Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.12 (PKG)
 2,515 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
Learn Mem
PMID:On the respective roles of nitric oxide and carbon monoxide in long-term potentiation in the hippocampus. 1048 62

Previous results have suggested that cGMP is involved in hippocampal long-term potentiation (LTP), perhaps as the presynaptic effector of a retrograde messenger. However, other studies have failed to replicate some of those results, making the role of cGMP uncertain. We therefore reexamined this question and identified several variables that can affect the contribution of cGMP. First, brief perfusion with 8-Br-cGMP before weak tetanic stimulation produced long-lasting potentiation in the CA1 region of hippocampal slices, but more prolonged perfusion with 8-Br-cGMP before the tetanus did not produce long-lasting potentiation. Second, the activity-dependent long-lasting potentiation by cGMP analogs was reduced when NMDA receptors were completely blocked, indicating that NMDA receptor activation contributes to, but is not required for, the potentiation. The amount of reduction of the potentiation differed with different protocols, and in some cases could be complete. Third, LTP produced by strong tetanic stimulation in the stratum radiatum of CA1 (which expresses eNOS) was blocked by inhibitors of soluble guanylyl cyclase or cGMP-dependent protein kinase, but LTP in the stratum oriens (which does not express eNOS) was not. The results of these experiments should help to explain some of the discrepant findings from previous studies, and, in addition, may provide insights into the mechanisms and functional role of the cGMP-dependent component of LTP.
Learn Mem
PMID:The specific role of cGMP in hippocampal LTP. 1045 67

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.
Learn Mem
PMID:On the respective roles of nitric oxide and carbon monoxide in long-term potentiation in the hippocampus. 1035 25

The Drosophila giant fiber jump-and-flight escape response is a model for genetic analysis of both the physiology and the plasticity of a sensorimotor behavioral pathway. We previously established the electrically induced giant fiber response in intact tethered flies as a model for habituation, a form of nonassociative learning. Here, we show that the rate of stimulus-dependent response decrement of this neural pathway in a habituation protocol is correlated with PKG (cGMP-Dependent Protein Kinase) activity and foraging behavior. We assayed response decrement for natural and mutant rover and sitter alleles of the foraging (for) gene that encodes a Drosophila PKG. Rover larvae and adults, which have higher PKG activities, travel significantly farther while foraging than sitters with lower PKG activities. Response decrement was most rapid in genotypes previously shown to have low PKG activities and sitter-like foraging behavior. We also found differences in spontaneous recovery (the reversal of response decrement during a rest from stimulation) and a dishabituation-like phenomenon (the reversal of response decrement evoked by a novel stimulus). This electrophysiological study in an intact animal preparation provides one of the first direct demonstrations that PKG can affect plasticity in a simple learning paradigm. It increases our understanding of the complex interplay of factors that can modulate the sensitivity of the giant fiber escape response, and it defines a new adult-stage phenotype of the foraging locus. Finally, these results show that behaviorally relevant neural plasticity in an identified circuit can be influenced by a single-locus genetic polymorphism existing in a natural population of Drosophila.
Learn Mem
PMID:A cGMP-dependent protein kinase gene, foraging, modifies habituation-like response decrement of the giant fiber escape circuit in Drosophila. 1104 Feb 66

The cGMP-dependent protein kinase (PKG) has many cellular functions in vertebrates and insects that affect complex behaviors such as locomotion and foraging. The foraging (for) gene encodes a PKG in Drosophila melanogaster. Here, we demonstrate a function for the for gene in sensory responsiveness and nonassociative learning. Larvae of the natural variant sitter (for(s)) show less locomotor activity during feeding and have a lower PKG activity than rover (for(R)) larvae. We used rover and sitter adult flies to test whether PKG activity affects (1) responsiveness to sucrose stimuli applied to the front tarsi, and (2) habituation of proboscis extension after repeated sucrose stimulation. To determine whether the differences observed resulted from variation in the for gene, we also tested for(s2), a sitter mutant produced on a rover genetic background. We found that rovers (for(R)) were more responsive to sucrose than sitters (for(s) and for(s2)) at 1-, 2-, and 3-wk old. This was true for both sexes. Differences in sucrose responsiveness between rovers and sitters were greater after 2 h of food deprivation than after 24 h. Of flies with similar sucrose responsiveness, for(R) rovers showed less habituation and generalization of habituation than for(s) and for(s2) sitters. These results show that the PKG encoded by for independently affects sensory responsiveness and habituation in Drosophila melanogaster.
Learn Mem
PMID:Activity of cGMP-dependent protein kinase (PKG) affects sucrose responsiveness and habituation in Drosophila melanogaster. 1516 60

