Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Synaptic activation in the presence of competitive (D,L-APV,CNQX) and noncompetitive (MK-801,GYKI-52466) ionotropic glutamate receptor antagonists induced fast (10-90% rise time of 15-30 msec) postsynaptic responses in CA3 pyramidal neurons from acute and cultured hippocampal slices. Postsynaptic currents were studied extensively in slice cultures, and displayed a linear current-voltage relationship, with a reversal potential between 0 mV and +10 mV, suggesting the activation of a nonselective cationic conductance. Inhibition of the GTPase cycle by intracellular perfusion with the nonhydrolyzable analog of GDP, GDP beta S, blocked the fast postsynaptic responses evoked in ionotropic antagonists, as well as baclofen-mediated outward K+ currents, known to be mediated by G protein-coupled GABAB receptors. Intracellular perfusion with GDP beta S did not affect the AMPA/kainate component of the synaptic currents. Irreversible activation of G proteins by intracellular perfusion with the nonhydrolyzable analog of GTP, GMP-PNP, occluded the baclofen responses, and evoked an inward current, consistent with the synaptically mediated conductance. Incubation of the slice cultures in pertussis toxin for 72 hr blocked baclofen-induced outward K+ currents, while the fast postsynaptic currents remained. The metabotropic glutamate receptor (mGluR) agonists 1S,3R-ACPD and 1S,3S-ACPD induced an inward current in the presence of the ionotropic antagonists, and occluded the fast EPSCs. The fast EPSCs were partially blocked by the mGluR antagonists L-AP3 and (+)MCPG, but there was differential antagonists sensitivity in two pathways stimulated (CA3 stratum radiatum vs CA3 stratum oriens). These data suggest that fast postsynaptic responses evoked in the presence of ionotropic glutamate receptor antagonists are mediated by G protein-coupled mGluRs linked to nonselective cationic channels.
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PMID:G protein-coupled receptors mediate a fast excitatory postsynaptic current in CA3 pyramidal neurons in hippocampal slices. 861 65

Orphanin FQ (OFQ) has recently been reported to be an endogenous ligand for the opioid-like LC132 receptor. The effect of OFQ on high voltage-gated calcium channels (VGCCs) was examined in freshly dissociated rat pyramidal neurons using the whole-cell configuration of the patch-clamp technique. High-threshold Ba2+ currents were reversibly inhibited by OFQ. The depression of the currents was associated with a slowed rate of activation and a change in the activation I-V relationship at step potentials higher than +30 mV. In concentration-response experiments, a mean (+/-SEM) pEC50 value of 7.0 +/- 0.07 and a Hill coefficient of 1.5 +/- 0.08 (n = 5) were obtained. The near-maximum inhibition of the Ba2+ currents by OFQ (1 microM) amounted to 31 +/- 2.2% of control (n = 15). Opioid receptors could not account for the effects of OFQ on VGCCs, because naloxone, a broad spectrum mu-, delta-, and kappa-receptor antagonist, did not reduce the effectiveness of OFQ. When GTP-gamma-S was included in the pipette, the depression of the currents by OFQ was irreversible, whereas currents from neurons preincubated with pertussis toxin were not inhibited by OFQ, consistent with the involvement of a PTX-sensitive G-protein. When selective blockers of VGCCs were used, it was demonstrated that all subtypes of VGCCs were affected by OFQ. In conclusion, the effect of OFQ on VGCCs expressed in hippocampal CA3 and CA1 neurons may play an important role in the regulation of hippocampal cell excitability and neurotransmitter release.
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PMID:Modulation of voltage-gated calcium channels by orphanin FQ in freshly dissociated hippocampal neurons. 882 6

