UMLS:C0011570 - FACTA Search

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Query: UMLS:C0011570 (depression)
172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A cDNA encoding the human metabotropic glutamate receptor type 4 (hmGluR4) was isolated from human brain cDNA libraries by cross-hybridization with rat mGluR4 probes. The deduced amino acid sequence of human mGluR4 consists of 912 residues and shows a sequence identity of 96% to the amino acid sequence of rat mGluR4. Northern blot analyses indicate that hmGluR4 is strongly expressed in the cerebellum of the adult human brain but also at low levels in hippocampus, hypothalamus and thalamus. Stimulation of hmGluR4 with L-2-amino-4-phosphonobutyrate (L-AP4), L-serine-O-phosphate (L-SOP), L-glutamate or (1S,3R)-1-aminocyclo-pentane-1,3-dicarboxylic acid ((1S,3R)-ACPD) in stably transfected Chinese hamster ovary (CHO) cells depressed forskolin-induced cAMP accumulation, whereas quisqualate (0.5 mM) was ineffective. The rank order of agonist potencies is: L-AP4 > L-SOP > L-glutamate > (1S,3R)-ACPD >> quisqualate. (R,S)-alpha-methyl-4-carboxyphenylglycine (1 mM), a reported antagonist at some mGluR subtypes, did not reduce the depression of forskolin-induced cAMP accumulation by L-AP4.
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PMID:Molecular cloning, functional expression and pharmacological characterization of the human metabotropic glutamate receptor type 4. 761 40

A cDNA encoding the human metabotropic glutamate receptor type 2 (hmGluR2) was isolated from human brain cDNA libraries by cross-hybridization with rat mGluR2 probes. The deduced amino acid sequence of the human mGluR2 receptor consists of 872 residues and shows a sequence identity of 97% to the amino acid sequence of rat mGluR2. Northern blot analyses showed that hmGluR2 is widely expressed in different regions of the adult brain as well as in fetal human brain. Genomic Southern blotting localized the mGluR2 gene to human chromosome 3. Chinese hamster ovary (CHO) cells stably transfected with the cloned hmGluR2 cDNA exhibit agonist induced depression of forskolin-stimulated cAMP accumulation. A direct comparison of CHO cells stably expressing human and rat mGluR2 with five agonists revealed the same rank order of potency [(2S,3S,4S)-alpha-(carboxycyclopropyl)-glycine >> (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid = L-glutamate >> quisqualate = L-2-amino-4-phosphonobutyric acid] and similar EC50 values for both homologous receptors. (R,S)-alpha-methyl-4-carboxyphenylglycine, a reported antagonist at some mGluR subtypes, reduced the depression of forskolin-induced cAMP accumulation by (1S,3R)-ACPD in both human and rat mGluR2.
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PMID:Molecular cloning, functional expression and pharmacological characterization of the human metabotropic glutamate receptor type 2. 762 Jun 13

Whole-cell voltage-clamp recordings were made in thin transverse slices from neurons of the dorsomedial subdivision of the nucleus of the tractus solitarius (NTS) of the rat. Cells were exposed to either the ionotropic glutamate receptor agonist (R, S)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) or the GABAA receptor agonist muscimol via pressure ejection directed at the cell soma. The metabotropic glutamate receptor agonist 1S,3R-1-aminocyclopentane-1,3-dicarboxylate (1S,3R-ACPD; 2-100 microM) reversibly depressed muscimol-evoked currents. Conversely, 1S,3R-ACPD reversibly potentiated AMPA-evoked currents. High-frequency stimulation of the tractus solitarius in the presence of 6,7-dinitroquinoxaline-2,3-dione and D-2-amino-5-phosphonopentanoic acid also produced a reversible depression of muscimol-evoked currents that was occluded in the presence of 100 microM 1S,3R-ACPD. 8-Br-cGMP or brain-derived natriuretic peptide mimicked the effects of 1S,3R-ACPD on AMPA and muscimol currents. However, agents that mimicked the actions of cAMP or diacylglycerol did not. These findings indicate that metabotropic glutamate receptors may mediate multiple components of excitatory transmission in the NTS including modulation of glutamate and GABA-activated ion channels.
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PMID:Activation of metabotropic glutamate receptors produces reciprocal regulation of ionotropic glutamate and GABA responses in the nucleus of the tractus solitarius of the rat. 768 73

