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)

CNS function depends on a capacity for plasticity during development, following injury, and in response to changing environmental conditions. Functional alterations in signal transduction pathways and in neurotransmitter receptor expression are possible mechanisms for the expression of such plasticity. In the present report, we demonstrate that exposure of astrocytes to specific growth factors alters both the functional activity and the protein levels of a specific glutamate receptor. Exposure of astrocytes to basic fibroblast growth factor, epidermal growth factor, or transforming growth factor-alpha produced marked increases in the ability of metabotropic glutamate receptor (mGluR) agonists to stimulate phosphoinositide hydrolysis. Using Western immunoblotting, we demonstrate that an increase in the levels of one of the phosphoinositide-coupled mGluR subtypes, mGluR5, accompanies the increased ability of mGluR agonists to stimulate phosphoinositide hydrolysis. In contrast, another phosphoinositide-coupled subtype of this receptor family, mGluR1 alpha, was not present at detectable levels in these cultures. The enhanced stimulation of phosphoinositide hydrolysis showed little sensitivity to pertussis toxin, and appeared to be selective to mGluR agonists, as there was not a similar increase in the ability of norepinephrine or carbachol to stimulate phosphoinositide hydrolysis. These findings demonstrate that expression of mGluRs in astrocytes is plastic, and indicate a novel pathway through which specific growth factors may selectively modulate neurotransmitter action.
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PMID:Growth factor upregulation of a phosphoinositide-coupled metabotropic glutamate receptor in cortical astrocytes. 766 94

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

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

Of the six metabotropic glutamate receptors (mGluRs) only mGluR1 and mGluR5, which possess a large carboxyl terminal domain, are positively linked to phosphoinositide (PI) hydrolysis. We expressed a 3' deletion of mGluR1 alpha (mGluR1T) lacking the terminal 290 codons and the full length mGluR1 alpha cDNAs in human embryonic kidney 293 cells. Agonist stimulation of both mGluR1 alpha and mGluR1T stimulated PI hydrolysis. Glutamate activation of PI hydrolysis was reduced by pertussis toxin when mediated via mGluR1 alpha, while mGluR1T required the presence of extracellular Ca2+. Glutamate-mediated reduction of adenylyl cyclase stimulation by forskolin occurred only in mGluR1T-expressing cells. The results suggest that the carboxyl terminal extension directs the coupling of mGluR1 with different signal transduction pathways.
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PMID:Carboxyl domain of glutamate receptor directs its coupling to metabolic pathways. 851 33

Thrombin is one of the first regulatory molecules present at sites of CNS trauma or injury. Exposure of neuronal and glial cells to thrombin produces potent morphological as well as cytoprotective and cytotoxic effects, but little is known about how this important modulator affects neurotransmitter signaling. In astrocyte cultures that have been morphologically differentiated by exposure to transforming growth factor-alpha, addition of thrombin induced a retraction of astrocytic processes and suppressed the stimulation of phosphoinositide hydrolysis by the selective metabotropic glutamate receptor (mGluR) agonist 1-aminocyclopentane-1S,3R-dicarboxylic acid. In addition to the suppression of phosphoinositide hydrolysis, thrombin treatment produced a corresponding reduction in level of mGluR5 mRNA as demonstrated with ribonuclease protection assay and reduced content of mGluR5 receptor protein as seen with western blotting. In contrast, thrombin exposure up-regulated astrocyte beta-actin mRNA levels. A synthetic hexapeptide with a sequence corresponding to the amino-terminus of the thrombin receptor's tethered ligand also mimicked the ability of thrombin to suppress mGluR5 levels and to increase beta-actin mRNA content, suggesting that these effects of thrombin are mediated by proteolytically activated cell surface thrombin receptors. Thrombin's suppressive effect on mGluR5 was resistant to pretreatment with pertussis toxin or various protein kinase and protein phosphatase inhibitors. However, the serine/threonine protein kinase inhibitor H-7 did prevent thrombin-induced reversal of astrocyte stellation and induction of beta-actin mRNA levels, indicating that these effects of thrombin involve a signaling pathway distinct from the one that mediates the suppressive effects of thrombin on mGluR5.
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PMID:Exposure of astrocytes to thrombin reduces levels of the metabotropic glutamate receptor mGluR5. 885 25

Metabotropic glutamate receptors (mGluRs) control intracellular signaling cascades through activation of G proteins. The inwardly rectifying K+ channel, GIRK, is activated by the beta gamma subunits of G proteins and is widely expressed in the brain. We investigated whether an interaction between mGluRs and GIRK is possible, using Xenopus oocytes expressing mGluRs and a cardiac/brain subunit of GIRK, GIRK1, with or without another brain subunit, GIRK2. mGluRs known to inhibit adenylyl cyclase (types 2, 3, 4, 6, and 7) activated the GIRK channel. The strongest response was observed with mGluR2; it was inhibited by pertussis toxin (PTX). This is consistent with the activation of GIRK by Gi/Go-coupled receptors. In contrast, mGluR1a and mGluR5 receptors known to activate phospholipase C, presumably via G proteins of the Gq class, inhibited the channel's activity. The inhibition was preceded by an initial weak activation, which was more prominent at higher levels of mGluR1a expression. The inhibition of GIRK activity by mGluR1a was suppressed by a broad-specificity protein kinase inhibitor, staurosporine, and by a specific protein kinase C (PKC) inhibitor, bis-indolylmaleimide, but not by PTX, Ca(2-)chelation, or calphostin C. Thus, mGluR1a inhibits the GIRK channel primarily via a pathway involving activation of a PTX-insensitive G protein and, eventually, of a subtype of PKC, possibly PKC-mu. In contrast, the initial activation of GIRK1 caused by mGluR1a was suppressed by PTX but not by the protein kinase inhibitors. Thus, this activation probably results from a promiscuous coupling of mGluR1a to a Gi/Go protein. The observed modulations may be involved in the mGluRs effects on neuronal excitability in the brain. Inhibition of GIRK by phospholipase C-activating mGluRs bears upon the problem of specificity of G protein (GIRK interaction) helping to explain why receptors coupled to Gq are inefficient in activating GIRK.
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PMID:Positive and negative coupling of the metabotropic glutamate receptors to a G protein-activated K+ channel, GIRK, in Xenopus oocytes. 910 6

