced a dose-dependent proconvulsant effect in both models of clonic, but not generalized tonic type of seizures. Pretreatment with either MB or L-NAME inhibited the proconvulsant effect of sildenafil, indicating the mediation of this effect by NO-cGMP pathway. In addition, a subeffective dose of sildenafil induced an additive proconvulsant effect when combined with either L-arginine or SNP. Sildenafil induces a proconvulsant effect on clonic seizure threshold that interacts with both exogenously and endogenously released NO and may be linked to activation of NO-cGMP pathway.
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PMID:The proconvulsant effect of sildenafil in mice: role of nitric oxide-cGMP pathway. 1647 13

Nitric oxide (NO) affects reproductive processes both at the level of the brain and reproductive tract and this review is focused on its role as an essential regulator of the hypothalamic control of reproduction. The data gathered indicate that glutamate stimulates noradrenergic neurons which subsequently activate NO-ergic cells via alpha1-adrenergic receptors. The released NO diffuses into luteinizing hormone-releasing hormone (LHRH) terminals where it triggers LHRH secretion by activation of guanylyl cyclase and cyclooxygenase. The NO released by estrogen-stimulated NO-ergic ventromedial neurons plays a crucial role in the regulation of sexual behavior. Furthermore, an increased expression of inducible nitric oxide synthase in the LHRH and oxytocin neurons underlies the destructive action of NO on the aging of the hypothalamic neuroendocrine pathways. Within the hypothalamo-hypophyseal system, NO exerts an inhibitory effect in the control of oxytocin secretion. This action seems to employ an indirect mechanism by which NO may modulate the release of GABA. This review provides an overview of the role of NO in hypothalamic control of LHRH and oxytocin release, aging of the LHRH and oxytocin neurons and sexual behavior.
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PMID:The role of nitric oxide in the hypothalamic control of LHRH and oxytocin release, sexual behavior and aging of the LHRH and oxytocin neurons. 1658 85

GABA is the inhibitory neurotransmitter in most brain stem nuclei. The properties of release of preloaded [(3)H]GABA were now investigated with slices from the mouse brain stem under normal and ischemic (oxygen and glucose deprivation) conditions, using a superfusion system. The ischemic GABA release increased about fourfold in comparison with normal conditions. The tyrosine kinase inhibitor genistein had no effect on GABA release, while the phospholipase inhibitor quinacrine reduced both the basal and K(+)-evoked release in normoxia and ischemia. The activator of protein kinase C (PKC) 4beta-phorbol 12-myristate 13-acetate had no effects on the releases, whereas the PKC inhibitor chelerythrine reduced the basal release in ischemia. When the cyclic guanosine monophosphate (cGMP) levels were increased by superfusion with zaprinast and other phosphodiesterase inhibitors, GABA release was reduced under normal conditions. The NO donors S-nitroso-N-acetylpenicillamine (SNAP) and hydroxylamine (HA) enhanced the basal and K(+)-stimulated release by acting directly on presynaptic terminals. Under ischemic conditions GABA release was enhanced when cGMP levels were increased by zaprinast. This effect was confirmed by inhibition of the release by the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). The NO-producing agents SNAP, HA, and sodium nitroprusside potentiated GABA release in ischemia. These effects were reduced by the NO synthase inhibitor N(G)-nitro-L: -arginine, but not by ODQ. The results show that particularly NO and cGMP regulate both normal and ischemic GABA release in the brain stem. Their effects are however complex.
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PMID:Modulation of GABA release by second messenger substances and NO in mouse brain stem slices under normal and ischemic conditions. 1705 71

Retinal blood flow is regulated by local factors. In vitro bioassay experiments give evidence that retinal tissue from different species (dogs, pigs, sheep, cows, rats, and mice) continuously releases a factor lowering tone of isolated retinal arteries. This factor is a general relaxant as it was effective in relaxing different types of vascular as well as nonvascular smooth muscle preparations. This factor is called the retinal relaxing factor (RRF) and its characteristics do not correspond with those of the many well-known vasorelaxants found in retina (i.e., NO, prostanoids, adenosine, ADP, ATP, lactate, glutamate, GABA, taurine, adrenomedullin, CGRP, ANP, BNP, and CNP). This unknown RRF is transferable, hydrophilic, and heat-stable. Its relaxing effect is independent of the presence of the vascular endothelium and of NO-synthase, adenylyl cyclase, guanylyl cyclase, and cyclooxygenase activity. RRF might have a role in hypoxic vasodilation in retinal arteries since hypoxia induces relaxation only when retinal tissue is present. Thus, the RRF pathway is sensitive to changes in oxygen tension and might be a sensitive mechanism for adjusting vascular diameter to retinal oxygen levels. Diminished RRF release might explain the decreased retinal circulation observed in disease with atrophic retina.
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PMID:Control of retinal arterial tone by a paracrine retinal relaxing factor. 1736 60

