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)

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

Synaptic transmission between embryonic chick dorsal root ganglion (DRG) neurons and spinal cord neurons was studied in dissociated cell culture. Stimulation of DRG neurons evoked monosynaptic and polysynaptic excitatory responses in the spinal neurons. These responses could be reversibly blocked by application of 6-cyano-7-nitroquinoxaline-2,3-dione (a selective non-NMDA receptor antagonist) and irreversibly eliminated through the presynaptic action of omega-conotoxin GVIA (a selective N-type calcium channel antagonist). As N-type calcium channels in DRG neuron somata are targets for modulation via GABAB receptors, we tested the role of these receptors as regulators of synaptic transmission. Baclofen (a selective GABAB receptor agonist) reversibly inhibited synaptic transmission via a presynaptic, pertussis toxin-sensitive mechanism; CGP 35348 (a selective GABAB receptor antagonist) blocked the actions of baclofen. Taken together, these results demonstrate that N-type calcium channels play a dominant role in glutamatergic sensory neurotransmission. They suggest, in addition, that modulation of N-channel activity may underlie, at least in part, presynaptic inhibition of synaptic transmission between DRG neurons and their targets in the intact spinal cord.
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PMID:Omega-conotoxin sensitivity and presynaptic inhibition of glutamatergic sensory neurotransmission in vitro. 791 Feb 2

1. The electrophysiological action of the mu-opioid receptor-preferring agonist D-Ala2, MePhe4, Met(O)5-ol-enkephalin (FK 33-824) on synaptic transmission has been studied in area CA3 of organotypic rat hippocampal slice cultures. 2. FK 33-824 (1 microM) had no effect on the amplitude of pharmacologically isolated N-methyl-D-aspartate (NMDA) or non-NMDA receptor-mediated EPSPs. 3. FK 33-824 (10 nM to 10 microM) reduced the amplitude of monosynaptic inhibitory postsynaptic potentials (IPSPs) that were elicited in pyramidal cells with local stimulation after pharmacological blockade of excitatory amino acid receptors. This effect was reversible, dose-dependent, and sensitive to naloxone and the mu-receptor antagonist Cys2,Tyr3,Orn5,Pen7-amide (CTOP). FK 33-824 at 1 microM caused a mean reduction in the amplitude of the monosynaptic IPSP of 70%. 4. Neither delta- nor kappa-receptor-preferring agonists had any effect on excitatory or inhibitory synaptic potentials. 5. The disinhibitory action of FK 33-824 was blocked by incubating the cultures with pertussis toxin (500 ng/ml for 48 h) or by stimulation of protein kinase C with phorbol 12,13-dibutyrate (PDBu, 0.5 microM). 6. The depression of monosynaptic IPSPs by FK 33-824 was unaffected by extracellular application of the K+ channel blockers Ba2+ or Cs+ (1 mM each). 7. FK 33-824 produced a decrease in the frequency of miniature, action potential-independent, spontaneous inhibitory synaptic currents (mIPSCs) recorded with whole-cell voltage-clamp techniques, but did not change their mean amplitude. Application of the Ca2+ channel blocker Cd2+ (100 microM) or of nominally Ca(2+)-free solutions did not alter either the frequency and amplitude of mIPSCs or the reduction of mIPSC frequency induced by FK 33-824. 8. The effect of FK 33-824 on spontaneous mIPSCs was prevented by naloxone, and by incubation of cultures with pertussis toxin. 9. These results indicate that mu-opioid receptors decrease GABA release presynaptically by a G protein-mediated inhibition of the vesicular GABA release process, and not by changes in axon terminal K+ or Ca2+ conductances that are sensitive to extracellular Ba2+, Cs+ or Cd2+.
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PMID:Mechanism of mu-opioid receptor-mediated presynaptic inhibition in the rat hippocampus in vitro. 830 42

Metabotropic glutamate receptors (mGluRs) form a receptor family that consists of diverse receptor subtypes; now, numbering 8--exclusive of splice variants. (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) has been suggested to be a selective agonist for the mGluRs. We have recently reported that, in rat dorsolateral septal nucleus (DLSN) neurones, a 1S,3R-ACPD-preferring inward current (ACPDi) persists in pertussis toxin-treated rats. We now report that this ACPDi-current: (1) persists in DLSN neurones dialyzed with a stable analog of GTP, namely, GTP gamma S; (2) exhibits a negative slope region with inward rectification in its I-V relationship; (3) persists in neurones superfused with tetrodotoxin or low calcium solutions; (4) is dependent upon both sodium and calcium ions; and (5) is independent of a reduction in temperature. Furthermore, pharmacological data suggest that this current may be activated by a unique type of excitatory amino acid (EAA) receptor, i.e. a receptor which prefers "metabotropic" EAA agonists and is insensitive to AP5 or CNQX. Activation by ACPD of inward currents associated with a conductance increase have also been reported at cultured mouse cerebellar Purkinje neurones; in slices of rat hippocampal CA1 neurones and slice cultures of hippocampal CA3 neurones. We suggest that this ACPDi current may play an important role within the CNS in the induction of long-term potentiation and other neurological processes; processes attributed previously to currents associated with NMDA receptor activation.
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PMID:1S,3R-ACPD-preferring inward current in rat dorsolateral septal neurons is mediated by a novel excitatory amino acid receptor. 853 72