1. Whole-cell patch-clamp recordings were made from sympathetic preganglionic neurons (SPNs) in transverse thoracolumbar spinal cord slices of 10- to 16-day-old rats, and the effects of L-glutamate (L-Glu) and analogues on excitatory (EPSCs) and inhibitory (IPSCs) postsynaptic currents evoked by stimulation of lateral funiculus were studied. 2. L-Glu (10-300 microM), quisqualate (QA, 0.1-3 microM), kainate (KA, 0.3-10 microM), ibotenate (10-25 microM), and L-2-amino-4-phosphonobutyrate (L-AP4, 25-300 microM) depressed the EPSCs and IPSCs in a concentration-dependent manner, the rank order being QA > KA > ibotenate > L-AP4 > or = L-Glu. The metabotropic glutamate receptor agonist trans-1-amino-1,3-cyclopentane-dicarboxylic acid (trans-ACPD, 25-100 microM) reduced the synaptic currents as well. A similar effect was not observed with N-methyl-D-aspartate (NMDA). 3. The excitatory amino acid uptake inhibitor L-aspartic acid-beta-hydroxamate (AAH, 100 microM), although having little or no direct effect on EPSCs, unmasked the inhibitory effect of low (< or = 1 microM) concentrations of L-Glu. 4. The synaptic depression was not accompanied by a detectable change in holding currents or EPSC reversal potentials and decay constants in the majority of SPNs studied. At higher concentrations, L-Glu and analogues, but not L-AP4, induced an inward current in some SPNs. 5. Although strongly depressing the EPSCs, L-AP4 and trans-ACPD had no significant effect on the amplitude of inward current induced by exogenous L-Glu.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Excitatory amino acids depress synaptic currents in neonate rat sympathetic preganglionic neurons. 768 99

In patch-clamped Purkinje cells (PCs), bath application of the ionotropic glutamate receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) prevents induction of long-term depression (LTD) of parallel fibre (PF)-mediated EPSPs by a pairing protocol between Ca2+ spike firing and PF stimulation whereas bath application of (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG), a metabotropic glutamate (mGLU) receptor antagonist, does not. On the other hand, LTD can be also induced by pairing direct depolarization of PCs with activation of mGLU receptors by 1S,3R-aminocyclopentyl-dicarboxylate (1S,3R-ACPD), even in the presence of CNQX. In this case, LTD induction is not consistently blocked by bath application of the nitric oxide synthase inhibitor, NG-methyl-L-arginine (L-NMMA), whereas it is strongly blocked when the protein kinase C inhibitor peptide 19-36 is dialysed into PCs. These results are at variance with LTD induced by a pairing protocol between Ca2+ spikes and PF-mediated EPSPs which depends to the same extent on both cascades. Finally, thapsigargin, which depletes most intracellular Ca2+ pools, does not block induction of LTD by a pairing protocol between Ca2+ spikes and PF-mediated EPSPs whereas it prevents the induction of LTD depending on strong mGLU receptor activation.
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PMID:Receptors and second messengers involved in long-term depression in rat cerebellar slices in vitro: a reappraisal. 771 36