Baclofen-induced hyperpolarization of hippocampal CA1 and CA3 pyramidal neurons was examined to assess the impact of ethanol on postsynaptic GABAB receptors. These receptors activate outward K+ currents via a pertussis toxin-sensitive G protein cascade to reduce membrane potential during the slow inhibitory postsynaptic potential. This inhibitory action may play a role in ethanol intoxication and withdrawal excitability. In both types of pyramidal neurons, baclofen applied consecutively in increasing concentrations caused concentration dependent hyperpolarization. There were no significant differences in resting membrane potential, input resistance, maximum baclofen-induced hyperpolarization or EC50 between CA1 and CA3 neurons, although slope values were significantly smaller in the former neurons. These parameters were not significantly changed in the presence of ethanol 10-100 mM. Chronic ethanol treatment (12 days) sufficient to induce physical dependence also did not shift sensitivity or maximum response to baclofen in CA1 neurons. These results suggest that GABAB receptors in this model are essentially insensitive to ethanol and do not confirm our earlier preliminary observation of a possible down-regulation of postsynaptic GABAB receptor function by chronic ethanol treatment.
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PMID:Sensitivity of postsynaptic GABAB receptors on hippocampal CA1 and CA3 pyramidal neurons to ethanol. 891 62

The role of guanosine triphosphate-binding proteins (G-proteins) in the generation of the outward current during transient oxygen-glucose deprivation (OGD) was investigated in CA3 pyramidal cells in rat hippocampal organotypic slice cultures using the single-electrode voltage-clamp technique with KMeSO4-filled microelectrodes. To simulate ischaemia, brief chemical OGD (2 mM 2-deoxyglucose and 3 mM NaN3 for 4-9 min) was used, which induced an outward K+ current associated with an increase in input conductance. OGD failed to induce the outward current under conditions where G-protein function was disrupted by loading cells with guanosine 5'-O-(2-thiodiphosphate) [GDPbetaS] or after prolonged injection of guanosine 5'-O(3-thiotdphosphate) [GTPgammaS]. However, in slices treated with pertussis toxin (PTX), OGD still elicited the outward current, indicating that PTX-insensitive G-proteins are involved. Consistent with this insensitivity to PTX, neither adenosine receptors nor GABA(B) (gamma-aminobutyric acid) receptors, which operate via PTX-sensitive G-proteins, mediate the OGD-induced outward current. When adenosine receptors or GABA(B) receptors were blocked with 1,3-dipropyl-8-psulphophenylxanthine (DPSPX, 5 microM) or CGP 52 432 (10 microM), respectively, the OGD-induced response was not modified. The response also persisted following pretreatment of slice cultures with tetanus toxin to prevent vesicular release of neurotransmitters and neuromodulators from presynaptic terminals. Both PTX-sensitive and PTX-insensitive G-protein-mediated responses were suppressed during OGD. The inward current induced by the metabotropic glutamate receptor agonist 1 S, 3R-1-aminocyclopentane-1,3-dicarboxylate (1S,3R-ACPD) and the outward current elicited by adenosine or baclofen were strongly or completely attenuated. In contrast, the ionotropic alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) response was not affected. These findings suggest that during OGD there is a functional uncoupling of receptors from G-proteins, and a direct receptor-independent activation of PTX-insensitive G-proteins leading to an increase in membrane K+ conductance.
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PMID:Effects of transient oxygen-glucose deprivation on G-proteins and G-protein-coupled receptors in rat CA3 pyramidal cells in vitro. 975 91

We report here the first direct functional evidence of an increase in the tonic activation of postsynaptic 5-HT1A receptors by antidepressant treatments. Because 5-HT1A receptor activation hyperpolarizes and inhibits CA3 pyramidal neurons in the dorsal hippocampus, we determined, using in vivo extracellular recording, whether the selective 5-HT1A receptor antagonist WAY 100635 could disinhibit these neurons. Unexpectedly, no disinhibition could be detected in controls. However, after long-term treatment with the tricyclic antidepressant imipramine, the selective 5-HT reuptake inhibitor paroxetine, the reversible monoamine oxidase-A inhibitor befloxatone, the alpha2-adrenergic antagonist mirtazapine, or the 5-HT1A receptor agonist gepirone or multiple electroconvulsive shock (ECS) administration, WAY 100635 markedly increased (60-200%) the firing activity of CA3 pyramidal neurons. Such a disinhibition was absent in rats treated with the nonantidepressant drug chlorpromazine, in rats receiving only one ECS, or in rats receiving multiple ECSs in combination with an intrahippocampal pertussis toxin treatment to inactivate Gi/o-coupled 5-HT1A receptors. These data indicate that such antidepressant treatments, acting on entirely different primary targets, might alleviate depression by enhancing the tonic activation of forebrain postsynaptic 5-HT1A receptors.
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PMID:Long-term antidepressant treatments result in a tonic activation of forebrain 5-HT1A receptors. 982 68

