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 signal transduction and pharmacological properties of a metabotropic glutamate receptor, mGluR1, were studied in CHO cells permanently expressing the cloned receptor. mGluR1 stimulated phosphatidylinositol (PI) hydrolysis in the potency rank order of quisqualate greater than L-glutamate greater than or equal to ibotenate greater than L-homocysteine sulfinate greater than or equal to trans-ACPD. This receptor also evoked the stimulation of cAMP formation and arachidonic acid release with comparable agonist potencies. DL-AP3 and L-AP4, the effective antagonists reported for glutamate-stimulated PI hydrolysis in brain slices, showed no appreciable effects on mGluR1, suggesting the existence of an additional subtype of this receptor family. Pertussis toxin and phorbol ester produced distinct effects on the three transduction cascades, implying that mGluR1 independently links to the multiple transduction pathways probably through different G proteins.
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PMID:Signal transduction and pharmacological characteristics of a metabotropic glutamate receptor, mGluR1, in transfected CHO cells. 131 23

The AP4 (2-amino-4-phosphonobutyrate) receptor is a presynaptic glutamate receptor that inhibits transmitter release via an unknown mechanism. We examined the action of L-AP4 on voltage-dependent calcium currents and excitatory synaptic transmission on cultured olfactory bulb neurons using whole-cell voltage-clamp methods. In neurons dialyzed with GTP, L-AP4 inhibited high-threshold calcium currents evoked in barium solutions. The inhibition was irreversible in the presence of GTP-gamma-S and blocked by removing intracellular Mg2+ or by preincubation with pertussis toxin (PTX), consistent with the involvement of a PTX-sensitive G-protein. Dialysis with staurosporine or buffering of intracellular calcium to pCa less than 8 did not block the action of L-AP4, suggesting that protein phosphorylation or release of intracellular calcium stores was not involved in calcium current inhibition under these experimental conditions. PTX also blocked the L-AP4-induced inhibition of monosynaptic EPSPs evoked by intracellular stimulation of cultured mitral cells. These results suggest that the presynaptic AP4 receptor is a G-protein-coupled glutamate receptor, and that inhibition of calcium influx by a membrane-delimited action of a G-protein may account for L-AP4-induced presynaptic inhibition.
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PMID:L-AP4 inhibits calcium currents and synaptic transmission via a G-protein-coupled glutamate receptor. 131 54

Glutamate induced an increase in cell volume within one minute and evoked cytosolic Ca2+ transients in type 1 astroglial cells in primary culture obtained from the cerebral cortex of newborn rat. Even the metabotropic glutamate receptor agonists (1S,3R)-1-aminocyclopentane- 1,3-dicarboxylic acid (1S-3R-ACPD) and L(+)-2-amino-4 phosphonobutyric acid (L-AP4) induced a cell swelling with ACPD inducing a parallel Ca2+ transient while L-AP4 did not. A new method was used where rapid changes in relative cell volume could be followed at the single cell level. Relative volume changes in cultured single astroglial cells were examined by microspectrofluorimetry after loading the cells with the highly fluorescent intracellular probe fura-2/AM. At its isosbestic point, 358 nm, fura-2 is ion-insensitive and the fluorescent signals emitted are related only to the intracellular dye concentration. By varying the excitation wavelengths, changes in intracellular Ca2+ transients could be recorded simultaneously with the relative volume variations of the individual cells. Thus, as rapid changes in cell volume were followed, the results from this method could be of physiological significance. Glutamate-induced cell swelling was blocked by BaCl2 and by tetraethylammonium, suggesting that K+ channels are operative in glutamate-induced cell swelling. Furthermore, the glutamate-induced swelling was blocked by the Na+; K+, and 2Cl- co-transport inhibitor furosemide. The glutamate-induced swelling was partially blocked by pertussis toxin and partially blocked also by the glutamate carrier-blocker dihydroaspartate. When the ionotropic glutamate receptor alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid was blocked with the antagonist 2,3-dihydroxy-6-nitro-7- sulfamoyl-benzo(F)quinoxaline, glutamate still induced a swelling, suggesting that this receptor was not directly involved in the glutamate-induced volume increase. Even in situations of blocked or partially blocked swelling, intracellular Ca2+ transients could be obtained. Furthermore, the glutamate-induced swelling was evoked even in low extracellular Ca2+ concentrations. Our data suggest that glutamate-induced rapid swelling is a complex process at the molecular level. One hypothetical mechanism might be that glutamate interacts with metabotropic glutamate receptors and induces a release of Ca2+ from internal stores. Furthermore glutamate interacts with K+ channels, and probably at least one co-transporter and the sodium-dependent high-affinity uptake glutamate carrier, resulting in cell swelling.
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PMID:Glutamate-induced swelling of single astroglial cells in primary culture. 753 92

