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)

The effects of (1S,3R)-ACPD, a selective metabotropic glutamate receptor agonist, on NMDA-induced 45Ca2+ accumulation and delayed neuronal cell death were determined using primary cerebrocortical cultures. Exposure to (1S,3R)-ACPD alone, although causing small increases in 45Ca2+ accumulation, was not neurotoxic. The presence of (1S,3R)-ACPD during exposure to NMDA attenuated the resulting sustained accumulation of 45Ca2+ and delayed neuronal cell death. Reductions in sustained Ca2+ accumulation were associated both with Ca2+ efflux, in the absence of cell death, and inhibition of delayed intracellular Ca2+ accumulation. The protective effects of (1S,3R)-ACPD on NMDA-induced cell death were inhibited by pretreatment of cultures with pertussis toxin. These results suggest that activation of metabotropic glutamate receptors may stimulate intracellular processes capable of limiting sustained elevations in intracellular calcium and the resulting excitotoxic neuronal damage.
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PMID:(1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid attenuates N-methyl-D-aspartate-induced neuronal cell death in cortical cultures via a reduction in delayed Ca2+ accumulation. 790 23

Previous results showed that within 30 s after glutamate stimulation of cultured rat hippocampal pyramidal neurons there occurred an elevation of Ca2+ and diacylglycerol, and the phosphorylation of three acidic protein kinase C substrates, i.e., an 87-kDa protein known as myristoylated alanine-rich C kinase substrate and a 120- and a 48-kDa protein. In addition, it was suggested that a metabotropic-type glutamate receptor might be responsible for the phosphorylation observed. This work examines the ability of metabotropic and inotropic glutamate receptor agonists to quickly activate phospholipases in 1.26 mM versus 50 nM extracellular Ca2+ by measuring the generation of inositol phosphates. NMDA, quisqualate, and trans-(+/-)-1-amino-1,3-cyclopentanedicarboxylic acid did not stimulate the generation of inositol phosphates in the presence of normal or low extracellular Ca2+ in pyramidal neurons. Kainate stimulated the production of inositol phosphates in the presence of 1.26 mM extracellular Ca2+ but not in 50 nM extracellular Ca2+. Other than glutamate, only ibotenate was able to stimulate the generation of inositol phosphatases in both normal and low extracellular Ca2+. The maximal response to ibotenate was approximately equal to that of glutamate, when pyramidal neurons were stimulated in 50 nM extracellular Ca2+. The generation of inositol phosphates by glutamate and ibotenate could be partially blocked (50-60% reduction) by pretreatment of neurons with pertussis toxin (250 ng/ml), suggesting that a GTP-binding protein might be involved. In addition, ibotenate stimulated the immediate phosphorylation of the same three protein kinase C substrates as glutamate. The NMDA receptor blocker MK-801 had no effect on this phosphorylation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:An ibotenate-selective metabotropic glutamate receptor mediates protein phosphorylation in cultured hippocampal pyramidal neurons. 790 44

Release of glutamate from cerebellar granule neurones was stimulated either by adding 50 mM K+ to normal Krebs medium, or by adding 5 mM Ca2+ to neurones continuously depolarised with 50 mM K+ in the absence of Ca2+. Pre-incubation of neurones for 16 h with pertussis toxin (PTX) increased the stimulated glutamate release in both K(+)-stimulated and continuously depolarised neurones. Under both conditions, the PTX-induced increase in release was abolished by cycloheximide. In contrast, in the presence of cycloheximide, PTX still prevented the GABAB agonist (-)-baclofen from inhibiting glutamate release. These results suggest that G-protein ADP-ribosylation by PTX in cerebellar granule neurones may increase synthesis of a protein associated with the L-type calcium channel.
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PMID:Cycloheximide abolishes pertussis toxin-induced increase in glutamate release from cerebellar granule neurones. 791 Jun 77