The effects of L-glutamate, acetylcholine, and serotonin (5HT) were examined on generation of inositol 1,4,5-triphosphate [Ins(1,4,5)P3], in membrane preparations of the cestode Hymenolepis diminuta. Only L-glutamate and acetylcholine stimulated a significant elevation in Ins(1,4,5)P3. The response to L-glutamate was stereospecific; D-glutamate or L-aspartate were not as potent. A role for G-protein(s) was supported by the observations that sodium fluoride stimulated Ins(1,4,5)P3 generation, and the L-glutamate response was potentiated by GTP and GTP-S and was suppressed by GDPS. However, studies with pertussis and cholera toxins indicated that the putative G-protein(s) was not pertussis or cholera toxin sensitive. The pharmacological profile of the L-glutamate response was examined partially. Trans-ACPD was a very effective agonist at 10(-5)M. While 10(-3)M L-glutamate, NMDA, and AMPA significantly elevated Ins(1,4,5)P3 levels, quisqualate and kainate did not. The elevation of Ins(1,4,5)P3 levels by L-glutamate and NMDA was antagonized by the specific glutamatergic antagonists AP-5, AP-7, CNQX, and CPP. While the response to ACPD was antagonized by AP5, CPP and CPG, CNQX was without effect. Collectively, the data support the hypothesis that in the cestode H. diminuta, L-glutamate activation of a metabotropic (ACPD) and/or ionotropic-like AMPA/NMDA receptor subtypes proceeds via a G protein(s) to enhance phospholipase C activity, ultimately resulting in the elevation of Ins(1,4,5)P3 levels in the tissues.
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PMID:The stimulatory effect of L-glutamate and related agents on inositol 1,4,5-trisphosphate production in the cestode Hymenolepis diminuta. 869 99

1. The effects of low micromolar concentrations of glutamate on fast excitatory synaptic responses were studied in microcultures of postnatal rat hippocampal neurons using whole-cell patch clamp recordings. 2. Glutamate depressed the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor component of excitatory autaptic currents (EACs) with an EC50 of 3.8 microM. 3. Both pre- and postsynaptic effects contributed to the depression of AMPA receptor-mediated EACs. Cyclothiazide and wheatgerm agglutinin, agents which inhibit AMPA receptor desensitization, partially reversed the depression produced by glutamate, as did pertussis toxin, an agent that blocks presynaptic inhibition mediated by metabotropic glutamate receptors. 4. In neurons in which both the AMPA and N-methyl-D-aspartate (NMDA) receptor components of EACs were examined, low concentrations of glutamate depressed the NMDA component of EACs to a greater extent. The EC50 for inhibiting the NMDA component was 1.3 microM. 5. Calcium-dependent desensitization of postsynaptic NMDA receptors contributed to the depression of NMDA receptor-mediated synaptic responses. Both depolarization of postsynaptic neurons to +70 mV to decrease Ca2+ influx via NMDA channels and inclusion of high concentrations of a calcium chelator in recording pipettes decreased the depression of NMDA receptor-mediated EACs. 6. Threo-3-hydroxy-aspartate (THA), an inhibitor of glutamate transport, depressed EACs by about 10% and increased the degree of depression produced by 2.5 microM glutamate, suggesting that glutamate transport in microcultures helps to control ambient glutamate levels. 7. Because the normal extracellular concentration of glutamate is about 1 microM, these results suggest that the ambient glutamate level is an important determinant of synaptic efficacy. Relatively small changes in extracellular glutamate can alter fast excitatory synaptic transmission by both presynaptic and postsynaptic mechanisms.
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PMID:Modulation of excitatory synaptic transmission by low concentrations of glutamate in cultured rat hippocampal neurons. 884 5

