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)

We previously demonstrated that secreted forms of the Alzheimer's beta-amyloid precursor protein (sAPP) elevate cyclic GMP (cGMP) in primary neuronal cultures and that this effect is responsible for the modulation of neuronal calcium homoeostasis by sAPP. We have investigated further the mechanism by which sAPP elevates cGMP. Inhibition of the formation of nitric oxide or carbon monoxide did not affect the ability of sAPP to lower rapidly intraneuronal calcium levels or elevate cGMP, suggesting that sAPP does not activate a soluble (cytosolic) guanylate cyclase. A dose-dependent stimulation of cGMP formation by sAPP was observed in brain membrane preparations. The stimulation was also dependent on the presence of ATP. These data suggest that sAPP activates a membrane-associated guanylate cyclase, perhaps similar to those present in the receptors for the natriuretic peptides and sperm motility factors.
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PMID:The secreted form of the Alzheimer's beta-amyloid precursor protein stimulates a membrane-associated guanylate cyclase. 757 79

Particulate and soluble guanylyl cyclase activities were studied in postmortem temporal cortex from a series of Alzheimer's disease patients and matched control subjects. Particulate guanylyl cyclase activity was not significantly different between groups. In contrast, the Vmax values for basal and sodium nitroprusside-stimulated soluble guanylyl cyclase activities were approximately 50% lower in the Alzheimer's disease cases, compared to controls. This difference between groups was statistically significant for sodium nitroprusside-stimulated, but not for the basal, enzyme activities. These results provide the first evidence for a loss of nitric oxide responsive guanylyl cyclase activity in Alzheimer's disease brain.
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PMID:Reduced nitric oxide responsive soluble guanylyl cyclase activity in the superior temporal cortex of patients with Alzheimer's disease. 761 1

beta-Amyloid precursor protein (beta APP), transforming growth factor beta (TGF beta), and tumor necrosis factor-alpha (TNF alpha) are remarkably pleiotropic neural cytokines/neurotrophic factors that orchestrate intricate injury-related cellular and molecular interactions. The links between these three factors include: their responses to injury; their interactive effects on astrocytes, microglia and neurons; their ability to induce cytoprotective responses in neurons; and their association with cytopathological alterations in Alzheimer's disease. Astrocytes and microglia each produce and respond to TGF beta and TNF alpha in characteristic ways when the brain is injured. TGF beta, TNF alpha and secreted forms of beta APP (sAPP) can protect neurons against excitotoxic, metabolic and oxidative insults and may thereby serve neuroprotective roles. On the other hand, under certain conditions TNF alpha and the fibrillogenic amyloid beta-peptide (A beta) derivative of beta APP can promote damage of neuronal and glial cells, and may play roles in neurodegenerative disorders. Studies of genetically manipulated mice in which TGF beta, TNF alpha or beta APP ligand or receptor levels are altered suggest important roles for each factor in cellular responses to brain injury and indicate that mediators of neural injury responses also have the potential to enhance amyloidogenesis and/or to interfere with neuroregeneration if expressed at abnormal levels or modified by strategic point mutations. Recent studies have elucidated signal transduction pathways of TGF beta (serine/threonine kinase cascades), TNF alpha (p55 receptor linked to a sphingomyelin-ceramide-NF kappa B pathway), and secreted forms of beta APP (sAPP; receptor guanylate cyclase-cGMP-cGMP-dependent kinase-K+ channel activation). Knowledge of these signaling pathways is revealing novel molecular targets on which to focus neuroprotective therapeutic strategies in disorders ranging from stroke to Alzheimer's disease.
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PMID:Cellular signaling roles of TGF beta, TNF alpha and beta APP in brain injury responses and Alzheimer's disease. 906 86