The protein kinase KSR-1 is a recently identified participant in the Ras signaling pathway. The subcellular localization of KSR-1 is variable. In serum-deprived cultured cells, KSR-1 is primarily found in the cytoplasm; in serum-stimulated cells, a significant portion of KSR-1 is found at the plasma membrane. To identify the mechanism that mediates KSR-1 translocation, we performed a yeast two-hybrid screen. Three clones that interacted with KSR-1 were found to encode the full-length gamma10 subunit of heterotrimeric G-proteins. KSR-1 also interacted with gamma2 and gamma3 in a two-hybrid assay. Deletion analysis demonstrated that the isolated CA3 domain of KSR-1, which contains a cysteine-rich zinc finger-like domain, interacted with gamma subunits. Coimmunoprecipitation experiments demonstrated that KSR-1 bound to beta1 gamma3 subunits when all three were transfected into cultured cells. Lysophosphatidic acid treatment of cells induced KSR-1 translocation to the plasma membrane from the cytoplasm that was blocked by administration of pertussis toxin but not by dominant-negative Ras. Finally, transfection of wild-type KSR-1 inhibited beta1 gamma3-induced mitogen-activated protein kinase activation in cultured cells. These results demonstrate that KSR-1 translocation to the plasma membrane is mediated, at least in part, by an interaction with beta gamma and that this interaction may modulate mitogen-activated protein kinase signaling.
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PMID:KSR-1 binds to G-protein betagamma subunits and inhibits beta gamma-induced mitogen-activated protein kinase activation. 1007 96

Kainate receptor activation depresses synaptic release of neurotransmitter at a number of synapses in the CNS. The mechanism underlying this depression is controversial, and both ionotropic and metabotropic mechanisms have been suggested. We report here that the AMPA/kainate receptor agonists domoate (DA) and kainate (KA) cause a presynaptic depression of glutamatergic transmission at CA3-->CA1 synapses in the hippocampus, which is not blocked by the AMPA receptor antagonist GYKI 53655 but is blocked by the AMPA/KA receptor antagonist CNQX. Neither a blockade of interneuronal discharge nor antagonists of several neuromodulators affect the depression, suggesting that it is not the result of indirect excitation and subsequent release of a neuromodulator. Presynaptic depolarization, achieved via increasing extracellular K(+), caused a depression of the presynaptic fiber volley and an increase in the frequency of miniature EPSCs. Neither effect was observed with DA, suggesting that DA does not depress transmission via a presynaptic depolarization. However, the effects of DA were abolished by the G-protein inhibitors N-ethylmaleimide and pertussis toxin. These results suggest that KA receptor activation depresses synaptic transmission at this synapse via a direct, presynaptic, metabotropic action.
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PMID:Kainate receptors depress excitatory synaptic transmission at CA3-->CA1 synapses in the hippocampus via a direct presynaptic action. 1131 79

Using mouse hippocampal slices, we studied the induction of depotentiation of long-term potentiation (LTP) at the mossy fiber synapses onto CA3 pyramidal neurons. A long train of low-frequency (1 Hz/900 pulses) stimulation (LFS) induced a long-term depression of baseline synaptic transmission or depotentiation of previously established LTP, which was reversible and was independent of NMDA receptor activation. This LFS-induced depotentiation was observed when the stimulus was delivered 1 or 10 min after LTP induction. However, when LFS was applied at 30 min after induction, significantly less depotentiation was found. The induction of depotentiation on one input was associated with a heterosynaptic reverse of the LTP induced previously on a separate pathway. In addition, this LFS-induced depotentiation appeared to be mediated by the activation of group 2 metabotropic glutamate receptors (mGluRs), because it was mimicked by the bath-applied group 2 agonist (2S,2'R,3'R)-2-(2', 3'-dicarboxycyclopropyl) glycine and was specifically inhibited by the group 2 antagonists (S)-alpha-methyl-4-carboxyphenylglycine and (alphaS)-alpha-amino-alpha-(1S,2S)-2-carboxycyclopropyl-9H-xanthine-9-propanic acid. Moreover, the induction of depotentiation was entirely normal when synaptic transmission is blocked by glutamate receptor antagonist kynurenic acid and was associated with a reversal of paired-pulse facilitation attenuation during LTP expression. Pretreatment of the hippocampal slices with G(i/o)-protein inhibitor pertussis toxin (PTX) prevented the LFS-induced depotentiation. These results suggest that the activation of presynaptic group 2 mGluRs and in turn triggering a PTX-sensitive G(i/o)-protein-coupled signaling cascade may contribute to the LFS-induced depotentiation at the mossy fiber-CA3 synapses.
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PMID:Time-dependent reversal of long-term potentiation by low-frequency stimulation at the hippocampal mossy fiber-CA3 synapses. 1135 57