The dorsal lateral geniculate nucleus (dLGN) is essential for the transfer of visual information from the retina to visual cortex, and inhibitory mechanisms can play a critical in regulating such information transfer. Nitric oxide (NO) is an atypical neuromodulator that is released in gaseous form and can alter neural activity without direct synaptic connections. Nitric oxide synthase (NOS), an essential enzyme for NO production, is localized in thalamic inhibitory neurons and cholinergic brain stem neurons that innervate the thalamus, although NO-mediated effects on thalamic inhibitory activity remain unknown. We investigated NO effects on inhibitory activity in dLGN using an in vitro slice preparation. The NO donor, SNAP, selectively potentiated the frequency, but not amplitude, of spontaneous inhibitory postsynaptic currents (sIPSCs) in thalamocortical relay neurons. This increase also persisted in tetrodotoxin (TTX), consistent with an increase in GABA release from presynaptic terminals. The SNAP-mediated actions were attenuated not only by the NO scavenger carboxy-PTIO but also by the guanylyl cyclase inhibitor ODQ. The endogenous NO precursor L-arginine produced actions similar to those of SNAP on sIPSC activity and these L-arginine-mediated actions were attenuated by the NOS inhibitor L-NMMA acetate. The SNAP-mediated increase in sIPSC activity was observed in both dLGN and ventrobasal thalamic nucleus (VB) neurons. Considering the lack of interneurons in rodent VB, the NO-mediated actions likely involve an increase in the output of axon terminals of thalamic reticular nucleus neurons. Our results indicate that NO upregulates thalamic inhibitory activity and thus these actions likely influence sensory information transfer through thalamocortical circuits.
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PMID:Modulation of inhibitory activity by nitric oxide in the thalamus. 1737 43

Excitatory brain synapses are strengthened or weakened in response to specific patterns of synaptic activation, and these changes in synaptic strength are thought to underlie persistent pathologies such as drug addiction, as well as learning. In contrast, there are few examples of synaptic plasticity of inhibitory GABA (gamma-aminobutyric acid)-releasing synapses. Here we report long-term potentiation of GABA(A)-mediated synaptic transmission (LTP(GABA)) onto dopamine neurons of the rat brain ventral tegmental area, a region required for the development of drug addiction. This novel form of LTP is heterosynaptic, requiring postsynaptic NMDA (N-methyl-d-aspartate) receptor activation at glutamate synapses, but resulting from increased GABA release at neighbouring inhibitory nerve terminals. NMDA receptor activation produces nitric oxide, a retrograde signal released from the postsynaptic dopamine neuron. Nitric oxide initiates LTP(GABA) by activating guanylate cyclase in GABA-releasing nerve terminals. Exposure to morphine both in vitro and in vivo prevents LTP(GABA). Whereas brief treatment with morphine in vitro blocks LTP(GABA) by inhibiting presynaptic glutamate release, in vivo exposure to morphine persistently interrupts signalling from nitric oxide to guanylate cyclase. These neuroadaptations to opioid drugs might contribute to early stages of addiction, and may potentially be exploited therapeutically using drugs targeting GABA(A) receptors.
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PMID:Opioids block long-term potentiation of inhibitory synapses. 1746 Jun 74

