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: EC:3.1.4.3 (phospholipase C)
18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We previously reported that a variant with extra amino acid residues exists in the metabotropic glutamate receptor subtype 5 (mGluR5). Either of the two isoforms, named mGluR5b and mGluR5a for the isoforms with and without the inserted sequence, respectively, generated Ca(2+)-activated Cl- current when expressed in Xenopus oocytes. We herein report that these two isoforms are produced by the alternative splicing of the exon skipping type. When examined during the course of postnatal development, the major mGluR5 isotype mRNA was observed to switch from mGluR5a to mGluR5b in the rat hippocampus and the cerebral cortex. We also investigated two cell lines that could be differentiated into neuron-like cells in vitro. Whereas the mGluR5b mRNA was hardly detectable in either undifferentiated or differentiated NG108-15 cells, the relative amounts of the two variant mRNAs changed after the induction of differentiation in the P19 cells. An extracellular application of trans-D,L-1-amino-1,3-cyclopentanedicarboxylate on the neuron-like P19 cells induced intracellular Ca2+ mobilization, thus suggesting that the cells could express functional mGluR(s) coupled to phospholipase C and other components that could mediate the signal transduction pathway. This cell line may thus provide a model system for studying both mGluR5 expression and other mGluR-induced phenomena at the molecular level.
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PMID:The expression of two splice variants of metabotropic glutamate receptor subtype 5 in the rat brain and neuronal cells during development. 756 47

Glutamate is the principal transmitter of retinal projections to the rodent suprachiasmatic nucleus, a circadian clock synchronized with the light-dark cycle through the activation of glutamate receptors of the ionotropic type. In vitro, an intracellular mobilization of calcium can be induced by glutamate within cells of the suprachiasmatic nucleus maintained in a calcium-free medium, suggesting a participation of metabotropic glutamate receptors coupled to phospholipase C. Using in situ hybridization histochemistry, we examined the expression of messenger RNAs encoding the mGluR1 and mGluR5 subtypes of metabotropic glutamate receptors in the suprachiasmatic nucleus of the adult rat and during postnatal development. In the adult, mGluR1 was expressed in a small subset of neurons segregated caudally within the ventrolateral subdivision of the nucleus, while mGluR5 was mainly expressed in ventrolateral neurons within the middle third of the nucleus. Both subtypes were expressed in morphologically similar small cells, but mGluR5 was also solely expressed in a small population of larger neurons located at the dorsalmost aspect of the ventrolateral subdivision. In addition, with mGluR1 probe silver grain clusters exhibiting a grain density close but below the significant level were observed throughout the ventrolateral subdivision of the nucleus. At birth, mGluR1 and mGluR5 were similarly expressed throughout the caudal half of the nucleus. The expression of mGluR1 increased during early postnatal development and exhibited an adult pattern at postnatal day 21. The expression of mGluR5 increased from postnatal day 7 and reached the adult pattern at postnatal day 45. These observations suggest that each subtype of metabotropic glutamate receptor coupled to phospholipase C underlies specific roles within the rat suprachiasmatic nucleus during postnatal development and in the adult. In the adult, ionotropic and metabotropic receptors likely co-expressed within neuronal subsets located in the retinal terminal field may have interactive and/or additive effects on intracellular calcium concentration. Metabotropic receptors may thus participate in the mediation of photic information conveyed to a subset of neurons. During postnatal development, metabotropic receptors may play a role in the maturation of glutamatergic synapses associated with the retinal input.
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PMID:The messenger RNAs encoding metabotropic glutamate receptor subtypes are expressed in different neuronal subpopulations of the rat suprachiasmatic nucleus. 763 67

To characterize G-proteins which mediate the signal transduction from ligand stimulated receptor to phospholipase C (PLC), we injected antisense DNAs complementary to Xenopus G(o) alpha or Gi-l alpha to suppress these endogenous G-proteins, together with the mRNAs encoding metabotropic glutamate receptor 1 (mGluR1), 5 (mGluR5) or with M1 type muscarinic receptor into oocytes. Receptor-stimulated chloride current responses were reduced by the suppression of Xenopus G(o) alpha regardless of the types of receptors. However, injection of Gi-1 antisense DNA resulted in the reduction of M1-stimulated responses but not mGluR-stimulated responses. These results suggested that all these receptors could use G(o) alpha, and M1 receptors, but not mGluRs, could also use Gi-1 proteins, to activate PLC in Xenopus oocytes.
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PMID:Inositol phospholipid metabolism in Xenopus oocytes mediated by endogenous G(o) and Gi proteins. 795 59