Presynaptic calcium influx at most excitatory central synapses is carried by both Cav2.1 and Cav2.2 channels. The kinetics and modulation of Cav2.1 and Cav2.2 channels differ and may affect presynaptic calcium influx. We compared release dynamics at CA3/CA1 synapses in rat hippocampus after selective blockade of either channel subtype and subsequent quantal content restoration. Selective blockade of Cav2.1 channels enhanced paired-pulse facilitation, whereas blockade of Cav2.2 channels decreased it. This effect was observed at short (50 msec) but not longer (500 msec) intervals and was maintained during prolonged bursts of presynaptic activity. It did not reflect differences in the distance of the channels from the calcium sensor. The suppression of this effect by preincubation with the G(o/i)-protein inhibitor pertussis toxin suggests instead that high-frequency stimulation relieves inhibition of Cav2.2 by G(o/i), thereby increasing the number of available channels.
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PMID:Presynaptic Cav2.1 and Cav2.2 differentially influence release dynamics at hippocampal excitatory synapses. 1554 55

Activation of G protein-coupled alpha(2) adrenergic receptors (ARs) inhibits epileptiform activity in the hippocampal CA3 region. The specific mechanism underlying this action is unclear. This study investigated which subtype(s) of alpha(2)ARs and G proteins (Galpha(o) or Galpha(i)) are involved in this response using recordings of mouse hippocampal CA3 epileptiform bursts. Application of epinephrine (EPI) or norepinephrine (NE) reduced the frequency of bursts in a concentration-dependent manner: (-)EPI > (-)NE >>> (+)NE. To identify the alpha(2)AR subtype involved, equilibrium dissociation constants (pK(b)) were determined for the selective alphaAR antagonists atipamezole (8.79), rauwolscine (7.75), 2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane hydrochloride (WB-4101; 6.87), and prazosin (5.71). Calculated pK(b) values correlated best with affinities determined previously for the mouse alpha(2A)AR subtype (r = 0.98, slope = 1.07). Furthermore, the inhibitory effects of EPI were lost in hippocampal slices from alpha(2A)AR-but not alpha(2C)AR-knockout mice. Pretreatment with pertussis toxin also reduced the EPI-mediated inhibition of epileptiform bursts. Finally, using knock-in mice with point mutations that disrupt regulator of G protein signaling (RGS) binding to Galpha subunits to enhance signaling by that G protein, the EPI-mediated inhibition of bursts was significantly more potent in slices from RGS-insensitive Galpha(o)(G184S) heterozygous (Galpha(o)+/GS) mice compared with either Galpha(i2)(G184S) heterozygous (Galpha(i2)+/GS) or control mice (EC(50) = 2.5 versus 19 and 23 nM, respectively). Together, these findings indicate that the inhibitory effect of EPI on hippocampal CA3 epileptiform activity uses an alpha(2A)AR/Galpha(o) protein-mediated pathway under strong inhibitory control by RGS proteins. This suggests a possible role for RGS inhibitors or selective alpha(2A)AR agonists as a novel antiepileptic drug therapy.
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PMID:Regulator of G protein signaling protein suppression of Galphao protein-mediated alpha2A adrenergic receptor inhibition of mouse hippocampal CA3 epileptiform activity. 1922 79


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