Humans are exposed to aluminum from environmental sources and therapeutic treatments. However, aluminum is neurotoxic and is considered a possible etiologic factor in Alzheimer's disease and other neurological disorders. The molecular mechanism of aluminum neurotoxicity is not understood. We tested the effects of aluminum on the glutamate-nitric oxide-cyclic GMP pathway in cultured neurons. Neurons were exposed to 50 microM aluminum in culture medium for short-term (4 h) or long-term (8-14 days) periods, or rats were prenatally exposed, i.e., 3.7% aluminum sulfate in the drinking water, during gestation. Chronic (but not short-term) exposure of neurons to aluminum decreased glutamate-induced activation of nitric oxide synthase by 38% and the formation of cyclic GMP by 77%. The formation of cyclic GMP induced by the nitric oxide-generating agent S-nitroso-N-acetylpenicillamine was reduced by 33%. In neurons from rats prenatally exposed to aluminum but not exposed to it during culture, glutamate-induced formation of cyclic GMP was inhibited by 81%, and activation of nitric oxide synthase was decreased by 85%. The formation of cyclic GMP induced by S-nitroso-N-acetylpenicillamine was not affected. These results indicate that chronic exposure to aluminum impairs glutamate-induced activation of nitric oxide synthase and nitric oxide-induced activation of guanylate cyclase. Impairment of the glutamate-nitric oxide-cyclic GMP pathway in neurons may contribute to aluminum neurotoxicity.
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PMID:Chronic exposure to aluminum impairs neuronal glutamate-nitric oxide-cyclic GMP pathway. 958 Jan 58

Nitric oxide (NO), generated by endothelial (e) NO synthase (NOS) and neuronal (n) NOS, plays a ubiquitous role in the body in controlling the function of almost every, if not every, organ system. Bacterial and viral products, such as bacterial lipopolysaccharide (LPS), induce inducible (i) NOS synthesis that produces massive amounts of NO toxic to the invading viruses and bacteria, but also host cells by inactivation of enzymes leading to cell death. The actions of all forms of NOS are mediated not only by the free radical oxidant properties of this soluble gas, but also by its activation of guanylate cyclase (GC), leading to the production of cyclic guanosine monophosphate (cGMP) that mediates many of its physiological actions. In addition, NO activates cyclooxygenase and lipoxygenase, leading to the production of physiologically relevant quantities of prostaglandin E2 (PGE2) and leukotrienes. In the case of iNOS, the massive release of NO, PGE2, and leukotrienes produces toxic effects. Systemic injection of LPS causes induction of interleukin (IL)-1 beta mRNA followed by IL-beta synthesis that induces iNOS mRNA with a latency of two and four hours, respectively, in the anterior pituitary and pineal glands, meninges, and choroid plexus, regions outside the blood-brain barrier, and shortly thereafter, in hypothalamic regions, such as the temperature-regulating centers, paraventricular nucleus containing releasing and inhibiting hormone neurons, and the arcuate nucleus, a region containing these neurons and axons bound for the median eminence. We are currently determining if LPS similarly activates cytokine and iNOS production in the cardiovascular system and the gonads. Our hypothesis is that recurrent infections over the life span play a significant role in producing aging changes in all systems outside the blood-brain barrier via release of toxic quantities of NO. NO may be a major factor in the development of coronary heart disease (CHD). Considerable evidence has accrued indicating a role for infections in the induction of CHD and, indeed, patients treated with a tetracycline derivative had 10 times less complications of CHD than their controls. Stress, inflammation, and infection have all been shown to cause induction of iNOS in rats, and it is likely that this triad of events is very important in progression of coronary arteriosclerosis leading to coronary occlusion. Aging of the anterior pituitary and pineal with resultant decreased secretion of pituitary hormones and the pineal hormone, melatonin, respectively, may be caused by NO. The induction of iNOS in the temperature-regulating centers by infections may cause the decreased febrile response in the aged by loss of thermosensitive neurons. iNOS induction in the paraventricular nucleus may cause the decreased nocturnal secretion of growth hormone (GH) and prolactin that occurs with age, and its induction in the arcuate nucleus may destroy luteinizing hormone-releasing hormone (LHRH) neurons, thereby leading to decreased release of gonadotropins. Recurrent infections may play a role in aging of other parts of the brain, because there are increased numbers of astrocytes expressing IL-1 beta throughout the brain in aged patients. IL-1 and products of NO activity accumulate around the plaques of Alzheimer's, and may play a role in the progression of the disease. Early onset Parkinsonism following flu encephalitis during World War I was possibly due to induction of iNOS in cells adjacent to substantia nigra dopaminergic neurons leading to death of these cells, which, coupled with ordinary aging fall out, led to Parkinsonism. The central nervous system (CNS) pathology in AIDS patients bears striking resemblance to aging changes, and may also be largely caused by the action of iNOS. Antioxidants, such as melatonin, vitamin C, and vitamin E, probably play an important acute and chronic role in reducing or eliminating the oxidant damage produced by NO.
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PMID:The nitric oxide hypothesis of aging. 995 25