Whole-cell patch-clamp recordings of evoked excitatory postsynaptic currents (EPSCs) were made from granule cells of the rat dentate gyrus in vitro. Tetanic stimulation in control media evoked a statistically identical long-term potentiation (LTP) of both the AMPA and NMDA receptor-mediated components of the dual component EPSC (AM-PAR and NMDAR EPSCs), as shown by a similar percentage increase in both components when measured at a holding potential of -30 mV, and also by an identical time course of the pre- and post-LTP induced EPSC at -30 mV and -70 mV. Application of the selective metabotropic glutamate receptor (mGluR) agonist 1S,3R-ACPD induced a transient depression followed by a rapid onset LTP of both the AMPAR and the NMDAR components of the dual component EPSC. The ACPD- and tetanically induced LTP of the AMPAR EPSC was NMDAR dependent, being abolished by the NMDAR antagonist AP5. Tetanic stimulation, and application of ACPD, also induced a relatively rapid onset LTP of the pharmacologically isolated NMDAR EPSC. Such tetanically and ACPD-induced LTP of the isolated NMDAR EPSC was also dependent on NMDAR activation, being strongly inhibited by AP5. The tetanically and the ACPD-induced LTP of the NMDAR EPSC were dependent on protein kinase C (PKC) stimulation, being strongly inhibited by the PKC inhibitor PKCI (19-31). The studies suggest that coactivation of the mGluR and NMDAR are required for induction of LTP of both the AMPAR- and NMDAR-mediated synaptic transmission. Moreover, LTP of the NMDAR-mediated synaptic transmission appears to be dependent on coincident activation of the NMDAR and mGluR.
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PMID:Tetanically induced LTP involves a similar increase in the AMPA and NMDA receptor components of the excitatory postsynaptic current: investigations of the involvement of mGlu receptors. 789 Nov 48

1. We have previously demonstrated that the metabotropic glutamate receptor (mGluR) agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate [(1S;3R)-ACPD] presynaptically inhibits evoked glutamatergic excitatory postsynaptic currents (EPSCs) in patch-clamped rat nucleus tractus solitarius (NTS) neurons recorded in thin slices. The present study investigated the ability of endogenously released glutamate to modulate EPSCs in the NTS. 2. A low-frequency tetanus of the tractus solitarius (TS) resulted in either posttetanic potentiation (PTP) (8 of 21 cells) or depression (13 of 21 cells) of monosynaptic EPSCs recorded in the presence of D(-)2-amino-5-phosphonopentanoic acid (AP5) and bicuculline. 3. The amplitude of the EPSC was not significantly affected by the bath application of the mGluR antagonist (+) alpha-methyl-4-carboxyphenylglycine (MCPG). 4. In the presence of MCPG, a low-frequency tetanus resulted in PTP of the EPSC in all neurons. PTP was significantly enhanced in those cells previously exhibiting PTP. 5. The results suggest that presynaptic mGluRs on TS projections to the NTS may be activated by endogenously released glutamate at physiologically relevant stimulus frequencies and therefore play a role in the modulation of autonomic afferent transmission.
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PMID:Metabotropic glutamate receptors depress afferent excitatory transmission in the rat nucleus tractus solitarii. 790 34

1. The presynaptic depressant action of L-2-amino-4-phosphonobutyrate (L-AP4) on the monosynaptic excitation of neonatal rat motoneurones has been differentiated from the similar effects produced by (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate ((1S,3R)-ACPD), (1S,3S)-ACPD and (2S,3S,4S)-alpha-(carboxycyclopropyl)glycine (L-CCG-I), and from the postsynaptic motoneuronal depolarization produced by (1S,3R)-ACPD, by the actions of two new antagonists, alpha-methyl-L-AP4 (MAP4) and alpha-methyl-L-CCG-I (MCCG). Such selectivity was not seen with a previously reported antagonist, (+)-alpha-methyl-4-carboxyphenylglycine (MCPG). 2. MAP4 selectively and competitively antagonized the depression of monosynaptic excitation produced by L-AP4 (KD 22 microM). At ten fold higher concentrations, MAP4 also antagonized synaptic depression produced by L-CCG-I but in an apparently non-competitive manner. MAP4 was virtually without effect on depression produced by (1S,3R)- or (1S,3S)-ACPD. 3. MCCG differentially antagonized the presynaptic depression produced by the range of agonists used. This antagonist had minimal effect on L-AP4-induced depression. The antagonism of the synaptic depression effected by (1S,3S)-ACPD and L-CCG-I was apparently competitive in each case but of varying effectiveness, with apparent KD values for the interaction between MCCG and the receptors activated by the two depressants calculated as 103 and 259 microM, respectively. MCCG also antagonized the presynaptic depression produced by (1S,3R)-ACPD. 4. Neither MAP4 nor MCCG (200-500 microM) significantly affected motoneuronal depolarizations produced by (1S,3R)-ACPD. At the same concentrations the two antagonists produced only very weak and variable effects (slight antagonism or potentiation) on depolarizations produced by (S)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and N-methyl-D-aspartate (NMDA).5. It is concluded that MAP4 is a potent and selective antagonist for those excitatory amino acid(EAA) receptors on neonatal rat primary afferent terminals that are preferentially activated by L-AP4,and that MCCG is a relatively selective antagonist for different presynaptic EAA receptors that are preferentially activated by (1S,3S)-ACPD and (perhaps less selectively) by L-CCG-I. These receptors probably comprise two sub-types of metabotropic glutamate receptors negatively linked to adenylyl cyclase activity.
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PMID:Actions of two new antagonists showing selectivity for different sub-types of metabotropic glutamate receptor in the neonatal rat spinal cord. 792 6