In the current report, we summarize our findings related to the involvement of nitric oxide (NO) in the pathology of spinal cord trauma. We initially studied the distribution of nitric oxide synthase (NOS)-immunolabeled and/or nicotinamide adenine dinucleotide phosphate diaphorase (NADPHd; which is highly colocalized with NOS)-stained somata and fibers in the spinal cord of the rabbit. Segmental and laminar distribution of NADPHd-stained neurons in the rabbit revealed a large number of NADPHd-stained neurons in the spinal cord falling into six categories, N1-N6, while others could not be classified. Large numbers of NADPHd-stained neurons were identified in the superficial dorsal horn and around the central canal. Four morphologically distinct kinds of NADPHd-stained axons 2.5-3.5 microm in diameter were identified throughout the white matter in the spinal cord. Moreover, a massive occurrence of axonal NADPHd-staining was detected in the juxtagriseal layer of the ventral funiculus along the rostrocaudal axis. The prominent NADPHd-stained fiber bundles were identified in the mediobasal and central portion of the ventral funiculus. The sulcomarginal fasciculus was found in the basal and medial portion of the ventral funiculus in all cervical and thoracic segments. Since the discovery that NO may act as a neuronal transmitter, an increasing interest has focused on its ability to modulate synaptic function. NO passes through cell membranes without specific release or uptake mechanisms inducing changes in signal-related functions by several means. In particular, the activation of the soluble guanylyl cyclases (sGC), the formation of cyclic guanosine 3',5'-monophosphate (cGMP) and the action of cGMP-dependent protein kinases has been identified as the main signal transduction pathways of NO in the nervous system including spinal cord. It is known that the intracellular level of cGMP is strictly controlled by its rate of synthesis via guanylyl cyclases (GC) and/or by the rate of its degradation via 3',5'-cyclic nucleotide phosphodiesterases (PDE). GC can be divided into two main groups, i.e., the membrane-bound or particular guanylyl cyclase (pGC) and the cytosolic or sGC. In the spinal cord, the activation of pGC has only been demonstrated for natriuretic peptides, which stimulate cGMP accumulation in GABA-ergic structures in laminae I-III of the rat cervical spinal cord. These neurons are involved in controlling the action of the locomotor circuit. In view of the abundance of NO-responsive structures in the brain, it is proposed that NO-cGMP signaling will be part of neuronal information processing at many levels. In relation to this, we found that surgically induced Th7 constriction of 24 h duration stimulated both the constitutive NOS activity and cGMP level by 120 and 131%, respectively, in non-compartmentalized white matter of Th8-Th9 segments, located just caudally to the site of injury. NO-mediated cGMP formation was only slightly increased in the dorsal funiculus of Th5-Th9 segments. There are some other sources that may influence the NO-mediated cGMP formation in spinal cord. A high level of glutamate produced at the site of the lesion and an excessive accumulation of intracellular Ca2+ may stimulate NOS activity and create suitable conditions for NO synthesis and its adverse effect on white matter. An increased interest has focused on the role of NO at the site of injury and in areas located close to the epicenter of the impact site and, in these connections an upregulation of NOS was noted in neurons and interneurons. However, the upregulation of NOS expression was also seen in interneurons located just rostrally and caudally to the lesion. A quantitative analysis of laminar distribution of multiple cauda equina constriction (MCEC) induced NADPHd-stained neurons revealed a considerable increase in these neurons in laminae VIII-IX 8h postconstriction, and a highly statistically significant increase of such neurons in laminae VII-X 5 days postconstriction in the lumbosacral segments. Concurrently, the number of NADPHd-stained neurons on laminae I-II in LS segments was greatly reduced. It is concluded that a greater understanding of NO changes after spinal cord trauma is essential for the possibility of targeting this pathway therapeutically.
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PMID:Traumatic injury of the spinal cord and nitric oxide. 1761 76

The present study investigated the cardiovascular effects of orexin (OX)-A and OX-B in the nucleus tractus solitarii (NTS) and delineated the engagement of nitric oxide (NO) and GABA in OX-induced cardiovascular responses. In adult male Sprague-Dawley rats maintained under propofol anesthesia, microinjection bilaterally into the NTS of OX-A or OX-B evoked bi-directional cardiovascular effects in a dose-dependent manner. At a lower dose (5 pmol), OX-A or OX-B decreased systemic arterial pressure (SAP), heart rate (HR), and power density of the vasomotor components of SAP signals, our experimental index for sympathetic neurogenic vasomotor tone. At higher doses (>20 pmol), these two compounds elicited cardiovascular excitatory responses. These bi-directional cardiovascular effects of OX were abolished by co-injection of an OX(1) receptor antagonist, 1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-yl-urea hydrochloride (SB-334867, 0.75 nmol) or the OX(2) receptor antiserum (1:20). In addition, the vasodepressor effects of low dose (5 pmol) OX-A or OX-B in the NTS were attenuated by a nitric oxide synthase (NOS) inhibitor, N(G)-nitro-l-arginine methyl ester (l-NAME, 5 nmol), a neuronal nitric oxide synthase (nNOS) inhibitor, 7-nitroindazole (2.5 pmol) or the soluble guanylate cyclase (sGC) inhibitor, 1H-[1,2,4]oxadiazole[4,3-alpha]quinoxalin-1-one (250 pmol). The vasopressor effects of high dose (200 pmol) OX were reversed by co-administration with GABA(A) or GABA(B) receptor antagonist, bicuculline methiodine (10 pmol) or 2-hydroxy saclofen (100 pmol), or l-NAME (5 nmol). Our results indicate that OX-A or OX-B elicited bi-directional cardiovascular effects via OX receptor-dependent mechanisms. The vasodepressor effects of OX were induced by the nNOS-derived NO and activation of sGC-associated signaling pathway, whereas the vasopressor effects were mediated by interaction with GABAergic or nitrergic neurotransmission in the NTS.
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PMID:Nitric oxide and GABA mediate bi-directional cardiovascular effects of orexin in the nucleus tractus solitarii of rats. 1791 8


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