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)

Long-term potentiation, a persistent increase in synaptic efficacy, may require a retrograde signal originating in the postsynaptic cell that induces an increase in presynaptic neurotransmitter release. We have constructed a mouse homozygous for a targeted null mutation in the endothelial isoform of nitric oxide synthase and report that long-term potentiation in the CA1 region of these mice is entirely absent under weak stimulation conditions. Application of a membrane-permeant guanosine-3',5'-cyclic monophosphate analogue during tetanus fails to compensate for this deficit, suggesting that nitric oxide produced by endothelial nitric oxide synthase may affect long-term potentiation through a cascade that does not include guanylyl cyclase. We also report that strong tetanic stimulation can induce robust long-term potentiation in these mice which is not blocked by pharmacological inhibitors of nitric oxide synthase. Furthermore, mice lacking endothelial nitric oxide synthase show no shift in the frequency-response curve for the induction of long-term potentiation. Basal synaptic transmission, paired-pulse facilitation and the electrical properties of CA1 cells in these mice were similar to controls. These results support a selective role for endothelial nitric oxide synthase in long-term potentiation, but also demonstrate that nitric oxide synthase is not involved in this process under all conditions.
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PMID:Mice deficient in endothelial nitric oxide synthase exhibit a selective deficit in hippocampal long-term potentiation. 1033 86

Perfusion of hippocampal slices with an inhibitor nitric oxide (NO) synthase blocked induction of long-term potentiation (LTP) produced by a one-train tetanus and significantly reduced LTP by a two-train tetanus, but only slightly reduced LTP by a four-train tetanus. Inhibitors of heme oxygenase, the synthetic enzyme for carbon monoxide (CO), significantly reduced LTP by either a two-train or four-train tetanus. These results suggest that NO and CO are both involved in LTP but may play somewhat different roles. One possibility is that NO serves a phasic, signaling role, whereas CO provides tonic, background stimulation. Another possibility is that NO and CO are phasically activated under somewhat different circumstances, perhaps involving different receptors and second messengers. Because NO is known to be activated by stimulation of NMDA receptors during tetanus, we investigated the possibility that CO might be activated by stimulation of metabotropic glutamate receptors (mGluRs). Consistent with this idea, long-lasting potentiation by the mGluR agonist tACPD was blocked by inhibitors of heme oxygenase but not NO synthase. Potentiation by tACPD was also blocked by inhibitors of soluble guanylyl cyclase (a target of both NO and CO) or cGMP-dependent protein kinase, and guanylyl cyclase was activated by tACPD in hippocampal slices. However, biochemical assays indicate that whereas heme oxygenase is constitutively active in hippocampus, it does not appear to be stimulated by either tetanus or tACPD. These results are most consistent with the possibility that constitutive (tonic) rather than stimulated (phasic) heme oxygenase activity is necessary for potentiation by tetanus or tACPD, and suggest that mGluR activation stimulates guanylyl cyclase phasically through some other pathway.
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PMID:On the respective roles of nitric oxide and carbon monoxide in long-term potentiation in the hippocampus. 1048 62

Perfusion of hippocampal slices with an inhibitor of nitric oxide (NO) synthase-blocked induction of long-term potentiation (LTP) produced by a one-train tetanus and significantly reduced LTP by a two-train tetanus, but only slightly reduced LTP by a four-train tetanus. Inhibitors of heme oxygenase, the synthetic enzyme for carbon monoxide (CO), significantly reduced LTP by either a two-train or four-train tetanus. These results suggest that NO and CO are both involved in LTP but may play somewhat different roles. One possibility is that NO serves a phasic, signaling role, whereas CO provides tonic, background stimulation. Another possibility is that NO and CO are phasically activated under somewhat different circumstances, perhaps involving different receptors and second messengers. Because NO is known to be activated by stimulation of NMDA receptors during tetanus, we investigated the possibility that CO might be activated by stimulation of metabotropic glutamate receptors (mGluRs). Consistent with this idea, long-lasting potentiation by the mGluR agonist tACPD was blocked by inhibitors of heme oxygenase but not NO synthase. Potentiation by tACPD was also blocked by inhibitors of soluble guanylyl cyclase (a target of both NO and CO) or cGMP-dependent protein kinase, and guanylyl cyclase was activated by tACPD in hippocampal slices. However, biochemical assays indicate that whereas heme oxygenase is constitutively active in hippocampus, it does not appear to be stimulated by either tetanus or tACPD. These results are most consistent with the possibility that constitutive (tonic) rather than stimulated (phasic) heme oxygenase activity is necessary for potentiation by tetanus or tACPD, and suggest that mGluR activation stimulates guanylyl cyclase phasically through some other pathway.
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PMID:On the respective roles of nitric oxide and carbon monoxide in long-term potentiation in the hippocampus. 1035 25

