Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the mechanisms by which metabotropic glutamate receptors (mGluRs) modulate specific Ca2+ channels in cerebellar granule cells. A large fraction of the current in granule cells is carried by L- and Q-type Ca2+ channels (about 26% each), whereas N- and P-type contribute proportionally less to the global current (9 and 15%, respectively). l-Aminocyclopentane-dicarboxylate (t-ACPD), (2S,3S,4S)-alpha-(carboxycyclopropyl)-glycine (L-CCGI) and (S)-4-carboxy-3-hydroxyphenylglycine [(S)-4C3HPG], but not L(+)-2-amino-4-phosphonobutyrate (L-AP4) reduced the Ca2+ current amplitude. The t-ACPD-induced inhibition was fully antagonized by (+/-)-methyl-4-carboxyphenylglycine [(+/-)-MCPG] and blocked by pertussis toxin (PTX). These results are consistent with inhibitory response mediated by mGluR2/R3. The use of specific Ca2+ channel blockers provided evidence that mGluR2/R3 inhibited both L- and N-type Ca2+ currents. In PTX-treated cells, Glu or t-ACPD, but not L-CCGI or L-AP4, increased the Ca2+ current. Consistent with the activation of mGluR1, the antagonists (+)-MCPG and (S)-4C3HPG prevented the facilitation of Ca2+ current produced by t-ACPD. The mGluR1-activated facilitation was completely blocked by nimodipine, indicating that L-type Ca2+ currents were selectively potentiated.
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PMID:Modulation of calcium channels by metabotropic glutamate receptors in cerebellar granule cells. 853 74

We investigated the mechanism of the inhibition of glutamate release by (L)-2-amino-4-phosphonobutyrate ((L)-AP4) in cerebrocortical nerve terminals from young rats (3 weeks of age). The Ca(2+)-dependent release of glutamate was reduced by (L)-AP4 in a concentration-dependent manner. This inhibitory effect was prevented by pertussis toxin, insensitive to staurosporine and associated with a reduction both in the depolarization-evoked increase in the cytoplasmic free Ca(2+) concentration ([Ca(2+)](c)) and in forskolin-stimulated cAMP formation. However, the reduction in [Ca(2+)](c) but not in cAMP seemed to be responsible for the decrease in release, since inhibition by (L)-AP4 can also be observed in the absence of detectable changes in cAMP The inhibitory modulation by (L)-AP4 was suppressed by the activation of protein kinase C with phorbol esters. The nerve terminals from young rats also exhibited a facilitatory pathway of glutamate release which was mediated by protein kinase C. Interestingly, stimulation of this pathway with the glutamate agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate in the presence of arachidonic acid also abolished the inhibitory action of (L)-AP4. The dominance of the facilitatory pathway in its interaction with the (L)-AP4-mediated inhibitory control may provide some clues to understand the presynaptic changes during synaptic plasticity.
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PMID:Decrease in [Ca2+]c but not in cAMP Mediates L-AP4 inhibition of glutamate release: PKC-mediated suppression of this inhibitory pathway. 908 21

The cDNA encoding the human metabotropic glutamate receptor type 6 (hmGlu6) was isolated from a human retinal cDNA library. The deduced primary sequence (877 amino acids) of the hmGlu6 receptor was 93.5% identical to its rat counterpart and shared 69.8% sequence identity with the related hmGlu4 receptor clone (912 amino acids), isolated in parallel from a human brain cDNA library. In situ hybridization revealed that the hmGlu6 mRNA is highly expressed in cells located in the inner nuclear layer of the human retina, presumably bipolar neurons. Neither PCR analysis nor in situ hybridization could detect hmGlu6 mRNA in human brain. When stably expressed in Chinese hamster ovary cells (CHO-K1) the hmGlu6 receptor inhibited adenylate cyclase through a pertussis toxin-sensitive G-protein, and reduced forskolin-elevated cyclic adenosine monophosphate (cAMP) levels in response to agonists. The rank order of agonist potency was L(+)-2-amino-4-phosphonobutyric acid (L-AP4) > L-serine-O-phosphate > L-glutamate > quisqualate = (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid ((1S,3R)-ACPD). (2S,3S,4S)-alpha-(carboxycyclopropyl)-glycine (L-CCG-I) was a partial agonist at the hmGlu6 receptor, with a potency approaching that of L-serine-O-phosphate.
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PMID:Cloning, distribution and functional expression of the human mGlu6 metabotropic glutamate receptor. 914 51

