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

The fear-potentiated startle paradigm has proven to be a useful system with which to analyze neural systems involved in fear and anxiety. This test measures conditioned fear by an increase in the amplitude of a simple reflex (the acoustic startle reflex) in the presence of a cue previously paired with a shock. Fear-potentiated startle is sensitive to a variety of drugs such as diazepam, morphine, and buspirone that reduce anxiety in people and can be measured reliably in humans when the eyeblink component of startle is elicited at a time when they are anticipating a shock. Electrical stimulation techniques suggest that a visual conditioned stimulus ultimately alters acoustic startle at a specific point along the acoustic startle pathway. The lateral, basolateral and central amygdaloid nuclei and the caudal branch of the ventral amygdalofugal pathway projecting to the brainstem are necessary for potentiated startle to occur. The central nucleus of the amygdala projects directly to one of the brainstem nuclei critical for startle and electrical stimulation of this nucleus increases startle amplitude. Chemical or electrolytic lesions of either the central nucleus or the lateral and basolateral nuclei of the amygdala block the expression of fear-potentiated startle. The perirhinal cortex, which projects directly to the lateral and basolateral amygdaloid nuclei, plays a critical role in the expression of fear-potentiated startle using either visual or auditory conditioned stimuli. These latter amygdaloid nuclei may actually be the site of plasticity for fear conditioning, because local infusion of the NMDA antagonist AP5 into these nuclei blocks the acquisition of fear-potentiated startle. On the other hand, the expression of fear-potentiated startle is blocked by local infusion of the non-NMDA ionotropic antagonist CNQX or the G-protein inactivating toxin, pertussis toxin, but not by AP5. Finally, we have begun to investigate brain systems that might be involved in the inhibition of fear. Local infusion of AP5 into the amygdala was found to block the acquisition of experimental extinction, a prototypical method for reducing fear. We have also established a reliable procedure for producing both external and conditioned inhibition of fear-potentiated startle and hope to eventually understand the neural systems involved in these phenomena.
 ...
PMID:Fear-potentiated startle: a neural and pharmacological analysis. 813 44

1. Characterization of excitatory amino acid-induced accumulation of [3H]-phosphoinositides was carried out in primary cerebrocortical cultures isolated from foetal rats. 2. All of the excitatory amino acid receptor agonists examined caused concentration-dependent enhancement of phosphoinositide (PI) formation. The most potent excitatory amino acid receptor agonists were quisqualate, (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid ((1S,3R)-ACPD), ibotenate and glutamate with mean EC50 values of 0.9 +/- 0.4 microM, 15 +/- 5 microM, 15 +/- 3 microM and 41 +/- 8 microM respectively. 3. The selective ionotropic receptor antagonists kynurenic acid (1 mM), 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo(F)quinoxaline (NBQX, 10 microM) and (+/-)-4-(3-phosphonopropyl)-2 piperazinecarboxylic acid (CPP, 100 microM), failed to block responses to quisqualate, (1S,3R)-ACPD or glutamate. D,L-2-Amino-3-phosphonopropionate (D,L-AP3) did not block 1S,3R-ACPD or quisqualate-induced PI turnover, but had an additive effect with quisqualate or (1S,3R)-ACPD. 4. Exposure of cultures to agonists in the absence of added extracellular calcium reduced the maximal quisqualate response by approximately 45%, revealing a two-component concentration-response curve. Concentration-response curves to ibotenate and glutamate became flattened by omission of extracellular calcium, whereas (1S,3R)-ACPD-stimulated PI turnover was unaffected. 5. Pretreatment of cultures with pertussis toxin markedly inhibited PI responses evoked by (1S,3R)-ACPD. 6. These results suggest that excitatory amino acid-stimulated PI turnover in cerebrocortical cultures is independent of ionotropic receptor activation and is mediated via specific G-protein-linked metabotropic receptors. The partial dependence of the responses to quisqualate, ibotenate and glutamate on the presence of extracellular calcium suggests that the effects of these agonists may be mediated by more than one receptor subtype.
 ...
PMID:Excitatory amino acid receptor-stimulated phosphoinositide turnover in primary cerebrocortical cultures. 839 85

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.
 ...
PMID:G protein-coupled receptors mediate a fast excitatory postsynaptic current in CA3 pyramidal neurons in hippocampal slices. 861 65

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.
 ...
PMID:The stimulatory effect of L-glutamate and related agents on inositol 1,4,5-trisphosphate production in the cestode Hymenolepis diminuta. 869 99