G protein-coupled glutamate receptors (mGluR) have recently been characterized. These receptors have seven putative transmembrane domains, but display no sequence homology with the large family of G protein-coupled receptors. They constitute therefore a new family of receptors. Whereas mGluR1 and mGluR5 activate phospholipase C (PLC), mGluR2, mGluR3, mGluR4 and mGluR6 inhibit adenylyl cyclase (AC) activity. The third putative intracellular loop, which determines the G protein specificity in many G protein-coupled receptors, is highly conserved among mGluRs, and may therefore not be involved in the specific recognition of G proteins in this receptor family. By constructing chimeric receptors between the AC-coupled mGluR3 and the PLC-coupled mGluR1c, we report here that both the C-terminal end of the second intracellular loop and the segment located downstream of the seventh transmembrane domain are necessary for the specific activation of PLC by mGluR1c. These two segments are rich in basic residues and are likely to be amphipathic alpha-helices, two characteristics of the G protein interacting domains of all G protein-coupled receptors. This indicates that whereas no amino acid sequence homology between mGluRs and the other G protein-coupled receptors can be found, their G protein interacting domains have similar structural features.
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PMID:Domains involved in the specificity of G protein activation in phospholipase C-coupled metabotropic glutamate receptors. 831 79

The metabotropic glutamate receptors (mGluRs) share no sequence homology and show different structural features compared with most other G protein-coupled receptors (GPCRs). In particular, some isoforms of the phospholipase C (PLC)-coupled mGluRs (mGluR1a, mGluR5a, and mGluR5b) have a surprisingly long carboxyl-terminal intracellular domain of more than 350 residues, whereas the splice variants mGluR1b and mGluR1c have a much shorter carboxyl terminus. In the current study, the different splice variants of mGluR1 were expressed in porcine kidney epithelial (LLC-PK1) or the human embryonic kidney (HEK 293) cells, and their levels of expression were examined with the use of Western blot analysis. Expression of the short isoforms mGluR1b and mGluR1c did not modify the basal inositol phosphate production. In contrast, expression to similar levels of mGluR1a resulted in a 2-fold increase in the basal inositol phosphate formation. This increase in basal PLC activity was due to neither the presence of a low concentration of glutamate in the incubation medium nor a modification of the PLC pathway, resulting, for example, from the constant activation of mGluR1a++ by glutamate during the culture. Surprisingly none of the known competitive antagonists of mGluR1 inhibited the basal PLC activity, indicating that none of these molecules act as inverse agonists. Taken together, these results indicate that the long carboxyl-terminal domain confers a small agonist-independent activity to mGluR1. This indicates that, as already observed for other GPCRs, little constitutive activity of wild-type mGluRs can be detected. Our results also add to the splice variants and further suggest that the long carboxyl-terminal domain of mGluR1a confers better coupling efficiency to the G proteins.
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PMID:Changes in the carboxyl-terminal domain of metabotropic glutamate receptor 1 by alternative splicing generate receptors with differing agonist-independent activity. 864 81

The role of phospholipase C-coupled (group I) metabotropic glutamate receptors (mGluR1 and mGluR5) in post-traumatic neuronal injury was examined using rat in vivo and in vitro models. Traumatic injury to mixed neuronal/glial cultures induced phosphoinositide hydrolysis and caused neuronal death. Pharmacological blockade of group I receptors significantly reduced these effects in vitro and decreased neurological deficits as well as neuronal loss produced by traumatic brain injury in vivo. In contrast, activation of group I receptors by a specific agonist in vitro exacerbated post-traumatic neuronal death in a dose-dependent manner. Antisense oligodeoxynucleotide directed to mGluR1, but not to mGluR5, was neuroprotective in vitro, although each oligodeoxynucleotide reduced the respective receptor-stimulated accumulation of inositol phosphates to a similar degree. Together, these findings suggest that activation of mGluR1 contributes to post-traumatic neuronal injury and that mGluR1 antagonists may have therapeutic potential in brain injury.
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PMID:Activation of metabotropic glutamate receptor subtype mGluR1 contributes to post-traumatic neuronal injury. 881 84