Animals must be able to find and evaluate food to ensure survival. The ability to associate a cue with the presence of food is advantageous because it allows an animal to quickly identify a situation associated with a good, bad, or even harmful food. Identifying genes underlying these natural learned responses is essential to understanding this ability. Here, we investigate whether natural variation in the foraging (for) gene in Drosophila melanogaster larvae is important in mediating associations between either an odor or a light stimulus and food reward. We found that for influences olfactory conditioning and that the mushroom bodies play a role in this for-mediated olfactory learning. Genotypes associated with high activity of the product of for, cGMP-dependent protein kinase (PKG), showed greater memory acquisition and retention compared with genotypes associated with low activity of PKG when trained with three conditioning trials. Interestingly, increasing the number of training trials resulted in decreased memory retention only in genotypes associated with high PKG activity. The difference in the dynamics of memory acquisition and retention between variants of for suggests that the ability to learn and retain an association may be linked to the foraging strategies of the two variants.
Learn Mem 2007 May
PMID:Natural variation in Drosophila larval reward learning and memory due to a cGMP-dependent protein kinase. 1752 25

The role of the foraging (for) gene, which encodes a cyclic guanosine-3',5'-monophosphate (cGMP)-dependent protein kinase (PKG), in food-search behavior in Drosophila has been intensively studied. However, its functions in other complex behaviors have not been well-characterized. Here, we show experimentally in Drosophila that the for gene is required in the operant visual learning paradigm. Visual pattern memory was normal in a natural variant rover (for(R)) but was impaired in another natural variant sitter (for(S)), which has a lower PKG level. Memory defects in for(S) flies could be rescued by either constitutive or adult-limited expression of for in the fan-shaped body. Interestingly, we showed that such rescue also occurred when for was expressed in the ellipsoid body. Additionally, expression of for in the fifth layer of the fan-shaped body restored sufficient memory for the pattern parameter "elevation" but not for "contour orientation," whereas expression of for in the ellipsoid body restored sufficient memory for both parameters. Our study defines a Drosophila model for further understanding the role of cGMP-PKG signaling in associative learning/memory and the neural circuit underlying this for-dependent visual pattern memory.
Learn Mem 2008 Mar
PMID:Visual pattern memory requires foraging function in the central complex of Drosophila. 1831 Apr 60

Recent studies have shown that nitric oxide (NO) signaling plays a crucial role in memory consolidation of Pavlovian fear conditioning and in synaptic plasticity in the lateral amygdala (LA). In the present experiments, we examined the role of the cGMP-dependent protein kinase (PKG), a downstream effector of NO, in fear memory consolidation and long-term potentiation (LTP) at thalamic and cortical input pathways to the LA. In behavioral experiments, rats given intra-LA infusions of either the PKG inhibitor Rp-8-Br-PET-cGMPS or the PKG activator 8-Br-cGMP exhibited dose-dependent impairments or enhancements of fear memory consolidation, respectively. In slice electrophysiology experiments, bath application of Rp-8-Br-PET-cGMPS or the guanylyl cyclase inhibitor LY83583 impaired LTP at thalamic, but not cortical inputs to the LA, while bath application of 8-Br-cGMP or the guanylyl cyclase activator YC-1 resulted in enhanced LTP at thalamic inputs to the LA. Interestingly, YC-1-induced enhancement of LTP in the LA was reversed by concurrent application of the MEK inhibitor U0126, suggesting that the NO-cGMP-PKG signaling pathway may promote synaptic plasticity and fear memory formation in the LA, in part by activating the ERK/MAPK signaling cascade. As a test of this hypothesis, we next showed that rats given intra-LA infusion of the PKG inhibitor Rp-8-Br-PET-cGMPS or the PKG activator 8-Br-cGMP exhibit impaired or enhanced activation, respectively, of ERK/MAPK in the LA after fear conditioning. Collectively, our findings suggest that an NO-cGMP-PKG-dependent form of synaptic plasticity at thalamic input synapses to the LA may underlie memory consolidation of Pavlovian fear conditioning, in part, via activation of the ERK/MAPK signaling cascade.
Learn Mem 2008 Oct
PMID:The NO-cGMP-PKG signaling pathway regulates synaptic plasticity and fear memory consolidation in the lateral amygdala via activation of ERK/MAP kinase. 1883 66

