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)

gamma-Aminobutyric acid (GABA)A receptor-mediated inhibitory synaptic transmission in visual cortex undergoes long-term potentiation (LTP), which is input-specific and associative. The present study, conducted under a blockade of ionotropic glutamate receptors, demonstrates an induction mechanism of LTP considerably different from those of associative LTP at excitatory synapses. Inhibitory responses of layer V cells evoked by layer IV stimulation were studied in developing rat visual cortex slices by using intracellular and whole-cell recording methods. LTP induction was prevented by the application of an antagonist for GABAB receptors but not for GABAA or metabotropic glutamate receptors. Inhibition of postsynaptic G-proteins, phospholipase C, inositol trisphosphate (IP3) receptors, or Ca2+ increase prevented the generation of LTP, as did the blockade of GABAB receptors. In rat cerebral cortex, GABAB receptor activation is not known to affect the IP3 level by itself. However, it facilitates IP3 formation induced by the activation of alpha 1 adrenoceptors, which are believed to be located postsynaptically. Accordingly, I examined the involvement of these and other amine receptors, including histamine H1, muscarinic acetylcholine, and serotonin 5-HT2 receptors, all of which are coupled to IP3 formation. Only the blockade of alpha 1 adrenoceptors or serotonin 5-HT2 receptors prevented LTP induction in most, but not all, of the cells. These results suggest that LTP induction requires the activation of postsynaptic GABAB receptors and that its effect is mediated at least partly by facilitation of the monoamine-induced IP3 formation, which then causes Ca2+ release from the internal stores in postsynaptic cells.
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PMID:GABAB receptors, monoamine receptors, and postsynaptic inositol trisphosphate-induced Ca2+ release are involved in the induction of long-term potentiation at visual cortical inhibitory synapses. 881 13

Outer (OHC) and inner (IHC) hair cells in the organ of Corti of the mammalian cochlea process sound. OHC and their efferent synapse are part of a feedback system assumed to control and modulate information carried by afferent neurons passing from IHC to the brain. Underlying mechanisms are not well understood. This paper discusses recent progress. In vivo and in vitro information is presented on structure, pharmacology, function and localization of the pre- and postsynaptic acetylcholine receptors (AChRs) at the efferent synapse. Recent data are given on a presynaptic M3 AChR subtype, probably an autoreceptor involved in transmitter release. Data from our lab on specific binding of [3H]3-quinuclidinyl benzilate ([3H]3-QNB) to non-enzymatically isolated guinea pig OHC reveal a KD several 100 x higher than that for any known muscarinic receptor subtype, including the above-mentioned presynaptic muscarinic AChR of the OHC efferent synapse. The extremely high concentrations of [3H]3-QNB needed for any binding at all to OHC thus rule out presynaptic membrane impurities as the cause of such binding, and also the presence of a typical mAChR subtype on OHC. The number of [3H]3-QNB binding sites (approximately 10(6)/OHC) we found on OHC was 1/10th of that we found for binding of nicotinic ligands to OHC, further making it questionable that an ACh-binding site on OHC binds [3H]3-QNB. Observations may instead point to the possibility of another binding site, e.g. an (allosteric) site involved with the as yet not understood 'weak' muscarinic properties of the OHC AChR. Further new data on the OHC AChR confirm reversible alpha-bungarotoxin, nicotine and d-tubocurarine binding. [3H]alpha-Bungarotoxin and [3H]-nicotine binding sites are estimated at approximately 6.10(7) sites/OHC. Strychnine, a glycine receptor blocker suggested to interfere with cholinergic sites of the efferent OHC synapse, was found to bind to OHC (cold strychnine for unspecific binding). This binding, not seen in the presence of high [glycine], increased in the presence of depolarizing [K+], while ACh (100 microM) had no significant effect. Results suggest strychnine binding to the outside of OHC, but also sites accessible only after cell depolarization, possibly to the hyperpolarizing Ca2(+)-dependent K+ channel. Recent molecular cloning of the OHC AChR indicates a novel alpha-subunit. An often observed ACh-activated Ca(2+)-influx close to zero into OHC leaves an unanswered question. OHC also carry P2-purinergic receptors (P2Rs), a more rapid ionotropic P2zR-like subtype and a quantitatively dominating slow metabotropic P2yR subtype coupled to a G protein-phospholipase C cascade and not desensitized. Both contribute to increased cytoplasmic [Ca2+], from respectively external and internal sources. Whether or not such receptors are part of efferent synaptic activity is unknown; their localization on the OHC plasma membrane is so far only indirect and synaptic vesicles of the efferent nerve endings have not yet been analyzed for their ATP content. Localization, function and interaction of [Ca2+] increases triggered by, respectively, ATP and ACh are currently studied in this laboratory.
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PMID:Cholinergic and purinergic signalling in outer hair cells of mammalian cochlea. 884 30