The results presented here show that the metabotropic glutamate receptor agonist L(+)-2-amino-4-phosphonobutyric acid (L-AP4) is capable of markedly stimulating the survival of rat cerebellar granule cells in culture. This is the first demonstration of a neurotrophic role for metabotropic glutamate receptors. The survival promoting action of L-AP4 does not involve a large, rapid rise in [Ca2+]i which is seen with other neurotrophic agents in granule cells such as N-methyl-D-aspartate, ionomycin and high potassium. In addition, the survival-promoting effect of L-AP4 did not appear to be related to changes in cAMP levels. Survival due to L-AP4 was enhanced by pertussis toxin and by forskolin and was unaffected by inhibitors of cAMP-dependent protein kinase. Measurement of cAMP levels after long-term treatment with neurotrophic agents showed no clear relationship between cAMP concentration and granule cell survival. The mechanism of L-AP4 stimulated cell survival is unknown but seems unlikely to involve an acute rise in [Ca2+]i or modulation of cAMP levels. Survival induced by L-AP4 was not blocked by the antagonist (RS)-alpha-methyl-4-carboxyphenylglycine. Similarity in these properties with those of the mGLu7 receptor suggests that granule cell survival was stimulated by an mGlu7-like metabotropic receptor.
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PMID:Activation of metabotropic glutamate receptors by L-AP4 stimulates survival of rat cerebellar granule cells in culture. 770 63

The effect of metabotropic glutamate receptor activation on Ca dihydropyridine (DHP)-sensitive channels recorded in the presence of 1 microM Bay K 8644 was examined on cultured cerebellar granule cells using the patch-clamp technique in the cell-attached configuration. Bath-applied agonist (trans-ACPD, 1S,3R-, and 1R,3S-ACPD isomers, and glutamate or quisqualate in the presence of CPP and CNQX) evoked an increase in Ca channel activity with a variable latency of 8.9 +/- 8.6 sec in 40% of the recorded cells. Neither L-CCG1, L-AP3, L-AP4, nor AMPA or NMDA activated Ca channels. Two dihydropyridine-sensitive channels present in this cell type were activated by trans-ACPD: the classical 24 pS L-type channel and a smaller-conductance 7 pS channel. The effect was shown to be mediated by neither intracellular Ca2+ nor a pertussis toxin (PTX)-sensitive G protein. Interestingly treatment with BAPTA-AM increased the number of responding patches and the activity was more sustained throughout the drug application. After overnight PTX treatment, activation of the Ca channels persisted even after washout of the agonist. These results indicate that mGluR1/mGluR5 probably mediate the facilitation of dihydropyridine-sensitive Ca channels.
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PMID:Facilitatory coupling between a glutamate metabotropic receptor and dihydropyridine-sensitive calcium channels in cultured cerebellar granule cells. 782 24

We have reported previously that a selective metabotropic glutamate receptor (mGluR) agonist, (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD), caused a slow membrane depolarization in rat dorsolateral septal nucleus (DLSN) neurons. Using single electrode voltage-clamp recording methods, we now investigate the pharmacological properties of the receptor that mediates ACPD-induced membrane currents in DLSN neurons recorded from pertussis toxin (PTX)-treated rats. Two pharmacologically distinct inward currents, that is, the ACPD current and Qm current, have been identified based on their agonist preference and sensitivity to various antagonists. The ACPD current is blocked by L-2-amino-4-phosphonobutyric acid (L-AP4), but is insensitive to L-aspartic acid-beta-hydroxamate (L-AA beta H), (+)-alpha-methyl-4-carboxyphenylglycine (+)-MCPG), or L-2-amino-3-phosphonopropionic acid (L-AP3). The Qm current is blocked by L-AA beta H and (+)-MCPG, but is insensitive to L-AP3 or L-AP4. These two inward currents distribute differentially within subpopulations of DLSN neurons. The ACPD current is the only current observed in most DLSN "burster" neurons, while the Qm current is observed more frequently in DLSN "nonburster" neurons. The pharmacological profiles of these currents suggest that the Qm current is likely mediated by mGluR1 or mGluR5, while the ACPD current is mediated by receptors that are pharmacologically distinct from any of the currently cloned mGluRs.
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PMID:Pharmacologically distinct, pertussis toxin-resistant inward currents evoked by metabotropic glutamate receptor (mGluR) agonists in dorsolateral septal nucleus (DLSN) neurons. 782 58