We have previously reported dual effects of mu-opioids on N-methyl-D-aspartate (NMDA)-receptor-mediated synaptic events in the hippocampal dentate gyrus: an indirect facilitating effect via suppression of GABAergic interneurons (disinhibition) and a direct inhibitory effect in the presence of gamma-aminobutyric acid-A (GABA(A)) antagonists. The cellular mechanism underlying the inhibitory effect of mu-opioids remains to be determined. In the present study we examine the role of adenosine 3',5'-cyclic monophosphate (cAMP)-dependent protein kinase (PKA) in mu-opioid-induced inhibition of NMDA currents in rat hippocampal slices. NMDA-receptor-mediated excitatory postsynaptic currents (NMDA EPSCs) were evoked by stimulating the lateral perforant path and were recorded from dentate granule cells with the use of whole cell voltage-clamp techniques in the presence of the GABA(A) antagonist and a non-NMDA type of glutamate receptor antagonist. Two selective mu-agonists, [N-MePhe3, D-Pro4]-morphiceptin and [D-Ala2, N-MePhe4, Gly-ol5]-enkephalin, induced dose-dependent inhibition of NMDA EPSCs in a concentration range of 0.3-10 microM. This inhibitory effect could be completely reversed by the opioid antagonists naloxone or prevented by a selective mu-antagonist cyprodime, but was not affected by removal of Mg2+ from the external perfusion medium. Intracellular application of pertussis toxin (PTX) into the granule cell via whole cell recording pipettes completely prevented mu-opioid-induced reduction in NMDA currents, suggesting that a postsynaptic mechanism involving PTX-sensitive G proteins might be responsible for the inhibitory action of mu-opioids. Further studies were conducted to identify the intracellular messengers that coupled with G proteins and transduced the effect of mu-opioids in granule cells. The adenylate cyclase activator forskolin was found to enhance NMDA-receptor-mediated synaptic responses and to reverse the inhibitory effect of mu-opioids. Sp-cAMPS, a specific PKA activator, also enhanced NMDA EPSCs, whereas the PKA inhibitor Rp-cAMPS reduced NMDA EPSCs and occluded further inhibition of the current by mu-opioids. These findings strongly suggest that NMDA receptor function is subject to the modulation by PKA, and that mu-opioids can inhibit NMDA currents through suppression of the cAMP cascade in the postsynaptic neuron. Combined with our previous findings, the present results also indicate that mu-opioids can modulate NMDA-receptor-mediated synaptic activity in a complex manner. The net effect of mu-opioids in the dentate gyrus may depend on the interplay between its disinhibitory action, which facilitates NMDA-receptor-mediated responses, and its inhibitory action on the cAMP cascade.
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PMID:Involvement of cAMP-dependent protein kinase in mu-opioid modulation of NMDA-mediated synaptic currents. 930 10

The purpose of this study was to determine the effect of infection brain edema (IBE) in the rat model induced by injecting pertussis bacilli (PB) into the left carotid artery. The specific binding of N-methyl-D-aspartate (NMDA) receptor with [3H] MK-801 was measured in the neuronal membrane of cerebral cortex. The Scatchard plots were performed. The Bmax values were 0.623 +/- 0.082 and 0.606 +/- 0.087 pmol/mg protein in the group that received normal saline (NS) and PB respectively (P < 0.05). The Kd values were 43.1 +/- 4.2 and 30.5 +/- 3.0 nM in the groups NS and PB respectively. The results indicated that the affinity of NMDA receptor was significantly higher in the group PB than group NS, whereas the total number of NMDA receptors had not changed in the IBE model. The increase of affinity of NMDA receptor can be blockaded by MK-801 pretreatment in vivo.
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PMID:Effect of infection brain edema on NMDA receptor binding in rat brain in vivo. 941 47

Anandamide is an endogenous ligand of cannabinoid receptors that induces pharmacological responses in animals similar to those of cannabinoids such as delta9-tetrahydrocannabinol (THC). Typical pharmacological effects of cannabinoids include disruption of pain, memory formation, and motor coordination, systems that all depend on NMDA receptor mediated neurotransmission. We investigated whether anandamide can influence NMDA receptor activity by examining NMDA-induced calcium flux (deltaCa2+NMDA) in rat brain slices. The presence of anandamide reduced deltaCa2+NMDA and the inhibition was disrupted by cannabinoid receptor antagonist, pertussis toxin treatment, and agatoxin (a calcium channel inhibitor). Whereas these treatments prevented anandamide inhibiting deltaCa2+NMDA, they also revealed another, underlying mechanism by which anandamide influences deltaCa2+NMDA. In the presence of cannabinoid receptor antagonist, anandamide potentiated deltaCa2+NMDA in cortical, cerebellar, and hippocampal slices. Anandamide (but not THC) also augmented NMDA-stimulated currents in Xenopus oocytes expressing cloned NMDA receptors, suggesting a capacity to directly modulate NMDA receptor activity. In a similar manner, anandamide enhanced neurotransmission across NMDA receptor-dependent synapses in hippocampus in a manner that was not mimicked by THC and was unaffected by cannabinoid receptor antagonist. These data demonstrate that anandamide can modulate NMDA receptor activity in addition to its role as a cannabinoid receptor ligand.
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PMID:Dual effects of anandamide on NMDA receptor-mediated responses and neurotransmission. 945 61

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


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