Evidence suggests that the NO/sGC/PKG pathway plays a key role in memory processing but the actual participation of this signaling cascade in the amygdala during memory consolidation remains unknown. Here, we show that when infused in the amygdala immediately after inhibitory avoidance training, but not later, the NO synthase inhibitor L-NNA hindered long-term memory retention without affecting locomotion, exploratory behavior, anxiety state or retrieval of the avoidance response. The amnesic effect of L-NNA was not state-dependent and was mimicked by the soluble guanylyl cyclase inhibitor LY83583 and the PKG inhibitor KT-5823. On the contrary, post-training intra-amygdala infusion of the NOS substrate L-Arg, the NO-releasing compound SNAP or the non-hydrolysable analog of cGMP 8Br-cGMP increased memory retention in a dose-dependent manner. Co-infusion of 8Br-cGMP reversed the amnesic effect of L-NNA and LY83583 but not that of KT-5823. Our data indicate that the NO-induced activation of PKG in the amygdala is a necessary step for consolidation of inhibitory avoidance memory.
Neurobiol Learn Mem 2009 Mar
PMID:On the requirement of nitric oxide signaling in the amygdala for consolidation of inhibitory avoidance memory. 1893 Aug 32

We have recently hypothesized that NO-cGMP-PKG signaling in the lateral nucleus of the amygdala (LA) during auditory fear conditioning coordinately regulates ERK-driven transcriptional changes in both auditory thalamic (MGm/PIN) and LA neurons that serve to promote pre- and postsynaptic alterations at thalamo-LA synapses, respectively. In the present series of experiments, we show that N-methyl-D-aspartate receptor (NMDAR)-driven synaptic plasticity and NO-cGMP-PKG signaling in the LA regulate the training-induced expression of ERK and the ERK-driven immediate early genes (IEGs) Arc/Arg3.1, c-Fos, and EGR-1 in the LA and the MGm/PIN. Rats receiving intra-LA infusion of the NR2B selective antagonist Ifenprodil, the NOS inhibitor 7-Ni, or the PKG inhibitor Rp-8-Br-PET-cGMPS exhibited significant decreases in ERK activation and in the training-induced expression of all three IEGs in the LA and MGm/PIN while intra-LA infusion of the PKG activator 8-Br-cGMP had the opposite effect. Remarkably, those rats given intra-LA infusion of the membrane impermeable NO scavenger c-PTIO exhibited significant decreases in ERK activation and ERK-driven IEG expression in the MGm/PIN, but not in the LA. Together with our previous experiments, these results suggest that synaptic plasticity and the NO-cGMP-PKG signaling pathway promote fear memory consolidation, in part, by regulating ERK-driven transcription in both the LA and the MGm/PIN. They further suggest that synaptic plasticity in the LA during fear conditioning promotes ERK-driven transcription in MGm/PIN neurons via NO-driven "retrograde signaling."
Learn Mem 2010 Apr
PMID:Synaptic plasticity and NO-cGMP-PKG signaling coordinately regulate ERK-driven gene expression in the lateral amygdala and in the auditory thalamus following Pavlovian fear conditioning. 2035 Oct 57


1 2 Next >>