The biological roles of nitric oxide (NO) and cGMP as inter- and intracellular messengers have been intensively investigated during the last decade. NO and cGMP both mediate physiological effects in the cardiovascular, endocrinological, and immunological systems as well as in central nervous system (CNS). In the CNS, activation of the N-methyl-D-aspartic acid (NMDA) type of glutamatergic receptor induces Ca(2+)-dependent NOS and NO release, which then activates soluble guanylate cyclase for the synthesis of cGMP. Both compounds appear to be important mediators in long-term potentiation and long-term depression, and thus may play important roles in the mechanisms of learning and memory. Aging and the accumulation of amyloid beta (A beta) peptides are important risk factors for the impairment of memory and development of dementia. In these studies, the mechanism of basal- and NMDA receptor-mediated cGMP formation in different parts of adult and aged brains was evaluated. The relative activity of the NO cascade was determined by assay of NOS and guanylate cyclase activities. In addition, the effect of the neurotoxic fragment 25-35 of A beta (A beta) peptide on basal and NMDA receptor-mediated NOS activity was investigated. The studies were carried out using slices of hippocampus, brain cortex, and cerebellum from 3- and 28-mo-old rats. Aging coincided with a decrease in the basal level of cGMP as a consequence of a more active degradation of cGMP by a phosphodiesterase in the aged brain as compared to the adult brain. Moreover, a loss of the NMDA receptor-stimulated enhancement of the cGMP level determined in the presence of cGMP-phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) was observed in hippocampus and cerebellum of aged rats. However, this NMDA receptor response was preserved in aged brain cerebral cortex. A significant enhancement of the basal activity of NOS by about 175 and 160% in hippocampus and cerebellum, respectively, of aged brain may be involved in the alteration of the NMDA receptor response. The neurotoxic fragment of A beta, peptide 25-35, decreased significantly the NMDA receptor-mediated calcium, and calmodulim-dependent NO synthesis that may then be responsible for disturbances of the NO and cGMP signaling pathway. We concluded that cGMP-dependent signal transduction in hippocampus and cerebellum may become insufficient in senescent brain and may have functional consequences in disturbances of learning and memory processes. A beta peptide accumulated during brain aging and in Alzheimer disease may be an important factor in decreasing the NO-dependent signal transduction mediated by NMDA receptors.
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PMID:Aging modulates nitric oxide synthesis and cGMP levels in hippocampus and cerebellum. Effects of amyloid beta peptide. 1034 72

Aluminium is neurotoxic and is considered a possible etiologic factor in Alzheimer's disease, dialysis syndrome and other neurological disorders. The molecular mechanism of aluminium-induced impairment of neurological functions remains unclear. We showed that aluminium impairs the glutamate-nitric oxide-cGMP pathway in cultured neurons. The aim of this work was to assess by in vivo brain microdialysis whether chronic administration of aluminium in the drinking water (2.5% aluminium sulfate) also impairs the glutamate-nitric oxide-cGMP pathway in the cerebellum of rats in vivo. Chronic exposure to aluminium reduced NMDA-induced increase of extracellular cGMP by ca 50%. The increase in extracellular cGMP induced by the nitric oxide generating agent S-nitroso-N-acetylpenicillamine was higher (240%) in rats treated with aluminium than in controls. Immunoblotting experiments showed that aluminium reduced the cerebellar content of calmodulin and nitric oxide synthase by 34 and 15%, respectively. Basal activity of soluble guanylate cyclase was decreased by 66% in aluminium-treated rats, while the activity after stimulation with S-nitroso-N-acetylpenicillamine was similar to controls. Basal cGMP in the cerebellar extracellular space was decreased by 50% in aluminium-treated rats. These results indicate that chronic exposure to aluminium reduces the basal activity of guanylate cyclase and impairs the glutamate-nitric oxide-cGMP pathway in the animal in vivo.
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PMID:Chronic exposure to aluminium impairs the glutamate-nitric oxide-cyclic GMP pathway in the rat in vivo. 1035 91