The present study was aimed at characterizing the metabotropic receptor subtype which is involved in the activation of phospholipase D (PLD) by glutamate in rat hippocampal slices. We first observed that the ontogenetic profile of glutamate-induced hydrolysis of phosphoinositides and of phosphatidylcholine was strikingly similar. Both pathways were significantly activated by glutamate in tissue taken from 3-, 8- and 15-day old rats, but not in adult rats. PLD activation was strongest in slices taken from 8-day old rats. At this age, quisqualate had a higher potency for PLD activation (EC50: 0.6 microM) than 1S,3R-ACPD (EC50: 16 microM) and DHPG, a specific activator of group I mGluR, was a full agonist at PLD activation (EC50: 3.5 microM) indicating an involvement of a group I mGluR (mGluR1 and 5). MCPG and AIDA, two putative antagonists at mGluR1 receptors, caused a small but (in the case of MCPG) significant inhibition. DCG-IV, an activator of group II mGluR, was a weak partial agonist at PLD activation (EC50: 22 nM) while L-AP 4, an activator at group III mGluR, was totally inactive. Likewise, forskolin, a stimulant of cyclic AMP formation, was inactive either alone, or in combination with glutamatergic agonists. Pretreatment of the slices with pertussis toxin did not affect PLD activation. In summary, the glutamate-mediated activation of hippocampal PLD, which occurs transiently during postnatal development, is mediated by a group I mGluR, possibly involving mGluR5.
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PMID:Ontogenetic and pharmacological studies on metabotropic glutamate receptors coupled to phospholipase D activation. 917 8

The corticostriatal pathway is among the largest glutamatergic pathways in the brain, and of particular interest to the study of glutamatergic transmission. The metabotropic glutamate receptors (mGluRs) couple the actions of glutamate to intracellular second messenger systems through G-proteins. The most prominent of the mGluRs present in the target of this pathway, the striatum, is mGluR5. The identity of the G-proteins mediating the actions of mGluR5 are unknown, but the receptor is linked to stimulation of phosphoinositide (PI) turnover and largely resistant to the effects of pertussis toxin, which inhibits some G-proteins. We used in situ hybridization to examine the expression and regulation of three pertussis toxin insensitive G-protein alpha sub-units: Gq, G11, and Gz. We found that these mRNAs are differentially distributed in the rat brain, but all three are expressed by striatal neurons. After glutamatergic deafferentation of the striatum by decortication, there is a modest upregulation of G11 mRNA, while expression of Gq and Gz are unchanged. Following dopaminergic deafferentation, expression of Gq, G11, and Gz are not altered, although expression of the pertussis-sensitive sub-unit Go is increased. Our data suggests that Gz, Gq, and G11 are each expressed by striatal neurons, and therefore may be involved in mediating the actions of mGluR5 in these cells. After decortication G11 is upregulated, but the magnitude of this effect is small, and alone seems insufficient to account for the marked biochemical supersensitivity of glutamate-stimulated PI turnover which is observed.
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PMID:Differential localization of the mRNAs for the pertussis toxin insensitive G-protein alpha sub-units Gq, G11, and Gz in the rat brain, and regulation of their expression after striatal deafferentation. 955 65

The metabotropic glutamate receptor (mGluR) agonist 1-aminocyclopentane-1S,3R-dicarboxylic acid (ACPD) potentiated the accumulation of cyclic AMP induced by either beta-adrenergic receptor stimulation (isoproterenol) or direct activation of adenylyl cyclase (AC) with forskolin in rat cerebral cortical astrocytes grown in a defined medium. In contrast, ACPD inhibits the cyclic AMP response in astrocytes cultured in a serum-containing medium. Pharmacological characterization indicated that a group I mGluR, of which only mGluR5 is detectable in these cells, is involved in the potentiation of cyclic AMP accumulation. Potentiation was elicited by mGluR I agonists [e.g., (R,S)-3,5-dihydroxyphenylglycine (DHPG)], but not by mGluR II or III agonists; it was pertussis toxin resistant and abolished by procedures suppressing mGluR5 function (phorbol ester pretreatment or DHPG-induced receptor down-regulation). Nevertheless, it appears that products generated through the mGluR5 transduction pathway, such as elevated [Ca2+]i or activated protein kinase C (PKC), are not involved in the potentiation as it was not influenced by either the intracellular calcium chelator BAPTA-AM or the PKC inhibitor Ro 31-8220. An inhibitor of phospholipase C, U-73122, markedly attenuated mGluR5-activated phosphoinositide hydrolysis but did not significantly affect the DHPG potentiation of the cyclic AMP response. A mechanism is proposed in which the potentiating effect on AC could be mediated by free betagamma complex that is liberated after the agonist-bound mGluR5 interacts with its coupled G protein.
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PMID:Metabotropic glutamate receptor agonists potentiate cyclic AMP formation induced by forskolin or beta-adrenergic receptor activation in cerebral cortical astrocytes in culture. 960 9


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