Previous studies indicate that cGMP is involved in long-term potentiation (LTP). However, the effects of application of tetanus to induce LTP on cGMP content and the mechanisms by which cGMP may modulate LTP have not been reported. The aim of this work was to study the time course of the changes in cGMP content and of the activity of soluble guanylate cyclase (sGC) (the enzyme that synthesizes cGMP) during LTP. Moreover, we also studied how the changes in cGMP affect cGMP-dependent protein kinase (PKG) and cGMP-degrading phosphodiesterase and the possible role of these changes in LTP. Application of tetanus induced a rise in cGMP, reaching a maximum 10 sec after tetanus. cGMP content decreased below basal levels 5 min after tetanus and remained decreased after 60 min. Activity of sGC increased 5 min after tetanus and returned to basal at 60 min. Tetanus increased the activity of cGMP-degrading phosphodiesterase at 5 and 60 min. GMP, the product of degradation, was increased at 5 and 60 min. Activation of phosphodiesterase and a decrease in cGMP were prevented by inhibiting PKG with Rp-8-bromoguanosine-cGMPS (Rp-8-Br-cGMPS). Inhibition of sGC [with ODQ (oxadiazolo quinoxalin-1-one) or NS 2028 (4H-8-bromo-1,2,4-oxadiazolo(3,4-d)benz(b)(1,4)oxazin-1-one)], of PKG (with Rp-8-Br-cGMPS), or of cGMP-degrading phosphodiesterase [with zaprinast or MBAM (4-[[3',4'-(methylenedioxy)benzyl]amino]-6-methoxyquinazoline) ] impairs LTP. The results indicate that induction of LTP involves transient activation of sGC and an increase in cGMP, followed by activation of cGMP-dependent protein kinase, which, in turn, activates cGMP-degrading phosphodiesterase, resulting in long-lasting reduction of cGMP content.
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PMID:Long-term potentiation in hippocampus involves sequential activation of soluble guanylate cyclase, cGMP-dependent protein kinase, and cGMP-degrading phosphodiesterase. 1245 Nov 12

Nitric oxide (NO) functions in several types of synaptic plasticity, including hippocampal long-term potentiation (LTP), in which it may serve as a retrograde messenger after postsynaptic NMDA receptor activation. In accordance with a prediction of this hypothesis, and with previous findings using guinea pig tissue, exogenous NO, when paired with a short tetanus (ST) to afferent fibers, generated a stable NMDA receptor-independent potentiation of rat CA1 hippocampal synaptic transmission that occluded LTP. Contrary to predictions, however, the pairing-induced potentiation was abolished in the presence of NO synthase inhibitors, indicating that endogenous NO is required for exogenous NO to facilitate LTP. Periodic application of NO while endogenous NO synthesis was blocked indicated that a tonic low level is necessary on both sides of the NO-ST pairing for the plasticity to occur. A similar dependence on tonic NO seems to extend to LTP, because application of an NO synthase inhibitor 5 min after tetanic stimulation blocked LTP as effectively as adding it beforehand. The posttetanus time window during which NO operated was restricted to <15 min. Inhibition of the guanylyl cyclase-coupled NO receptor indicated that the potentiation resulting from NO-ST pairing and the NO signal transduction pathway during early LTP are both through cGMP. We conclude that NO does not function simply as an acute signaling molecule in LTP induction but has an equally important role outside this phase. The results resonate with observations concerning the role of the hippocampal NO-cGMP pathway in certain types of learning behavior.
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PMID:On the role of nitric oxide in hippocampal long-term potentiation. 1262 99