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.
 ...
PMID:Effects of transient oxygen-glucose deprivation on G-proteins and G-protein-coupled receptors in rat CA3 pyramidal cells in vitro. 975 91

Oligodendroglial cells express ionotropic glutamate receptors of alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid hydrobromide (AMPA) and kainate (KA) subtypes. Recently, we reported that AMPA receptor agonists increased 45Ca2+ uptake and phospholipase C (PLC) activity. To further elucidate the intracellular signaling mechanisms, we examined the effects of AMPA and KA on mitogen-activated protein kinase (MAPK). KA caused a time- and concentration-dependent increase in MAPK activity (predominantly the p42mapk or ERK2) and the effect was blocked by 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX), a competitive AMPA/KA receptor antagonist. Furthermore, the noncompetitive antagonists of AMPA receptor GYKI 52466 and LY 303070 prevented the actions of the agonists, indicating that the effect of KA on MAPK activation is mediated through AMPA receptors in oligodendrocyte progenitors. Chelation of extracellular Ca2+ by EDTA or inhibition of PLC with U73122 abolished MAPK activation by KA. In addition, KA-stimulated MAPK activation was reduced by the protein kinase C (PKC) inhibitors, H7 and bisindolylmaleimide, as well as downregulation of PKC by prolonged exposure to phorbol esters. The involvement of PKC in the signal transduction pathways was further supported by the ability of KA to induce translocation of PKC measured by [3H]PDBu binding. Interestingly, a wortmannin-sensitive phosphatidylinositol 3-kinase and a pertussis toxin (PTX)-sensitive G protein form part of the molecular pathways mediating MAPK activation by AMPA receptor. A specific inhibitor of MAPK kinase, PD 098059, blocked MAPK activation and reduced KA-induced c-fos gene expression. All together, these results indicate that MAPK is implicated in the transmission of AMPA signaling to the nucleus and requires extracellular Ca2+, and PLC/PKC activation.
 ...
PMID:Molecular pathways mediating activation by kainate of mitogen-activated protein kinase in oligodendrocyte progenitors. 1009 77

Kainate receptors are a subtype of ionotropic glutamate receptors, permeable to cations and thus expected to have an excitatory depolarizing action on neurons. However, kainate receptor activation inhibits gamma-aminobutyric acid release in the hippocampus through activation of protein kinase C in a pertussis toxin-dependent manner, suggesting a coupling of kainate receptors to G proteins. Thus, we directly investigated the G protein coupling of kainate receptors in the rat hippocampus by using a selective kainate receptor agonist, [(3)H](2S,4R)-4-methylglutamate ([(3)H]MGA). [(3)H]MGA bound to a single site to hippocampal membranes with a K(D) value of 32 nM and a B(max) value of 1024 fmol/mg protein. This binding likely represents kainate receptors because it was displaced by domoate (K(i) = 4 nM), kainate (K(i) = 11 nM), and 6-cyano-7-nitroquinoxaline-2,3-dione (K(i) = 1.4 microM), but not by alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (K(i) > 10 microM), (RS)-alpha-methyl-4-phosphonophenylglycine (K(i) > 10 microM), or (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (K(i) > 10 microM). Guanylylimidodiphosphate (30 microM), which uncouples all G protein-coupled receptors, shifted to the right the saturation curve of [(3)H]MGA (K(D) = 133 nM). This effect was mimicked by pretreatment of hippocampal membranes with modifiers of G(i)/G(o) proteins [30 microM N-ethylmaleimide (K(D) = 98 nM) or 25 microgram/ml pertussis toxin (K(D) = 95 nM)] but not by a modifier of G(s) proteins [50 microgram/ml cholera toxin (K(D) = 32 nM)]. Treatment of solubilized hippocampal membranes with pertussis toxin (25 microgram/ml) decreased [(3)H]MGA affinity (K(D) = 105-113 nM), which was recovered by reconstitution of these pretreated solubilized hippocampal membranes with G(i)/G(o) proteins (K(D) = 41-76 nM). These results indicate that hippocampal kainate receptors are coupled to G(i)/G(o) proteins.
 ...
PMID:Kainate receptors coupled to G(i)/G(o) proteins in the rat hippocampus. 1041 64