1. Neuronal plasticity has been suggested to be the physical substrate for changes underlying the expression of memory. One model which has attracted wide attention as a possible candidate of such neuronal plasticity is long-term potentiation (LTP), mainly investigated in the hippocampus of rodents. Moreover, various processes with different time constants may underlie LTP, and these phases show striking correspondence to different phases of memory. 2. Pharmacological evidence strongly implicates that the neurotransmitter glutamate plays a major role in LTP. Although the involvement of ionotropic glutamate receptors has been proven, the role of the newly discovered metabotropic glutamate receptors is still uncertain. 3. Metabotropic glutamate receptors (mGluRs) comprise a whole family with currently eight members grouped into three classes according to their amino acid sequence identity and pharmacological profile. They are G-protein coupled, either positively linked to phospholipase C (class I) or negatively linked to adenylate cyclase (class II and III), and among other effects are known to induce phosphorylation of ionotropic glutamate receptors as well as modulate the excitability of neurons. Finally, they are heterogeneously distributed throughout the brain. 4. In hippocampal slice preparations, mGluRs have been shown to be involved in the induction of LTP in CA1 and dentate gyrus by some investigators, but others have failed to reproduce such experiments, leaving the question: what are the appropriate conditions for mGluR-mediated LTP? 5. In vivo, metabotropic receptor antagonists have been shown to block, and agonists to facilitate, induction and maintenance of LTP, mainly at perforant path/dentate granule cell synapses. As demonstrated in behavioral investigations, mGluRs apparently play an important part in hippocampus-dependent learning paradigms. As in LTP, antagonists block memory formation; in contrast to LTP, agonists also prevent memory formation. In memory recall metabotropic receptors seem to play no role. 6. Based on current information the authors develop models for a role of mGluRs in both LTP and memory formation. Activation of metabotropic receptors plays a particular modulatory role when high frequency stimulation is weak. Strong tetanization may bypass mGluRs by stimulating other systems leading to, at least phenomenologically, similar LTP, Behaviorally, mGluRs possibly set the signal to noise ratio of the hippocampal circuit.
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PMID:Comparing the role of metabotropic glutamate receptors in long-term potentiation and in learning and memory. 887 63

The functional properties of the G protein-coupled P2Y1 receptor were investigated in Xenopus oocytes. Incubation of oocytes expressing either the human or turkey P2Y1 receptor with adenine nucleotide agonists resulted in an increase in Cl- current and activation of a novel cation current with an inwardly rectifying current-voltage relationship. Activation of either the human P2Y2 (P2U-purinergic) or M1 muscarinic receptor expressed in oocytes resulted in an increase in Cl- current similar to that observed in P2Y1 receptor-expressing oocytes but had no effect on cation current. P2 receptor agonists stimulated both the cation current and Cl- current in P2Y1 receptor-expressing oocytes with EC50 values and an order of potency (2-methylthioadenosine diphosphate > 2-methylthioadenosine triphosphate (2MeSATP) > ATP > UTP) that were similar to those previously observed for activation of phospholipase C in 1321N1 human astrocytoma cells stably expressing the human or turkey P2Y1 receptor. The P2Y receptor antagonists suramin and pyridoxal phosphate 6-azophenyl-2'-4'-disulfonic acid both shifted to the right the concentration-response relationship for 2MeSATP for stimulation of oocyte currents. Although injection of oocytes with either GDPbetaS (guanyl-5'-yl thiophosphate) or GTPgammaS (guanosine 5'-3-O-(thio)triphosphate) resulted in loss of adenine nucleotide-promoted Cl- channel activation, neither guanine nucleotide altered the 2MeSATP-stimulated cation current. These data are consistent with the view that activation of the novel cation current by the P2Y1 receptor does not involve a G protein. Tail current analysis of the novel P2Y1 receptor-associated cation conductance revealed that the open channel current-voltage relationship was outwardly rectifying with a reversal potential of -38 mV for the turkey P2Y1 receptor and -36 mV for the human P2Y1 receptor. Replacement of Na+ with K+ ions in the bathing solution produced a shift in reversal potential to near zero mV, but significant outward rectification remained. The cation current was not permeable to either Ca2+ or Ba2+ and exhibited steady-state inactivation at holding potentials below -60 mV. These results indicate that the P2Y1 receptor exhibits both metabotropic properties and a novel G protein-independent ionotropic response when expressed in Xenopus oocytes.
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PMID:A guanine nucleotide-independent inwardly rectifying cation permeability is associated with P2Y1 receptor expression in Xenopus oocytes. 891 May 62

The intracellular calcium signalling was studied on subpopulation of freshly isolated adult mouse dorsal root ganglia (DRG) neurones with large somatas (30-45 microns in diameter). The cytoplasmic Ca2+ concentration ([Ca2+]i) was measured using indo-1 based microfluorimetry. The extracellular application of ATP (100 microM) triggered both inward current and [Ca2+]i elevation. Removal of extracellular Ca2+ had no effect on both ATP-induced current and [Ca2+]i transient. The ATP-induced Ca2+ elevation was inhibited by intracellular perfusion of DRG neurones with 20 microM heparin, or by cells incubation with thapsigargin or ryanodine. We conclude that mouse proprioceptive sensory neurones are endowed with Ca2+-impermeable ionotropic P2X purinoreceptors and metabotropic P2Y purinoreceptors, which, by means of phospholipase C-driven inositol-trisphosphate (InsP3) production, trigger the InsP3-induced Ca2+ release from intracellular stores.
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PMID:InsP3-induced Ca2+ release in dorsal root ganglion neurones. 918 Feb 15