This study describes the inhibition of 57Co2+ influx through Ca2+-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, consequent to the application of L-2-amino-4-phosphonobutanoic acid (L-AP4), D-AP4 and L-serine-O-phosphate (L-SOP) in cultured cerebellar granule cells. The forskolin-stimulated accumulation of cyclic AMP was inhibited by (2S,1'S,2'S)-2-(carboxycyclopropyl)glycine (L-CCG-1) with an IC50 = 491 +/- 135 nM and by L-AP4 in a biphasic manner (IC50(1) = 232 +/- 61 nM and IC50(2) = >300 microM), confirming the presence of group II and group III mGlu receptors, respectively. 57Co2+ influx was stimulated by kainate (EC50 = 42.2 +/- 11.3 microM) and, in the presence of 30 microM cyclothiazide, by (S)-5-fluorowillardiine (EC50 = 0.7 +/- 0.1 microM) and (S)-AMPA (EC50 = 2.8 +/- 0.5 microM). The effects of the latter were abolished by 10 microM 6-nitro-7-sulphamoylbenzo[f]quinoxaline-2,3-dione (NBQX). L-AP4 (IC50 = >300 microM), D-AP4 (IC50 = >100 microM) and L-SOP (IC50 = 199 +/- 6 microM) inhibited 6 microM (S)-AMPA-stimulated 57Co2+ influx, whereas L-CCG-1 (up to 10 microM), 300 microM (RS)-3,5-dihydroxyphenylglycine, 300 microM (+/-)-baclofen and 1 mM carbachol were ineffective. Pre-incubation with either pertussis toxin (250 ng/ml, 48 hr), 1 mM dibutyryl cyclic AMP, or the potent group III mGlu receptor antagonist (RS)-alpha-cyclopropyl-4-phosphonophenylglycine ((RS)-CPPG), tested at 400 microM, failed to alter the inhibition of AMPA receptor activity by 300 microM L-SOP. Unlike 10 microM NBQX, neither L-AP4, D-AP4 or L-SOP (tested at 1 mM) inhibited the binding of 10 nM (S)-[3H]5-fluorowillardiine (a selective AMPA receptor ligand) to granule cell membranes. Therefore, in these neurones, high concentrations (>100 microM) of L-AP4, L-SOP and D-AP4 inhibit Ca2+-permeable AMPA receptors by a mechanism distinct from known mGlu receptor action and at a site independent from that for AMPA receptor agonists.
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PMID:Inhibition of AMPA receptor-stimulated 57Co2+ influx by D- and L-2-amino-4-phosphonobutanoic acid (D- and L-AP4) and L-serine-O-phosphate (L-SOP) in cultured cerebellar granule cells. 917 12

The effect of (+)-5-oxo-D-prolinepiperidinamide monohydrate (NS-105), a novel cognition enhancer, on adenylate cyclase activity was investigated in cultured neurons of the mouse cerebral cortex. NS-105 (10(-7) and 10(-6) M) inhibited forskolin-stimulated cyclic AMP formation, an action that was dependent on pertussis toxin-sensitive G proteins. Conversely, in pertussis toxin-pretreated neurons, NS-105 (10(-7)-10(-5) M) significantly enhanced the forskolin-stimulated cyclic AMP formation, and this action was completely reversed by cholera toxin. A metabotropic glutamate receptor agonist (1S, 3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S, 3R-ACPD) produced similar bi-directional actions on the cyclic AMP formation. Both of these inhibitory and facilitatory actions of NS-105 and 1S, 3R-ACPD were blocked by L(+)-2-amino-3-phosphopropinoic acid (L-AP3). NS-105 (10(-6) M) and 1S, 3R-ACPD (10(-4) M) significantly enhanced isoproterenol- and adenosine-stimulated cyclic AMP formation. The enhancement of such Gs-coupled receptor agonists-stimulated cyclic AMP formation was also produced by quisqualate but not by L(+)-2-amino-4-phosphonobutanoate (L-AP4). The phosphoinositides hydrolysis was enhanced by 1S, 3R-ACPD (10(-4) M) but not by NS-105 (10(-6) M), however, 1S, 3R-ACPD-induced increase in phosphoinositides turnover was attenuated by NS-105. These findings suggest that NS-105 stimulates metabotropic glutamate receptor subclasses that are coupled both negatively and positively to adenylate cyclase, but it acts as an antagonist at the receptor subclasses that are linked to phosphoinositides hydrolysis.
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PMID:A novel cognition enhancer NS-105 modulates adenylate cyclase activity through metabotropic glutamate receptors in primary neuronal culture. 927 24