Natural polyamines have been proposed to induce histamine release from mast cells through a direct interaction with G proteins. Alternatively, the polyamine binding site of ionotropic N-methyl-D-aspartate (NMDA) receptors has been suggested as a target for spermine on mast cells. We reexamined both hypotheses. Incubation of rat peritoneal mast cells with spermine resulted in a concentration-dependent histamine release (EC50 270 microM). Incubation with NMDA receptor agonists, glutamate or NMDA, associated to the co-agonist glycine, did not induce secretion. Western blot experiments did not reveal NMDA R1, R2a, R2b or R2c subunit expression in rat peritoneal mast cell membranes. The NMDA receptor antagonist at the glycine site, L-689,560, did not modify, at relevant concentrations, the spermine-induced secretion. The NMDA receptor antagonists, ifenprodil and LY 235959, and the NMDA channel blocker, MK801, slightly inhibited, at high concentrations, the secretory effect of spermine. The polyamine arcaine, an antagonist of the NMDA receptor polyamine binding site, induced histamine secretion (EC50 350 microM). Both spermine- and arcaine-induced effects were independent upon extracellular calcium and were largely inhibited by treatment of mast cells with pertussis toxin or benzalkonium chloride. The response to spermine and arcaine was prevented by the hydrolysis of sialic acid residues of the cell surface by neuraminidase, and was restored by permeabilization of the plasma membrane with streptolysine-O, indicating that polyamines act intracellularly. These results confirm the involvement of pertussis toxin-sensitive G proteins in the secretory effect of polyamines and demonstrate the absence of NMDA receptors on rat peritoneal mast cells. Nonselective effects of some NMDA receptor ligands on mast cells cannot be excluded.
 ...
PMID:Effect of NMDA receptor ligands on mast cell histamine release, a reappraisal. 1043 64

Kainate receptors are ionotropic receptors, also reported to couple to G(i)/G(o) proteins, increasing neuronal excitability through disinhibition of neuronal circuits. We directly tested in hippocampal synaptosomes if kainate receptor-mediated inhibition of GABA release involved a metabotropic action. The kainate analogue, domoate (3 microM), inhibited by 24% [(3)H]GABA-evoked release, an effect reduced by 76% in synaptosomes pre-treated with pertussis toxin. Protein kinase C inhibition attenuated by 82% domoate-induced inhibition of GABA release whereas protein kinase C activation did not change kainate receptor binding. Thus, domoate inhibition of GABA release recruits G(i)/G(o) proteins and a protein kinase C pathway.
 ...
PMID:Pertussis toxin prevents presynaptic inhibition by kainate receptors of rat hippocampal [(3)H]GABA release. 1071 63

The endogenous mechanisms modulating ATP-induced dopamine release in the nucleus accumbens (NAc) were studied by microdialysis in freely moving rats. The ATP analog 2-Methylthio ATP (2-MeSATP) facilitated the release of dopamine in a manner sensitive to pertussis toxin and tetrodotoxin. It is suggested that G-protein-coupled P2Y receptors and voltage-gated sodium channels are involved in this process. N-methyl-D-aspartate (NMDA) applied in a concentration of 100 microM decreased the extracellular dopamine level, whereas 1 and 10 mM NMDA enhanced it. The endogenous agonist glutamate (10 microM) inhibited the basal and facilitated release of dopamine. Infusion with a combination of the ionotropic glutamate receptor antagonists (+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), as well as with the metabotropic glutamate receptor antagonist (+/-)-alpha-methyl-4-carboxyphenylglycine (MCPG) increased the basal level of dopamine and potentiated the 2-MeSATP-facilitated dopamine release, suggesting an ATP-mediated glutamate release. The GABA(A) receptor antagonist bicuculline infused into the NAc also enhanced the basal level of dopamine; however, the application of 2-MeSATP in the presence of bicuculline caused an early decrease and a subsequent increase of dopamine release. The facilitatory phase of the 2-MeSATP effect was comparable with that measured in the absence of bicuculline. By contrast, when bicuculline was infused into the ventral tegmental area (VTA) it elevated the accumbal basal dopamine level and in addition facilitated the 2-MeSATP- and the glutamate-induced dopamine release above that measured in the absence of bicuculline. These results suggest that ATP in the NAc has a physiologically relevant function in modulating dopaminergic transmission depending on the mesolimbic neuronal activity. The first component of the ATP effect involves a direct stimulation of the terminals of VTA neurons, while the second inhibitory component involves a sequential activation of glutamate and, finally, via ionotropic and metabotropic glutamate receptors, of GABA neurons projecting to the VTA.
 ...
PMID:Mechanisms of adenosine 5'-triphosphate-induced dopamine release in the rat nucleus accumbens in vivo. 1116 71


<< Previous 1 2 3 4 5 Next >>