1. The metabotropic glutamate (mGlu) response was investigated in dissociated rat hippocampal CA1 pyramidal neurones using conventional and nystatin-perforated whole-cell modes of the patch recording configuration. 2. In the perforated patch recording configuration, the application of glutamate (Glu), quisqualate (QA), aspartate (Asp) and N-methyl-D-aspartate (NMDA) induced a slow outward current superimposed on a fast ionotropic inward current, whereas alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and kainate (KA) induced only an ionotropic inward current at a holding potential (VH) of -20 mV. A specific agonist of the mGlu receptor (mGluR), trans-1-aminocyclopentane-1,3-dicarboxylate (tACPD), induced an outward current in approximately 80% of the neurones tested. Asp- and NMDA-induced outward currents were antagonized by D-2-amino-5-phosphonopentanoate (D-AP5) whereas Glu-, QA- and tACPD-induced outward currents were not antagonized by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), 6,7-dinitroquinoxaline-2,3-dione (DNQX) and D-AP5, indicating that the mGlu response is an outward current component. 3. L-2-Amino-3-phosphonopropionate (L-AP3) and DL-2-amino-4-phosphonobutyrate (AP4) did not block the mGlu response. 4. The relative potencies of mGlu agonists were QA > Glu > tACPD. The threshold and EC50 values of metabotropic outward currents were 10-100 times lower than those of the ionotropic inward current (iGlu response). 5. The reversal potential of the mGlu response (EmGlu) was close to EK (K+ equilibrium potential), and it shifted 59.5 mV for a tenfold change in extracellular K+ concentration. 6. In Ca(2+)-free external solution, the mGlu response was elicited by an initial application of Glu, but subsequent applications failed to induce the response. There was also an increase in the intracellular free Ca2+ concentration ([Ca2+]i) during the application of Glu and QA but not of AMPA, indicating Ca2+ release from an intracellular Ca2+ store. 7. During the activation of a Ca(2+)-dependent K+ current (IK(Ca)) by inositol trisphosphate (IP3) in the internal solution, the mGlu response was suppressed. Addition of GDP-beta-S, neomycin or heparin to the internal solution also suppressed the mGlu response, but staurosporine had no effect. The mGlu response was abolished by pretreatment with either caffeine or ryanodine, but treatment with pertussis toxin (IAP) for 6-8 h had no effect. 8. The mGlu response was suppressed by tetraethylammonium, but not by either apamin or iberiotoxin, suggesting that intermediate-conductance Ca(2+)-dependent K+ (KCa+) channels are involved.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Metabotropic glutamate response in acutely dissociated hippocampal CA1 pyramidal neurones of the rat. 791 30

We have previously demonstrated that Fos immunoreactivity can be stimulated by KCl, forskolin or glutamate in cultured tyrosine hydroxylase-immunoreactive (TH-ir) hypothalamic neurons. The present study was performed to determine whether agents that regulate dopaminergic activity, particularly D1 and D2 receptor agonists, modulate the intracellular cascade leading to Fos expression. Dissociated hypothalamic cultures were prepared from neonatal rats. The cultures were treated with D1- or D2-specific agonists, followed by KCl, forskolin or glutamate. Cultures were fixed after 2 h and immunocytochemically stained for tyrosine hydroxylase and Fos. Pretreatment of the cultures with the D2 agonist LY163502 inhibited KCl- and forskolin-stimulated Fos-ir in TH-ir neurons in a saturable dose-dependent manner. The maximal effective dose was 30 microM LY163502, which decreased Fos-ir by 23% in cultures treated with 50 mM KCl and by 33% in those treated with 30 microM forskolin. The D2 agonist had no effect on glutamate-stimulated Fos-ir. LY163502 inhibition of Fos-ir was blocked by D2 antagonist or Bordetella pertussis toxin pretreatment which demonstrates that the effect is mediated by D2 receptor activation of an inhibitory G protein. Treatment of the cultures with the D1 agonist SKF82526 had no effect on basal or stimulated levels of Fos-ir. These results demonstrate that in neonatal TH-ir hypothalamic neurons the D2 receptor system may regulate levels of the immediate-early gene product Fos and, therefore, subsequent genetic expression in these neurons.
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PMID:D2 inhibition of stimulated Fos immunoreactivity in cultured tyrosine hydroxylase-ir hypothalamic neurons. 792 80