Sodium-dependent high-affinity uptake of glutamate is thought to play a major role in the maintenance of very low extracellular concentrations of excitatory amino acids (EAA), and may modulate the actions of released transmitter at G-protein-coupled receptors and extrasynaptic receptors that are activated over a longer distance and time course. We have examined the effects of the recently developed uptake inhibitor L-trans-pyrrolidine-2,4-dicarboxylate (L-trans-PDC) on monosynaptically evoked excitatory postsynaptic currents (EPSCs) in very-low-density cultures of hippocampal neurons. L-Trans-PDC produced a decreased amplitude of both the non-NMDA and NMDA receptor-mediated components of monosynaptically evoked EPSCs. Examination of miniature EPSCs (mEPSCs) indicated that changes in the sensitivity of postsynaptic non-NMDA receptors did not underline the decrease in evoked EPSC amplitudes. The metabotropic receptor agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) also depressed both components of the EPSC. The competitive metabotropic receptor antagonist (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG) blocked the depression of EPSC amplitude induced by 1S,3R-ACPD and also blocked the effects of L-trans-PDC. Finally, low concentrations of L-glutamate (2 microM) mimicked the effects of L-trans-PDC on EPSC amplitude. From these results we conclude that the application of L-trans-PDC to cultured hippocampal neurons results in the activation of presynaptic metabotropic receptors, leading to a decrease in synaptic transmission. We propose that this effect is due to an increase in ambient glutamate concentrations following inhibition of glutamate uptake, resulting in presynaptic inhibition of excitatory synaptic transmission.
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PMID:The glutamate uptake inhibitor L-trans-pyrrolidine-2,4-dicarboxylate depresses excitatory synaptic transmission via a presynaptic mechanism in cultured hippocampal neurons. 796 76

The effects of iontophoretically applied (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD), a metabotropic glutamate receptor (mGluR) agonist, were studied on extracellularly recorded neurons throughout the depth of the primary somatosensory cortex in the anaesthetized adult rat. Distinct excitatory effects were found almost exclusively in neurons recorded in layer V. Postsynaptic depressant effects dominated neurons recorded in layers I-IV. In layer VI, neurons were equally divided as to excitation and depression. Both the excitatory and postsynaptic depressant effects could be antagonized by the mGluR antagonist (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG). Experiments using bicuculline and several lines of analysis suggested that the postsynaptic depressant effects were mediated directly, rather than through disfacilitation. In a proportion of neurons 1S,3R-ACPD selectively depressed synaptically evoked responses (produced by vibrissa deflections), with little or no effect on the postsynaptic level of firing. Comparing the depressant effects of 1S,3R-ACPD with those of GABA supported a presynaptic mGluR site. Responses to centre and surround receptive field stimulation were depressed to the same extent, suggesting that thalamocortical and intracortical axon terminals are equally endowed with presynaptic receptors. In contrast to previous studies, the actions of L-2-amino-4-phosphonobutyric acid (L-AP4) were shown to be qualitatively different to those of 1S,3R-ACPD, in particular suggesting that the presynaptic depression produced by 1S,3R-ACPD is not mediated by L-AP4-type receptors. The functional implications of different mGluR actions in the primary somatosensory cortex are discussed.
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PMID:Cortical layer-specific effects of the metabotropic glutamate receptor agonist 1S,3R-ACPD in rat primary somatosensory cortex in vivo. 800 May 74

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