Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.3.1.21 (CPT)
 4,580 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We examined the effect of two novel phenylglycine derivative drugs on excitotoxicity in murine cortical cell cultures: S-4-carboxy-3-hydroxy-phenylglycine (4C3HPG), a selective agonist of mGluRs 2/3 and an antagonist at mGluRs 1/5, and S-3 hydroxy-phenylglycine (3HPG), an agonist of mGluRs 1/5. 4C3HPG attenuated slowly-triggered NMDA-induced excitotoxic neuronal death, as well as the death induced by combined oxygen-glucose deprivation, but did not affect slowly-triggered excitotoxicity induced by AMPA or kainate. As expected, 4C3HPG also reduced NMDA-induced increases in cAMP in near-pure neuronal cultures, and the protective effect of 4C3HPG on NMDA toxicity could be reversed by adding 8-(4-chlorophenylthio)-adenosine 3':5'-cyclic-monophosphate (CPT cAMP) to the exposure medium. In contrast, 3HPG did not did not have any protective effects in these paradigms; in fact, slowly-triggered NMDA-induced excitotoxicity and the neuronal cell death induced by oxygen-glucose deprivation were potentiated. These results are consistent with the idea that the "inhibitory" mGluRs 2/3 exert a negative modulatory action on NMDA receptor-mediated excitotoxicity via reduction in neuronal cAMP levels.
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PMID:The inhibitory mGluR agonist, S-4-carboxy-3-hydroxy-phenylglycine selectively attenuates NMDA neurotoxicity and oxygen-glucose deprivation-induced neuronal death. 853 57

Motoneuron membrane potentials were recorded from the ventral roots of isolated, hemisected frog spinal cords using sucrose gap techniques. The effects of the selective 5-HT3 agonist 2-methyl-serotonin (2-Me-5HT) on the changes in motoneuron membrane potential produced by dorsal root stimulation and by superfusion of excitatory amino acid agonists were evaluated. Application of 2-Me-5HT (100 microM) did not alter motoneuron membrane potential, but did substantially reduce (approximately 20%) the polysynaptic ventral root potentials evoked by dorsal root stimulation. 2-Me-5HT did not change motoneuron depolarizations generated by addition to the Ringer's solution of the excitatory amino acid agonists AMPA (10-30 microM), kainate (30 microM), or t-ACPD (100 microM), but NMDA-induced motoneuron depolarizations (100 microM) were significantly and reversibly reduced (approximately 20%) by exposure to 2-Me-5HT (100 microM). 2-Me-5HT-evoked decreases of NMDA depolarizations were blocked by the 5-HT3 antagonists ICS 205 930 (50-100 microM) and D-tubocurarine (3-10 microM), but not by MDL 72222 (20-100 microM), the 5-HT2 receptor antagonist ketanserin (10 microM), or the 5-HT1A/5-HT2A antagonist spiperone (10 microM). Two lines of evidence support the hypothesis that the effects of 2-Me-5HT are generated by an indirect mechanism involving interneurons: (1) TTX (0.781 microM) eliminated the effect of 2-Me-5HT on NMDA-induced motoneuron depolarizations, and (2) 2-Me-5HT reduced spontaneous ventral root potentials that result from interneuronal discharges. We attempted to establish the identity of a putative transmitter released by interneurons responsible for the effects on NMDA-depolarizations produced by 2-Me-5HT, but the AMPA receptor antagonist, CNQX (10 microM), the GABAA receptor antagonist, bicuculline (50 microM), the GABAB receptor antagonist, saclofen (100 microM), the opioid antagonist, naloxone (100 microM), and the adenosine antagonists, CPT (20-100 microM) and CSC (10-100 microM) did not alter 2-Me-5HT-induced reductions of NMDA-depolarizations. In sum, the site of interaction between 2-Me-5HT and NMDA appears to be at interneuronal locus, but the mechanism remains unclear.
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PMID:Modulation of frog spinal cord interneuronal activity by activation of 5-HT3 receptors. 878 13