Hyperammonemia impairs long-term potentiation (LTP) in hippocampus, by an unknown mechanism. LTP in hippocampal slices requires activation of the soluble guanylate cyclase (sGC)-protein kinase G (PKG)-cGMP-degrading phosphodiesterase pathway. The aim of this work was to assess whether hyperammonemia impairs LTP by impairing the tetanus-induced activation of this pathway. The tetanus induced a rapid cGMP rise, reaching a maximum at 10 s, both in the absence or presence of ammonia. The increase in cGMP is followed in control slices by a sustained decrease in cGMP due to PKG-mediated activation of cGMP-degrading phosphodiesterase, which is required for maintenance of LTP. Hyperammonemia prevents completely tetanus-induced cGMP decrease by impairing PKG-mediated activation of cGMP-degrading phosphodiesterase. Addition of 8Br-cGMP to slices treated with ammonia restores both phosphodiesterase activation and maintenance of LTP. Impairment of LTP in hyperammonemia may be involved in the impairment of the cognitive function in patients with hepatic encephalopathy.
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PMID:Hyperammonemia impairs long-term potentiation in hippocampus by altering the modulation of cGMP-degrading phosphodiesterase by protein kinase G. 1475 65

Long-term potentiation (LTP) is a long-lasting enhancement of synaptic transmission efficacy and is considered the base for some forms of learning and memory. Nitric oxide (NO)-induced formation of cGMP is involved in hippocampal LTP. We have studied in hippocampal slices the effects of application of a tetanus to induce LTP on cGMP metabolism and the mechanisms by which cGMP modulates LTP. Tetanus application induced a transient rise in cGMP, reaching a maximum at 10s and decreasing below basal levels 5 min after the tetanus, remaining below basal levels after 60 min. Soluble guanylate cyclase (sGC) activity increased 5 min after tetanus and returned to basal levels at 60 min. The decrease in cGMP was due to sustained tetanus-induced increase in cGMP-degrading phosphodiesterase activity, which remained activated 60 min after tetanus. Tetanus-induced activation of PDE and decrease of cGMP were prevented by inhibiting protein kinase G (PKG). This indicates that the initial increase in cGMP activates PKG that phosphorylates (and activates) cGMP-degrading PDE, which, in turn, degrades cGMP. Inhibition of sGC, of PKG or of cGMP-degrading phosphodiesterase impairs LTP, indicating that proper induction of LTP involves transient activation of sGC and increase in cGMP, followed by activation of cGMP-dependent protein kinase, which, in turn, activates cGMP-degrading phosphodiesterase, resulting in long-lasting reduction of cGMP content. Hyperammonemia is the main responsible for the neurological alterations found in liver disease and hepatic encephalopathy, including impaired intellectual function. Hyperammonemia impairs LTP in hippocampus by altering the modulation of this sGC-PKG-cGMP-degrading PDE pathway. Exposure of hippocampal slices to 1 mM ammonia completely prevents tetanus-induced decrease of cGMP by impairing PKG-mediated activation of cGMP-degrading phosphodiesterase. This impairment is responsible for the loss of the maintenance of LTP in hyperammonemia, and may be also involved in the cognitive impairment in patients with hyperammonemia and hepatic encephalopathy.
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PMID:Sequential activation of soluble guanylate cyclase, protein kinase G and cGMP-degrading phosphodiesterase is necessary for proper induction of long-term potentiation in CA1 of hippocampus. Alterations in hyperammonemia. 1531 84

