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 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

Catfish cone horizontal cells contain a voltage-gated L-type calcium channel that is modulated by activation of metabotropic glutamate receptors (mGluRs). Activation of group I mGluRs with the mGluR I agonist, (S)-3,5-dihydroxyphenylglycine [(S) 3,5-DHPG], potentiated peak calcium current amplitude, shifted the membrane potential corresponding to peak current activity, and widened the calcium current's activation range. In this study, we have examined the mechanisms linking activation of the mGluRs with "up-regulation" of calcium current activity. Under whole-cell voltage-clamp conditions favoring expression of the L-type calcium current, we provide evidence that activation of mGluRs initiate the diacylglyceral (DG) second messenger pathway to activate protein kinase C (PKC) and up-regulate calcium channel activity. This evidence was based on results using a number of PKC activators and inhibitors. PKC activators mimicked the effect of (S) 3,5-DHPG on calcium current activity. Up-regulation of the calcium channel by PKC activators or (S) 3,5-DHPG was eliminated if PKC inhibitors were present. These results also demonstrated that activation of group I mGluRs were linked to a pertussis toxin sensitive G-protein. When the GTP analog, guanosine 5-0-(3-thiotriphosphate (GTPgammaS), was allowed to diffuse into voltage-clamp cells, up-regulation of the calcium channel occurred and mimicked the effect of (S) 3,5-DHPG. However, when pertussis toxin (PTX) was allowed to diffuse into the cell along with GTPgammaS, GTPgammaS failed to modulate calcium current activity. IP3 (inositol 1,4,5 triphosphate) is a second product produced by activation of group I mGluRs. Once formed, IP3 can trigger calcium release from IP3-sensitive intracellular stores. To determine if the IP3 second messenger system was involved in up-regulation of calcium channel, (S) 3,5-DHPG was applied to voltage-clamped cone horizontal cells containing different concentrations of the calcium buffer, EGTA. Low concentrations of EGTA failed to buffer calcium released from intracellular stores. In the presence of low EGTA concentrations, (S) 3,5-DHPG's enhancement of the calcium current amplitude was reduced. Inhibition of the calcium current amplitude in low concentrations of EGTA was eliminated in the presence of the intracellular calcium store blocker, heparin. These results suggest that both the DG and IP3 second messenger pathways are involved in modulation of the voltage-gated calcium channel in catfish cone horizontal cells. The DG pathway up-regulates the voltage-gated calcium channel activity whereas calcium released from IP3 intracellular stores inhibits peak current amplitude.
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PMID:Second messenger pathways involved in up-regulation of an L-type calcium channel. 1091 Jan 13

Low-frequency stimulation of primary afferent Adelta-fibers can induce long-term depression of synaptic transmission in rat superficial spinal dorsal horn. Here, we have identified another form of long-term depression in superficial spinal dorsal horn neurons that is induced by specific group I but not group II metabotropic glutamate receptor (mGluR) agonists. Synaptic strength between Adelta-fibers and dorsal horn neurons was examined by intracellular recordings in a spinal cord-dorsal root slice preparation from young rat. In the presence of bicuculline and strychnine, bath application of (1S,3R)-1-aminocyclopentane-1, 3-dicarboxylic acid ((1S,3R)-ACPD) or the specific group I mGluR agonist (S)-3,5-dihydroxyphenylglycine ((S)-3,5-DHPG) but not the specific group II mGluR agonist (2S,2'R,3'R)-2-(2', 3'-dicarboxycyclopropyl)glycine (DCG-IV) for 20 min produced an acute and a long-term depression of synaptic strength. Bath application of the N-methyl-D-aspartate receptor antagonist D-2-amino-5-phosphonovaleric acid did not affect these depressions by (1S,3R)-ACPD. After pre-incubation of slices with pertussis toxin, a G-protein inhibitor, (1S,3R)-ACPD still induced acute and long-term depressions. The phospholipase C inhibitor U73122 stereoselectively blocked the induction of long-term depression without affecting acute synaptic inhibition. This study demonstrates that, in the spinal cord, direct activation of group I mGluRs that are coupled to phospholipase C through pertussis toxin-insensitive G-proteins induces a long-term depression of synaptic strength. This may be relevant to the processing of sensory information in the spinal cord, including nociception.
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PMID:Activation of group I metabotropic glutamate receptors induces long-term depression at sensory synapses in superficial spinal dorsal horn. 1097 7