In the CA1 region of hippocampal slices prepared from young adult rats, we studied the ability of several specific agonists of metabotropic glutamate receptors (mGluRs) to depress excitatory synaptic transmission at the CA3-CA1 pyramidal cell synapses. Three groups of mGluRs have been described: group 1 (mGluR1 and 5) receptors are positively coupled to phospholipase C whereas group 2 (mGluR2 and 3) and group 3 (mGluR4, 6, 7 and 8) receptors are negatively coupled to adenylate cyclase. We found that the broad-spectrum agonist (1S,3R)-1-aminocyclopentyl-1,3-dicarboxylate and the group 1-specific agonist (R,S)-dihydroxyphenylglycine both reversibly inhibited evoked field excitatory postsynaptic potentials, indicating the involvement of group 1 mGluRs. (R,S)-3,5-dihydroxyphenylglycine presumably inhibited transmission via a presynaptic mechanism, as whole-cell voltage-clamp recordings revealed that inhibition of the synaptic transmission was always accompanied with an increase in paired-pulse facilitation. Treatment with a specific blocker of mGluR1 receptors, the phenylglycine derivative (S)-4-carboxyphenylglycine, was without effect on the (1S,3R)-1-amino-cyclopentyl-1,3-dicarboxylate-induced depression of the field excitatory postsynaptic potentials, strongly suggesting that mGluR5 receptors are responsible for the (1S,3R)-1-aminocyclopentyl-1,3-dicarboxylate effect. Two selective agonists of group 2 mGluRs, (2S,1's,2's)-2-(2'-carboxycyclopropyl)glycine and 4-carboxy-3-hydroxyphenylglycine, were totally ineffective in blocking CA3-CA1-evoked synaptic transmission, excluding the involvement of mGluR2/3 subtypes at this developmental stage.
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PMID:Metabotropic glutamate receptors inhibiting excitatory synapses in the CA1 area of rat hippocampus. 884 58