As metabotropic glutamate receptor type 1 (mGluR1) is known to couple L-type Ca2+ channels and ryanodine receptors (RyR, Chavis et al., 1996) in cerebellar granule cells, we examined if such a coupling could activate a Ca2+-sensitive K+ channel, the big K+ (BK) channel, in cultured cerebellar granule cells. We observed that (+/-)-1-amino-cyclopentane-trans-1,3-dicarboxylic acid (t-ACPD) and quisqualate (QA) stimulated the activity of BK channels. On the other hand, (2S, 3S, 4S)-alpha-carboxycyclopropyl-glycine (L-CCG-I) and L-(+)-2-amino-4-phosphonobutyrate (L-AP4) had no effect on BK channels, indicating a specific activation by group I mGluRs. Group I mGluRs stimulation of the basal BK channel activity was mimicked by caffeine and both effects were blocked by ryanodine and nifedipine. Interestingly, carbachol stimulated BK channel activity but through a pertussis toxin (PTX)-sensitive pathway that was independent of L-type Ca2+ channel activity. Our report indicates that unlike the muscarinic receptors, group I mGluRs activate BK channels by mobilizing an additional pathway involving RyR and L-type Ca2+ channels.
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PMID:Modulation of big K+ channel activity by ryanodine receptors and L-type Ca2+ channels in neurons. 974 60

1. The metabotropic glutamate receptor (mGluR) agonist trans-(+/-)-1-amino-1,3-cyclopentanedicarboxylic acid (trans-ACPD) (10-100 microM) depolarized isolated frog spinal cord motoneurones, a process sensitive to kynurenate (1.0 mM) and tetrodotoxin (TTX) (0.783 microM). 2. In the presence of NMDA open channel blockers [Mg2+; (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK801); 3,5-dimethyl-1-adamantanamine hydrochloride (memantine)] and TTX, trans-ACPD significantly potentiated NMDA-induced motoneurone depolarizations, but not alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionate (AMPA)- or kainate-induced depolarizations. 3. NMDA potentiation was blocked by (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG) (240 microM), but not by alpha-methyl-(2S,3S,4S)-alpha-(carboxycyclopropyl)-glycine (MCCG) (290 microM) or by alpha-methyl-(S)-2-amino-4-phosphonobutyrate (L-MAP4) (250 microM), and was mimicked by 3,5-dihydroxyphenylglycine (DHPG) (30 microM), but not by L(+)-2-amino-4-phosphonobutyrate (L-AP4) (100 microM). Therefore, trans-ACPD's facilitatory effects appear to involve group I mGluRs. 4. Potentiation was prevented by the G-protein decoupling agent pertussis toxin (3-6 ng ml(-1), 36 h preincubation). The protein kinase C inhibitors staurosporine (2.0 microM) and N-(2-aminoethyl)-5-isoquinolinesulphonamide HCI (H9) (77 microM) did not significantly reduce enhanced NMDA responses. Protein kinase C activation with phorbol-12-myristate 13-acetate (5.0 microM) had no effect. 5. Intracellular Ca2+ depletion with thapsigargin (0.1 microM) (which inhibits Ca2+/ATPase), 1,2-bis(O-aminophenoxy)ethane-N,N,N',N'-tetracetic acid acetyl methyl ester (BAPTA-AM) (50 microM) (which buffers elevations of [Ca2+]i), and bathing spinal cords in nominally Ca2+-free medium all reduced trans-ACPD's effects. 6. The calmodulin antagonists N-(6-aminohexyl)-5-chloro-1-naphthalenesulphonamide (W7) (100 microM) and chlorpromazine (100 microM) diminished the potentiation. 7. In summary, group I mGluRs selectively facilitate NMDA-depolarization of frog motoneurones via a G-protein, a rise in [Ca2+]i from the presumed generation of phosphoinositides, binding of Ca2+ to calmodulin, and lessening of the Mg2+-produced channel block of the NMDA receptor.
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PMID:Mechanisms involved in the metabotropic glutamate receptor-enhancement of NMDA-mediated motoneurone responses in frog spinal cord. 1005 Nov 53

Glutamate-induced glutamate release may be involved in the delayed neuronal death induced by N-methyl-D-aspartate (NMDA). In order to examine a possible modulatory effect of the presynaptic group III mGluRs on glutamate excitotoxicity, the effect of L-2-amino-4-phosphonobutyrate (L-AP4) was examined on NMDA-induced delayed death of mouse cerebellar granule neurons in culture. We found that L-AP4, at high concentration (in the millimolar range), inhibited in a non-competitive manner the NMDA-induced toxicity. This effect was mimicked by high concentration of L-serine-o-phosphate (L-SOP), and was inhibited by pertussis toxin (PTX) indicating the involvement of a Gi/o protein. This suggests the involvement of mGluR7 in the L-AP4 effect, and this was consistent with the detection of both mGluR7 protein and mRNA in these cultured neurons. To examine the mechanism of the L-AP4-induced protection from excitotoxic damage, the effect of L-AP4 on glutamate release was examined. L-AP4 (> or = 1 mM) noncompetitively inhibited by more than 60% the glutamate release induced by NMDA during the insult. We also observed that the 10-min NMDA receptor stimulation resulted in a dramatic increase in the extracellular glutamate concentration reaching 6000% of the control value 24 h after the insult. This large increase was also inhibited when NMDA was applied in the presence of > or = 1 mM L-AP4. Part of the L-AP4-induced protection from excitotoxic damage of granule neurons may therefore result from the inhibition of the vicious cycle: dying cells release glutamate, glutamate induced cell death. The present results add to the hypothesis that presynaptic mGluRs, probably mGluR7, may be the targets of drugs decreasing glutamate release and then neuronal death observed in some pathological situations.
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PMID:mGluR7-like metabotropic glutamate receptors inhibit NMDA-mediated excitotoxicity in cultured mouse cerebellar granule neurons. 1005 67