As shown on cultured astrocytes from the mouse, in the presence of adenosine deaminase, 2-chloroadenosine by acting on A1-adenosine receptors potentiated the activation of phospholipase C induced by the alpha 1-adrenergic agonist, methoxamine. This potentiation required the presence of external calcium and was blocked by pertussis toxin. Moreover, this potentiation resulted from a cascade of events: activation (by calcium and protein kinase C) of a phospholipase A2 coupled to A1-adenosine receptors, release of arachidonic acid, which inhibited the reuptake of glutamate into astrocytes and finally additional activation of phospholipase C by externally accumulated glutamate through metabotropic receptors. The effects of 2-chloroadenosine and methoxamine were respectively mimicked by somatostatin and substance P while endothelins reproduced the combined effects of 2-chloroadenosine and methoxamine. Conditioned media from treated astrocytes enriched in glutamate stimulated phospholipase C in cultured striatal neurones. In addition, glutamate alone was also found to stimulate phospholipase A2 in astrocytes through receptors exhibiting a pharmacological profile distinct from metabotropic receptors coupled to phospholipase C and the glutamate response was potentiated by ATP. Moreover, the neuronal arachidonic acid production evoked by glutamate was potentiated by acetylcholine. Finally, the combined application of 2-chloroadenosine and methoxamine on striatal astrocytes reduced the permeability of gap junctions between astrocytes and this response was mimicked by arachidonic acid. Together, these results emphasized the contribution of astrocytes in the regulation of glutamatergic transmission.
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PMID:Glial receptors and their intervention in astrocyto-astrocytic and astrocyto-neuronal interactions. 792 48

We have mutated the aspartate residue in the putative second transmembrane spanning domain of the alpha 2A-adrenergic receptor (alpha 2AAR) to the non-negatively charged asparagine (D79N) and glutamine (D79Q) and the negatively charged glutamate (D79E) residue in an effort to better characterize the role of this residue, highly conserved among G-protein-coupled receptors, in Na+ regulation of ligand binding and in receptor G-protein coupling. Allosteric modulation of receptor-ligand interactions by Na+ is retained by the D79E alpha 2AAR but lost upon mutation to the uncharged D79N and D79Q residues. Loss of allosteric effects of Na+ is paralleled by a complete loss of retrograde information transfer from G-proteins to alpha 2AAR in AtT20 cells, measured via the sensitivity of radiolabeled agonist binding to Gpp(NH)p. In contrast to the complete elimination of retrograde signaling via the D79N and D79Q alpha 2AAR, anterograde information transfer from receptor to G-protein is modified in a more subtle quantitative way, since agonist-stimulated GTPase activity via D79N and D79Q alpha 2AAR, although apparently attenuated compared to wild type and D79E alpha 2AAR, is no less than the GTPase activity elicited by endogenous somatostatin receptors in AtT20 cells. These data indicate that a negative charge at amino acid residue 79 forecasts sensitivity to allosteric regulation by monovalent cations and its mutation to non-negatively charged residues elicits a nonparallel modulation of receptor-->G-protein versus G-protein-->receptor communication between alpha 2AAR and pertussis toxin-sensitive GTP-binding proteins.
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PMID:Mutation of an aspartate residue highly conserved among G-protein-coupled receptors results in nonreciprocal disruption of alpha 2-adrenergic receptor-G-protein interactions. A negative charge at amino acid residue 79 forecasts alpha 2A-adrenergic receptor sensitivity to allosteric modulation by monovalent cations and fully effective receptor/G-protein coupling. 796 41

Tryptamine dose-dependently increased phosphoinositide (PI) hydrolysis by approximately fourfold in primary cultures of rat cerebellar granule cells (EC50 = 56 microM). The PI response stimulated by tryptamine was dependent on the presence of extracellular Ca2+ and Na+. Tryptamine-induced PI breakdown could be partially inhibited by pretreatment with 4 beta-phorbol 12-myristate 13-acetate but not pertussis toxin. The presence of tryptamine markedly attenuated PI responses induced by norepinephrine (NE) and carbachol, with no apparent effect on the responses to 5-hydroxytryptamine and glutamate. The inhibition of NE- and carbachol-induced PI turnover by tryptamine was dose dependent with IC50 values of approximately 0.4 and approximately 2.5 mM, respectively. Pretreatment of cells with tryptamine (0.5 mM) also attenuated NE- and carbachol-induced PI turnover, but failed to affect 5-hydroxytryptamine- and glutamate-induced responses. Furthermore, ketanserin, atropine, and prazosin did not have any effect on inositol phosphate formation induced by tryptamine. These observations indicate that tryptamine markedly increased Ca(2+)- and Na(+)-dependent PI turnover in cerebellar neurons and selectively inhibited NE- and carbachol-induced PI hydrolysis.
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PMID:Tryptamine induces phosphoinositide turnover and modulates adrenergic and muscarinic cholinergic receptor function in cultured cerebellar granule cells. 796 26