1. Whole cell recordings from dentate granule neurons in the hippocampal slice preparation reveal that (1 S, 3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD), a selective agonist at metabotropic glutamate receptors (mGluRs), inhibits a calcium-activated potassium current (IAHP) responsible for the postspike after-hyperpolarization. Inclusion of 1 mM of the Ca2+ chelator ethylene glycol-bis (beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid in the patch pipette reduced the inhibitory action of ACPD on IAHP while having no effect on a similar action of serotonin (5-HT). Thus the known action of ACPD of mobilizing intracellular Ca2+ may be involved in this inhibitor action of ACPD. 2. Inhibition of IAHP is not secondary to effects on Ca2+ currents, because 10 microM ACPD, which inhibits IAHP by 95 +/- 5% (mean +/- SE), reduced the Ca2+ current by only 8 +/- 4%. 3. Activation of mGluRs accelerates the irreversible inhibition of IAHP that develops when 88 microM GTP-gamma-S is included in the pipette filling solution, whereas inclusion of 1 mM GDP-beta-S attenuated the inhibitory action of ACPD. These results indicate that the response to mGluR activation is G protein mediated. 4. Group I mGluRs, which includes mGluR1 and mGluR5, are G-protein-coupled receptors that are known to stimulate phospholipase C (PLC)-mediated hydrolysis of phosphoinositides to produce 1,4,5-triphosphate (IP3), which in turn is known to mobilize the release of intracellular Ca2+. The weak but selective mGluR1 agonist (S)-3-hydroxyphenylglycine (100 microM) completely inhibited IAHP, and the mGluR1 antagonist (S)-4-carboxyphenylglycine (500 microM) reduced IAHP inhibition produced by 5 microM ACPD from 73 +/- 6% to 22 +/- 4%. These results indicate that the mGluR responsible for IAHP inhibition has a similar pharmacological profile to that of those coupled to IP3 production. 5. The effects of agents known to interfere with IP3 production and action also support IP3 involvement in ACPD action. Neomycin (1 mM in pipette solution), which should reduce IP3 production through inhibition of PLC, reduced the ability of 10 microM ACPD to inhibit IAHP from almost 100% to 57 +/- 8% (n = 8). Heparin, an IP3 receptor antagonist that reduces Ca2+ mobilization, attenuated the inhibitory action 10 microM ACPD from almost 100% to 39 +/- 5% (n = 5). Heparin by itself increased the amplitude and duration of IAHP, suggesting that resting levels of IP3 are sufficient to suppress of IAHP partially. 6. In addition to the pool of intracellular Ca2+ that is mobilized by IP3, there is a distinct pool that is responsible for Ca(2+)-triggered Ca2+ release and is blocked by ryanodine or dantrolene. These drugs caused a small reduction of both IAHP and the inhibitory action of ACPD. Possibly the Ca2+ signal mobilized by IP3 is partially amplified by Ca2+ released from the ryanodine-sensitive stores. 7. Activation of PLC can also lead to the production of diacylglycerol and activation of protein kinase C (PKC). However, the inhibitory action of ACPD on IAHP was not affected by staurosporine at a concentration (1 microM) that inhibits both protein kinase A (PKA) and PKC and blocks the action of 5-HT to inhibit IAHP. 8. Activation of PKA by the adenylate cyclase activator forskolin led to inhibition of IAHP. Although activation of mGluR1 agonists can also stimulate adenylate cyclase and activate PKA, inhibition of PKA and the effect of forskolin on IAHP with the Walsh peptide did not affect ACPD inhibition of IAHP. 9. All of our results support the hypothesis that mGluR-mediated inhibition of IAHP is initiated by the production of IP3 and the mobilization of intracellular Ca2+.
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PMID:Metabotropic glutamate receptors coupled to IP3 production mediate inhibition of IAHP in rat dentate granule neurons. 889 38

We investigated the expression and coupling to the phospholipase C signal transduction pathway of metabotropic glutamate receptor (mGluR) subtypes by Western blot analysis and agonist-stimulated inositol monophosphate formation in several brain regions of postnatal day 9 (P9) and adult rats. In the cerebral cortex, hippocampus, corpus striatum, olfactory bulb, cerebellum and hypothalamus, the expression level of mGluR5 was greater at P9 than in adulthood. The mGluR5 signal was very low or absent in the adult cerebellum and hypothalamus. The expression of mGluR1a was slightly greater at P9 in the hypothalamus, hippocampus and olfactory bulb, whereas it substantially increased with age in the cerebellum, and did not change in the cerebral cortex and corpus striatum. mGluR1b and -1c were nearly undetectable by Western blot analysis. The expression level of mGluR5, but not that of mGluR1a, was significantly correlated with the extent of phosphoinositide hydrolysis stimulated by mGluR agonists in slices prepared from these brain regions. The mGluR antagonist cyclopropan[b]chromen-1a-carboxylic acid ethylester (CPCCOEt), potently antagonized responses mediated by mGluR1, but much less potently those mediated by mGluR5a in recombinant cells. CPCCOEt, at a concentration which efficiently blocks mGluR1 responses, did not substantially affect the polyphosphoinositide response in hippocampal or cerebellar slices from newborn animals, and antagonized only a minor component of the polyphosphoinositide response in adult hippocampal slices. CPCCOEt, however, prevented the small stimulation of polyphosphoinositide hydrolysis by mGluR agonists in adult cerebellar slices. We conclude that (i) the efficient mGluR-mediated polyphosphoinositide hydrolysis in 9-day-old rats is mediated by mGluR5; (ii) the increased expression of mGluR1 in the adult cerebellum does not substitute for the decline of mGluR5 expression in the ability to mediate polyphosphoinositide hydrolysis; and therefore (iii) mGluR1a might couple less efficiently than mGluR5 to polyphosphoinositide hydrolysis.
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PMID:Expression and coupling to polyphosphoinositide hydrolysis of group I metabotropic glutamate receptors in early postnatal and adult rat brain. 904 64

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


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