The metabotropic autoreceptor of glutamatergic nerve terminals from the cerebral cortex of adult rats has been characterized. Receptor activation involves a rapid and transient increase in diacylglycerol, which is sensitive to L-2-amino-3-phosphonopropionate (L-AP3) and L-2-amino-4-phosphonobutanoic acid (L-AP4) and is partially blocked by pertussis toxin. Protein kinase C (PKC) has a negative feedback control in this transduction pathway because the activation of the kinase, either by phorbol esters or by the endogenous diacylglycerol produced by the receptor, results in a reversible receptor desensitization, with loss of the ability to further facilitate glutamate release. It is concluded that the facilitatory metabotropic receptor located at the glutamatergic nerve endings belongs to the subclass coupled to phosphoinositide hydrolysis and that the rapid and use-dependent desensitization of the facilitatory pathway may underlie a mechanism to prevent its permanent activation and thereby to avoid neurotoxicity.
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PMID:Rapid desensitization of the metabotropic glutamate receptor that facilitates glutamate release in rat cerebrocortical nerve terminals. 790 19

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

The mRNA for the type IV metabotropic glutamate receptor (mGluR4) is most prominently expressed in cerebellar granule cells, the olfactory system, the lateral septal nucleus, and most thalamic nuclei, but lower amount of the mRNA is found in many different brain regions. Agonist stimulation as studied in transfected cells was found to inhibit forskolin-stimulated cyclic-adenosine-monophosphate formation through a pertussis toxin-sensitive mechanism. Agonist rank order of potencies was: L-2-amino-4-phosphonobutyrate (L-AP4) > glutamate > (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (t-ACPD) > quisqualate > L-homocysteate = ibotenate. The results suggests that the mGluR4 may be responsible for many, but not all, effects of L-AP4.
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PMID:Expression pattern and pharmacology of the rat type IV metabotropic glutamate receptor. 810 23

The modulation of high-threshold Ca2+ currents by the selective metabotropic glutamate receptor (mGluR) agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD), was investigated in cultured hippocampal neurons using whole-cell voltage-clamp recording. ACPD reduced high-threshold Ca2+ currents carried by Ba2+ with an EC50 of 15.5 microM. The inhibition was reversible, voltage dependent, and blocked by L-2-amino-3-phosphonopropionic acid (1 mM) or by pretreatment with pertussis toxin. Inhibition by ACPD was greatly enhanced, and became irreversible, when the nonhydrolyzable GTP analog GTP gamma S was included in the whole-cell pipette. In some neurons, the Ba2+ current was inhibited by L(+)-2-amino-4-phosphonobutanoic acid (L-AP4) as well as ACPD while most cells were insensitive to L-AP4, suggesting that these agonists activate distinct receptors. The inhibition of Ca2+ currents was reduced but not eliminated in the presence of either omega-conotoxin GVIA or nifedipine, suggesting that both N- and L-type Ca2+ currents were affected. The degree and kinetics of inhibition were dependent on intracellular calcium. With [Ca]i < 1 nM, inhibition had a fast onset (t approximately 1-2 sec) and a rapid recovery, consistent with a membrane-delimited pathway. However, a slow component of inhibition appeared when the steady state [Ca]i was increased to 100 nM (t onset approximately 3 min). The slow component did not require transient Ca2+ influx or release of intracellular Ca2+. We suggest that Ca2+ channel modulation by ACPD involves either two mGluR subtypes with separate coupling mechanisms or a single mGluR that couples to both mechanisms.
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PMID:Modulation of calcium currents by a metabotropic glutamate receptor involves fast and slow kinetic components in cultured hippocampal neurons. 839 38


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