We examined the effects of activation of metabotropic glutamate receptors (mGluRs) on glutamatergic synaptic transmission at the neuromuscular junction of newly hatched Drosophila larvae. In nominally Ca(2+)-free solutions puff-application of low concentrations of glutamate evoked a transient frequency increase of miniature synaptic currents (mSCs). The mean amplitude of mSCs was unaffected, suggesting that this effect was presynaptic. Similar alterations of the mSC frequency were obtained using the mGluR agonists, (S)-4C3HPG, DCG-IV, or (1S,3S)-ACPD, but not when using agonists for ionotropic glutamate receptors, NMDA, AMPA or kainate. An mGluR antagonist, MCCG-I, blocked the effect of agonists on the mSC frequency. An adenylate cyclase activator, forskolin, and a cAMP analog, CPT-cAMP, mimicked the effects of mGluR activation. Meanwhile, an adenylate cyclase inhibitor, SQ22,536, blocked the mGluR agonist-induced effects, and in rutabaga, an adenylate-cyclase-defective mutant, the effect of the agonist was greatly reduced. In the presence of external Ca2+, (S)-4C3HPG decreased the failure rate and increased the mean amplitude of stimulus-evoked SCs, while MCCG-I decreased the amplitudes. We suggest that at the larval Drosophila neuromuscular junction endogenous glutamate released at the terminal potentiates synaptic transmission via a process involving cAMP.
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PMID:Activation of metabotropic glutamate receptors enhances synaptic transmission at the Drosophila neuromuscular junction. 1034 Mar 2

Effects of application of glutamate and glutamatergic ligands were studied to characterize the receptors for glutamate present on the soma membrane of the dorsal unpaired median (DUM) neurons in the thoracic ganglia of the cockroach, Periplaneta americana, using the intracellular recording technique. Application of L-glutamate did not block the GABA-response, and application of beta-guanidino-propionic acid, a competitive antagonist for GABA, failed to block the response to L-glutamate. These results indicate that most of L-glutamate action may not be mediated by a GABA-activated channel. To examine glutamate receptor types on the DUM neurons, glutamate receptor agonists were applied. The ionotropic glutamate receptor (iGluR) agonists evoked depolarizations with the following relative rank of order of potency: kainate > AMPA > quisqualate. Metabotropic glutamate receptor (mGluR) agonists also elicited membrane depolarizations or hyperpolarizations associated with an increase in membrane conductance. The mGluR agonists evoked depolarizations or hyperpolarizations with the following relative rank of order: L-CCG-1 > 1S, 3R-ACPD > L-AP4. Depolarization of the same DUM neuron was detected following exposure of kainate and L-CCG-I, suggesting the coexistence of distinct iGluR and mGluR types. A membrane permeable cAMP analog, CPT-cAMP, could not mimic the effect of mGluR agonists. The mGluR selective antagonists, MCCG and MCPG, failed to antagonize the response to mGluR agonists. The involvement of cAMP in the mGluR response was not confirmed in DUM neurons. Although the functional roles of these receptors are unknown, it might be possible then that these extrasynaptic receptors have a modulatory effect on the excitability of the DUM neurons.
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PMID:Glutamate receptors on the somata of dorsal unpaired median neurons in cockroach, Periplaneta americana, thoracic ganglia. 1201 77