Signal transduction mechanisms of group II metabotropic glutamate receptors (mGlu(2/3)) remains a matter of some controversy, therefore we sought to gain new insights into its regulation by studying cAMP production in cultured neurons and astrocytes, and by examining inter-relationships of mGlu(2/3)-induced signalling with cellular calcium and various signalling cascades. mGlu(2/3) agonists 2R,4R-4-aminopyrrolidine-2,4-dicarboxylic acid (2R,4R-APDC) and (-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylic acid (LY379268) inhibited 10 microM forskolin-stimulated production of cAMP in murine cortical neurons, striatal neurons and forebrain astrocytes in the absence of extracellular Ca(2+). These agonists potentiated cAMP production in the presence of 1.8 mM Ca(2+) in astrocytes only. This potentiation was dependent on the extracellular Ca(2+) concentration (0.001-10 mM) and inhibited by the mGlu(2/3) antagonist LY341495 (1 microM), adenosine deaminase (1 U/ml) and the adenosine A(2A) receptor antagonist ZM241385 (1 microM). Pre-incubation with the phospholipase C (PLC) inhibitor U73122 (10 microM), L-type Ca(2+)-channel blockers nifedipine (1 microM) and nimodipine (1 microM), the calmodulin kinase II (CaMKII) inhibitor KN-62 (10 microM) or pertussis toxin (100 ng/ml) inhibited this potentiation. In the absence of 1.8 mM Ca(2+), thapsigargin (1 microM) facilitated the potentiation of cAMP production. Measurement of the Ca(2+)-binding dye Fluo-3/AM showed that, compared to Ca(2+)-free conditions, thapsigargin and 1.8 mM Ca(2+) elevated [Ca(2+)](i) in astrocytes; the latter effect being prevented by L-type Ca(2+)-channel blockers. Potentiation of cAMP production was also demonstrated when astrocytes were stimulated with the beta-adrenoceptor agonist isoprenaline (10 microM) in the presence of 1.8 mM Ca(2+), but not with the adenosine agonist NECA (10 microM) or the group I mGlu receptor agonist DHPG (100 microM). BaCl(2) (1.8 mM) in place of Ca(2+) did not facilitate forskolin-stimulated mGlu(2/3)-potentiation of cAMP. In short, this study in astrocytes demonstrates that under physiological Ca(2+) and adenylate cyclase stimulation an elevation of cAMP production is achieved that is mediated by PLC/IP(3)- and CaMKII-dependent pathways and results in the release of endogenous adenosine which acts at G(s) protein-coupled A(2A) receptors. These findings provide new insights into mGlu(2/3) signalling in astrocytes versus neurons, and which could determine the functional phenotypy of astrocytes under physiological and pathological conditions.
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PMID:Astrocyte mGlu(2/3)-mediated cAMP potentiation is calcium sensitive: studies in murine neuronal and astrocyte cultures. 1221 73

Several excitatory amino acid ligands were found potently to inhibit forskolin-stimulated cAMP accumulation in rat cultured cerebellar astrocytes: L-cysteine sulfinic acid (L-CSA) = L-aspartate > L-glutamate >/= the glutamate uptake inhibitor, L-PDC. This property did not reflect activation of conventional glutamate receptors, since the selective ionotropic glutamate receptor agonists NMDA, AMPA, and kainate, as well as several mGlu receptor agonists [(1S,3R)-ACPD, (S)-DHPG, DCG-IV, L-AP4, L-quisqualate, and L-CCG-I], were without activity. In addition, the mGlu receptor antagonists, L-AP3, (S)-4CPG, Eglu, LY341495, (RS)-CPPG, and (S)-MCPG failed to reverse 30 microM glutamate-mediated inhibitory responses. L-PDC-mediated inhibition was abolished by the addition of the enzyme glutamate-pyruvate transaminase. This finding suggests that the effect of L-PDC is indirect and that it is mediated through endogenously released L-glutamate. Interestingly, L-glutamate-mediated inhibitory responses were resistant to pertussis toxin, suggesting that G(i)/G(o) type G proteins were not involved. However, inhibition of protein kinase C (PKC, either via the selective PKC inhibitor GF109203X or chronic PMA treatment) augmented glutamate-mediated inhibitory responses. Although mGlu3 receptors (which are negatively coupled to adenylyl cyclase) are expressed in astrocyte populations, in our study Western blot analysis indicated that this receptor type was not expressed in cerebellar astrocytes. We therefore suggest that cerebellar astrocytes express a novel mGlu receptor, which is negatively coupled to adenylyl cyclase, and possesses an atypical pharmacological profile.
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PMID:Novel metabotropic glutamate receptor negatively coupled to adenylyl cyclase in cultured rat cerebellar astrocytes. 1499 8