Mechanisms of the process of neuronal degeneration in neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and Alzheimer's disease (AD) remain unsolved. Oxidative stress might be a possible mechanism of neuronal cell death. Glutamate is an excitatory amino acid and its excessive release can cause intracellular calcium influx, activation of calcium-dependent enzymes such as nitric oxide (NO) synthase (NOS), and production of toxic oxygen radicals. Excessive release of glutamate, therefore, can be used as a model of experimental oxidative stress. Continuous exposure to low levels of glutamate potentiates selective motor neuronal death mediated by NO, which inversely protects nonmotor neurons through the guanylyl cyclase-cGMP cascade. Mesencephalic dopaminergic neurons are resistant to cytotoxicity induced by NO. The protecting mechanism from NO neurotoxicity in dopaminergic neurons is based on inhibition of conversion of NO to peroxynitrite anion, and is possibly due to suppression of superoxide anion production. Dopamine D 2 agonists provide protection mediated not only by the inhibition of dopamine turnover but also via D 2-type dopamine receptor stimulation and the subsequent synthesis of proteins that scavenge free radicals. In addition, nicotinic receptor stimulation may be able to protect neurons from oxidative stress induced by A beta.
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PMID:[Neuronal cell death in neurodegenerative disorders and oxidative stress]. 1037 84

Within the central nervous system, acetylcholine (ACh) functions as a state-dependent modulator at a range of sites, but its signaling mechanisms are yet unclear. Cholinergic projections from the brain stem and basal forebrain innervate the suprachiasmatic nucleus (SCN), the master circadian clock in mammals, and cholinergic stimuli adjust clock timing. Cholinergic effects on clock state require muscarinic receptor-mediated activation of guanylyl cyclase and cGMP synthesis, although the effect is indirect. Here we evaluate the roles of carbon monoxide (CO) and nitric oxide (NO), major activators of cGMP synthesis. Both heme oxygenase 2 (HO-2) and neuronal nitric oxide synthase (nNOS), enzymes that synthesize CO and NO, respectively, are expressed in rat SCN, with HO-2 localized to the central core of the SCN, whereas nNOS is a punctate plexus. Hemin, an activator of HO-2, but not the NO donor, SNAP, mimicked cholinergic effects on circadian timing. Selective inhibitors of HO fully blocked cholinergic clock resetting, whereas NOS inhibition partially attenuated this effect. Hemoglobin, an extracellular scavenger of both NO and CO, blocked cholinergic stimulation of cGMP synthesis, whereas l-NAME, a specific inhibitor of NOS, had no effect on cholinergic stimulation of cGMP, but decreased the cGMP basal level. We conclude that basal NO production generates cGMP tone that primes the clock for cholinergic signaling, whereas HO/CO transmit muscarinic receptor activation to the cGMP-signaling pathway that modulates clock state. In light of the recently reported inhibitory interaction between HO-2/CO and amyloid-beta, a marker of Alzheimer's disease (AD), we speculate that HO-2/CO signaling may be a defective component of cholinergic neurotransmission in the pathophysiology of AD, whose manifestations include disintegration of circadian timing.
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PMID:Carbon monoxide and nitric oxide: interacting messengers in muscarinic signaling to the brain's circadian clock. 1157 81

Aluminium (Al) is a neurotoxicant and appears as a possible etiological factor in Alzheimer's disease and other neurological disorders. The mechanisms of Al neurotoxicity are presently unclear but evidence has emerged suggesting that Al accumulation in the brain can alter neuronal signal transduction pathways associated with glutamate receptors. In cerebellar neurons in culture, long term-exposure to Al added 'in vitro' impaired the glutamate-nitric oxide (NO)-cyclic GMP (cGMP) pathway, reducing glutamate-induced activation of NO synthase and NO-induced activation of the cGMP generating enzyme, guanylate cyclase. Prenatal exposure to Al also affected strongly the function of the glutamate-NO-cGMP pathway. In cultured neurons from rats prenatally exposed to Al, we found reduced content of NO synthase and of guanylate cyclase, and a dramatic decrease in the ability of glutamate to increase cGMP formation. Activation of the glutamate-NO-cGMP pathway was also strongly impaired in cerebellum of rats chronically treated with Al, as assessed by in vivo brain microdialysis in freely moving rats. These findings suggest that the impairment of the Glu-NO-cGMP pathway in the brain may be responsible for some of the neurological alterations induced by Al.
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PMID:Aluminium impairs the glutamate-nitric oxide-cGMP pathway in cultured neurons and in rat brain in vivo: molecular mechanisms and implications for neuropathology. 1170 15


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