We tested a proposal that the hyperpolarization-activated cation channel (I(h) channel) is involved in the induction of short- and long-term plasticity at the hippocampal mossy fiber-CA3 synapses. Bath application of a specific I(h) channel blocker ZD 7288, at a concentration at which it blocked I(h) channels, substantially depressed mossy fiber synaptic transmission, and this inhibition was occluded by previous blockade of these channels by CsCl. In addition, ZD 7288 attenuated the amplitude of both AMPA and NMDA receptor-mediated excitatory postsynaptic currents (EPSCs) equally and caused a coincident increase in the failure rate of single-fiber EPSCs and paired-pulse facilitation (PPF). It also blocked long-term potentiation (LTP) induction when applied before high-frequency tetanic stimulation (TS), and reversed LTP when applied afterwards. Continuous application of CsCl, which efficiently blocks I(h) channels, mimicked ZD 7288 in inhibiting LTP. Furthermore, ZD 7288 blocked both forskolin- and Sp-8-CPT-cAMPS-mediated enhancements of synaptic transmission. However, it did not affect the frequency facilitation induced by increasing the stimulus frequency from 0.05-1 Hz and the expression of the long-term depression (LTD) induced by low-frequency stimulation (LFS) or DCG-IV. Perforated patch-clamp recordings from granule cells revealed that the voltage for half-maximal activation (V(1/2)) of I(h) was significantly shifted towards the depolarizing direction following forskolin or Sp-8-CPT-cAMPS treatment. This enhanced I(h) current was not due to persistent activation of protein kinase A (PKA), because PKA inhibitor KT5720 did not abolish the difference between the activation curves. Therefore, we conclude that I(h) channels may contribute to the development and regulation of short- and long-term plasticity at the mossy fiber-CA3 synapses.
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PMID:Reexamination of the role of hyperpolarization-activated cation channels in short- and long-term plasticity at hippocampal mossy fiber synapses. 1272 28

When a synapse is stimulated in rapid succession, the second post-synaptic response can be larger than the first and termed paired-pulse facilitation. It has been reported that the paired-pulse ratio (PPR), which is the ratio of the amplitude of the second response to that of the first, depends on the probability of vesicular release at the synapse, and PPR has been used as an easy measure of the release probability. To re-examine the relation of PPR with transmitter release probability, we made whole-cell recordings from astrocytes and pyramidal neurons in the CA1 area of rat hippocampal slices, and studied responses evoked by paired-pulse stimulus of the Schaffer collaterals. In a control condition in which blockers for ionotropic glutamate receptors were added to the artificial cerebrospinal fluid, synaptically induced transporter currents (STCs) recorded from astrocytes showed PPF with similar dependency on stimulus interval as the AMPA-receptor-mediated excitatory post-synaptic currents (AMPA-EPSCs) recorded from pyramidal neurons. When the transmitter release was enhanced by raising Ca2+ concentration in the bathing medium or by applying 8-CPT, an adenosine A1 receptor antagonist, the PPR of the neuronal AMPA-EPSCs decreased significantly. In the same condition, although the amplitude of STCs was significantly increased, the PPR of STCs did not show significant change. The PPR of AMPA-EPSCs, however, recovered by lowering the stimulus intensity or by applying low concentration of NBQX, a competitive antagonist for AMPA-receptor. These results imply that the PPR of transmitter release at Schaffer collateral synapses stays constant as the release probability was altered.
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PMID:Paired-pulse ratio of synaptically induced transporter currents at hippocampal CA1 synapses is not related to release probability. 1748 82

cAMP is a critical second messenger involved in synaptic transmission and synaptic plasticity. Here, we show that activation of the adenylyl cyclase by forskolin and application of the cAMP-analog Sp-5,6-DCl-cBIMPS both mimicked and occluded tetanus-induced long-term potentiation (LTP) in subicular bursting neurons, but not in subicular regular firing cells. Furthermore, LTP in bursting cells was inhibited by protein kinase A (PKA) inhibitors Rp-8-CPT-cAMP and H-89. Variations in the degree of EPSC blockade by the low-affinity competitive AMPA receptor-antagonist gamma-d-glutamyl-glycine (gamma-DGG), analysis of the coefficient of variance as well as changes in short-term potentiation suggest an increase of glutamate concentration in the synaptic cleft after expression of LTP. We conclude that presynaptic LTP in bursting cells requires activation of PKA by a calcium-dependent adenylyl cyclase while LTP in regular firing cells is independent of elevated cAMP levels. Our results provide evidence for a differential role of cAMP in LTP at hippocampal output synapses.
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PMID:Differential cAMP signaling at hippocampal output synapses. 1911 68