Retinal amacrine cells express metabotropic glutamate receptors (mGluRs), but their physiological role is unknown. We investigated the effect of mGluR on [(3)H]acetylcholine release ([(3)H]ACh) from cultured chick amacrine-like neurons. Activation of group III mGluR with the agonist L(+)-2-amino-4-phosphonobutyric acid (L-AP4) inhibited [(3)H]ACh release evoked by 25 mM KCl in a dose-dependent manner, and this effect was sensitive to pertussis toxin. In contrast, activation of group I or II mGluR with (S)-3, 5-dihydroxyphenylglycine (DHPG) and (2S,2'R,3'R)-2-(2', 3'-dicarboxycyclopropyl)glycine (DCG-IV), respectively, did not affect significantly [(3)H]ACh release. The effect of L-AP4 on [(3)H]ACh release was sensitive to nitrendipine, suggesting that it is, at least in part, due to inhibition of L-type Ca(2+) channels. Activation of group III mGluR also partly inhibited omega-conotoxin GVIA-sensitive Ca(2+) channels, coupled to [(3)H]ACh release. The L-AP4 did not affect the cAMP levels measured in amacrine-like neurons depolarized with 25 mM KCl or stimulated with forskolin, indicating that the effect of group III mGluR on [(3)H]ACh release is not due to inhibition of adenylyl cyclase activity. Inhibition of protein kinase A with KT-5720 was without effect on [(3)H]ACh release evoked by 25 mM KCl, further indicating that the effect of group III mGluR on [(3)H]ACh release cannot be attributed to the inhibition of the kinase. The effect of L-AP4 on [(3)H]ACh release was reversed by DHPG or by DCG-IV, and activation of group II mGluR also partially inhibited cAMP production stimulated by forskolin. Taken together, our results show that the effect of group III mGluR on [(3)H]ACh release may be due to a direct inhibition of L- and N-type Ca(2+) channels and is modulated by group I and group II mGluR.
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PMID:Metabotropic glutamate receptors modulate [(3)H]acetylcholine release from cultured amacrine-like neurons. 1053 43

Presynaptic inhibition is one of the major control mechanisms in the CNS. Previously we reported that adenosine A1 receptors mediate presynaptic inhibition at the retinotectal synapse of goldfish. Here we extend these findings to metabotropic glutamate receptors (mGluRs) and report that presynaptic inhibition produced by both A1 adenosine receptors and group II mGluRs is due to G(i) protein coupling to inhibition of N-type calcium channels in the retinal ganglion cells. Adenosine (100 microM) and an A1 (but not A2) receptor agonist reduced calcium current (I(Ca2+)) by 16-19% in cultured retinal ganglion cells, consistent with their inhibition of retinotectal synaptic transmission (-30% amplitude of field potentials). The general metabotropic glutamate receptor (mGluR) agonist 1S,3R-1-amino-cyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD, 50 microM) and the selective group II mGluR receptor agonist (2S, 2'R,3'R)-2-(2',3'-dicarboxy-cyclopropyl)glycine (DCG-IV, 300 nM) inhibited both synaptic transmission and I(Ca2+), whereas the group III mGluR agonist L-2-amino-4-phosphono-butyrate (L-AP4) inhibited neither synaptic transmission nor I(Ca2+). When the N-type calcium channels were blocked with omega-conotoxin GVIA, both adenosine and DCG-IV had much smaller percentage effects on the residual 20% of I(Ca2+), suggesting effects mainly on the N-type calcium channels. The inhibitory effects of A1 adenosine receptors and mGluRs were both blocked by pertussis toxin, indicating that they are mediated by either G(i) or G(o). They were also inhibited by activation of protein kinase C (PKC), which is known to phosphorylate and inhibit G(i). Finally, when applied sequentially, inhibition by adenosine and DCG-IV were not additive but occluded each other. Together these results suggest that adenosine A1 receptors and group II mGluRs mediate presynaptic inhibition of retinotectal synaptic transmission by sharing a pertussis toxin (PTX)-sensitive, PKC-regulated G(i) protein coupled to N-type calcium channels.
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PMID:Adenosine A1 and class II metabotropic glutamate receptors mediate shared presynaptic inhibition of retinotectal transmission. 1060 31


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