Long-term potentiation (LTP) is impaired in the CA1 area of hippocampal slices from rats with chronic moderate hyperammonemia. We studied the mechanisms by which hyperammonemia in vivo impairs LTP. This process requires sequential activation of soluble guanylate cyclase, cyclic GMP-dependent protein kinase (PKG) and cyclic GMP-degrading phosphodiesterase. Application of the tetanus induced a rapid increase of cyclic GMP in slices from control or hyperammonemic rats, which is followed in control slices by a sustained decrease in cyclic GMP due to sustained activation of cyclic GMP-degrading phosphodiesterase, which in turn is due to sustained activation of PKG. In slices from rats with chronic hyperammonemia tetanus-induced decrease in cyclic GMP was delayed and transient due to lower and transient activation of PKG and of the phosphodiesterase. Hyperammonemia-induced impairment of LTP may be involved in the alterations of cognitive function in patients with hepatic encephalopathy.
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PMID:Chronic hyperammonemia in vivo impairs long-term potentiation in hippocampus by altering activation of cyclic GMP-dependent-protein kinase and of phosphodiesterase 5. 1609 38

Long-term potentiation (LTP) is a long-lasting enhancement of synaptic transmission efficacy and is considered the base for some forms of learning and memory. Hyperammonemia impairs LTP in hippocampus. Proper LTP induction in hippocampal slices requires activation of the soluble guanylate cyclase (sGC)-protein kinase G (PKG)-cyclic guanosine monophosphate (cGMP)-degrading phosphodiesterase pathway. Hyperammonemia impairs LTP by impairing the tetanus-induced activation of this pathway. The tetanus induces a rapid cGMP rise, reaching a maximum at 10 s, both in the absence or in the presence of ammonia. The increase in cGMP is followed, in control slices, by a sustained decrease in cGMP because of PKG-mediated activation of cGMP-degrading phosphodiesterase, which is required for maintenance of LTP. Hyperammonemia prevents completely tetanus-induced decrease in cGMP by impairing PKG-mediated activation of cGMP-degrading phosphodiesterase. Addition of 8 Br-cGMP to slices treated with ammonia restores both phosphodiesterase activation and maintenance of LTP. Impairment of LTP in hyperammonemia may be involved in the impairment of the cognitive function in patients with hepatic encephalopathy.
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PMID:Molecular mechanisms of the alterations in NMDA receptor-dependent long-term potentiation in hyperammonemia. 1638 37

The role of the cyclic nucleotide-gated (CNG) channel CNGA3 is well established in cone photoreceptors and guanylyl cyclase-D-expressing olfactory neurons. To assess a potential function of CNGA3 in the mouse amygdala and hippocampus, we examined synaptic plasticity and performed a comparative analysis of spatial learning, fear conditioning and step-down avoidance in wild-type mice and CNGA3 null mutants (CNGA3(-/-) ). CNGA3(-/-) mice showed normal basal synaptic transmission in the amygdala and the hippocampus. However, cornu Ammonis (CA1) hippocampal long-term potentiation (LTP) induced by a strong tetanus was significantly enhanced in CNGA3(-/-) mice as compared with their wild-type littermates. Unlike in the hippocampus, LTP was not significantly altered in the amygdala of CNGA3(-/-) mice. Enhanced hippocampal LTP did not coincide with changes in hippocampus-dependent learning, as both wild-type and mutant mice showed a similar performance in water maze tasks and contextual fear conditioning, except for a trend toward higher step-down latencies in a passive avoidance task. In contrast, CNGA3(-/-) mice showed markedly reduced freezing to the conditioned tone in the amygdala-dependent cued fear conditioning task. In conclusion, our study adds a new entry on the list of physiological functions of the CNGA3 channel. Despite the dissociation between physiological and behavioral parameters, our data describe a so far unrecognized role of CNGA3 in modulation of hippocampal plasticity and amygdala-dependent fear memory.
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PMID:Altered synaptic plasticity and behavioral abnormalities in CNGA3-deficient mice. 2084 78


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