1. Metabotropic glutamate receptors (mGluRs) have been suggested to modulate neurotransmission of glutamatergic pathways via autoreceptive action. Visceral sensory afferents and baroreceptor afferents in particular are thought to utilize L-glutamate (L-glu) as a primary neurotransmitter. The purpose of this study was to investigate whether visceral sensory afferents possess a mGluR and determine the effect of mGluR activation on voltage-gated calcium currents in these neurons. 2. Activation of mGluRs by the selective agonist trans-(+/-)-1-amino-1,3-cyclopentanedicarboxylic acid (t-ACPD) reversibly suppressed the voltage-gated calcium currents in visceral sensory afferents of the nodose ganglion. Concentrations of t-ACPD ranging from 50 to 1,000 microM consistently decreased the evoked calcium current with a maximum suppression of the peak current of 25-30%. This response was repeatable and reversible within a given cell. 3. Metabotropic GluR activation selectively decreased the high-threshold calcium current evoked from step potentials greater than -30 mV and had no effect on the low-threshold calcium current. The inhibitory effects of t-ACPD on the high-threshold channel was partially blocked by omega-conotoxin (omega-CTx-GVIA) suggesting that at least part of the effects of mGluR inhibition of the voltage-gated calcium current is because of a modulation of the omega-CTx-GVIA sensitive high-threshold current. 4. Finally, the inhibitory effects of quisqualate (quis) on the high-threshold calcium current were blocked by pretreatment of the neurons with pertussis toxin (PTX). These results suggest that visceral sensory afferents do possess a PTX-sensitive mGluR and activation of this receptor results in the inhibition of a omega-CTx-GVIA sensitive high-threshold calcium channel.
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PMID:Glutamate metabotropic receptor inhibition of voltage-gated calcium currents in visceral sensory neurons. 796 24

Modulation of Ca2+ channels by metabotropic glutamate receptors (mGluRs) was investigated in cerebellar granule cells using the cell-attached configuration of the patch-clamp technique. Experiments were performed in the absence of external Ca2+ and Ba2+ was used as charge carrier. Bath applied glutamate or (1S,3R) trans-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R t-ACPD) inhibited Ca2+ channels activated by depolarizing pulses. These channels were sensitive to dihydropyridines and displayed a 23 pS conductance. This effect was mimicked by (2S,1'S,2'S)-2-(carboxycyclopropyl)glycine (L-CCG-I), a selective agonist of mGluR2/R3 receptors, but not by quisqualate at a concentration that stimulated inositol phosphate (InsP) synthesis, showing that mGluR1 and mGluR5 did not participate to this mechanism. The phosphodiesterase inhibitor, isobutylmethylxanthine (IBMX), did not alter the action of the mGluR agonists and biochemical measurements showed that 1S,3R t-ACPD, in the presence of IBMX, decreased cAMP formation in such a small amount that this change could not explain the almost complete inhibition of the channel activity observed under similar experimental conditions. Moreover, whole-cell recorded L-type Ca2+ currents were inhibited by L-CCG-I, in the presence of 1 mM intracellular cAMP. These observations were consistent with the hypothesis that cyclic nucleotide second messengers were not involved in this effect. Neither the protein kinase C activator phorbol-12,13-dibutyrate (PDBU) nor the phosphatase inhibitor okadaic acid affected the action of 1S,3R t-ACPD. The inhibitory action of 1S,3R t-ACPD was abolished by pertussis toxin (PTX). These results suggest that mGluR2 or mGluR3 receptors suppress the activity of L-type Ca2+ channels by a mechanism involving Gi or G(o) proteins. A likely direct effect of G-proteins on the channels is discussed.
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PMID:The metabotropic glutamate receptor types 2/3 inhibit L-type calcium channels via a pertussis toxin-sensitive G-protein in cultured cerebellar granule cells. 796 99


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