Adenosine 5'-triphosphate (ATP) and/or related nucleotides act at both ionotropic (P2X) and metabotropic (P2Y) receptors. P2X receptor subunits (P2X1-P2X7) form ligand-gated cation channels, as homomultimers or heteromultimers. Recent work indicates that P2X3 subunits participate in channels expressed by nociceptive sensory neurons, and that the second of the two transmembrane domains of each subunit contributes to the ion permeation pathway. P2X7 subunits form large cytolytic pores in addition to cation channels; they have been found in macrophages and brain microglia. P2Y receptors form a distinct subset of G-protein-coupled receptors; most couple through G proteins to phospholipase C, but inhibition of adenylate cyclase and N-type Ca2+ channels, and activation of K+ channels also occurs. Expressed P2Y receptors have generally been distinguished pharmacologically by the rank order of effectiveness of agonists; some prefer pyrimidines to purines. Recent studies suggest that it is important to use purified nucleotides in such classifications. Several P2Y receptors have a very widespread tissue distribution.
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PMID:Nucleotide receptors. 923 9

1. Glutamate suppressed high-voltage-activated barium currents (IBa, HVA) in tiger salamander retinal ganglion cells. Both ionotropic (iGluR) and metabotropic (mGluR) receptors contributed to this calcium channel inhibition. 2. Trans-ACPD (1-aminocyclopentane-trans-1S,3R-dicarboxylic acid), a broad-spectrum metabotropic glutamate receptor agonist, suppressed a dihydropyridine-sensitive barium current. Kainate, an ionotropic glutamate receptor agonist, reduced an omega-conotoxin GVIA-sensitive current. 3. The relative effectiveness of selective agonists indicated that the predominant metabotropic receptor was the L-2-amino-4-phosphonobutyrate (L-AP4)-sensitive, group III receptor. This receptor reversed the action of forskolin, but this was not responsible for calcium channel suppression. l-AP4 raised internal calcium concentration. Antagonists of phospholipase C, inositol trisphosphate (IP3) receptors and ryanodine receptors inhibited the action of metabotropic agonists, indicating that group III receptor transduction was linked to this pathway. 4. The action of kainate was partially suppressed by BAPTA, by calmodulin antagonists and by blockers of calmodulin-dependent phosphatase. Suppression by kainate of the calcium channel current was more rapid when calcium was the charge carrier, instead of barium. The results indicate that calcium influx through kainate-sensitive glutamate receptors can activate calmodulin, which stimulates phosphatases that may directly suppress voltage-sensitive calcium channels. 5. Thus, ionotropic and metabotropic glutamate receptors inhibit distinct calcium channels. They could act synergistically, since both increase internal calcium. These pathways provide negative feedback that can reduce calcium influx when ganglion cells are depolarized.
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PMID:Metabotropic and ionotropic glutamate receptors regulate calcium channel currents in salamander retinal ganglion cells. 966 Aug 96

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.
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PMID:Molecular pathways mediating activation by kainate of mitogen-activated protein kinase in oligodendrocyte progenitors. 1009 77

The response of rat submandibular glands to extracellular purines was tested. In crude cellular suspensions, ATP increased the [Ca2+]i mostly by promoting uptake of extracellular calcium. ATP caused the pHi to drop, a response blocked by chloride channel inhibitors. ATP also inhibited the basal and isoproterenol-stimulated activity of the Na+ -K+ -2Cl-cotransporter. These effects were reproduced by benzoyl-ATP, an agonist of ionotropic purinoceptors. In pure ductal suspensions, ATP activated a metabotropic P2Y1 purinergic receptor coupled to phospholipase C and opened a non-specific cation channel coupled to a P2X7 receptor. Activation of these receptors stimulated a Ca2+ -dependent and a Ca2+ -independent phospholipase A2, the latter resulting in kallikrein secretion. We conclude that purinergic agonists can modulate the activity of both acinar and ductal phases of secretion. Activation of metabotropic receptors coupled to phospholipase C could lead to responses resembling those to muscarinic or adrenergic agonists. Activation of ionotropic receptors could stimulate new intracellular responses also involved in secretory function.
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PMID:Purines, a new class of agonists in salivary glands? 1041 54

Glutamate is the major excitatory neurotransmitter in the brain and plays a unique role in a variety of central nervous system (CNS) functions. The discovery of the metabotropic receptors (mGluRs), a family of G-protein coupled receptors than can be activated by glutamate, has led to an impressive number of studies in recent years aimed at understanding their biochemical, physiological and pharmacological characteristics. The eight mGluRs now known are divided into three groups according to their sequence homology, signal transduction mechanisms, and agonist selectivity. Group I mGluRs include mGluR1 and mGluR5, which are linked to the activation of phospholipase C; Groups II and III include all others and are negatively coupled to adenylyl cyclases. The availability in recent years of agents selective for Group I mGluRs has made possible the study of the physiological roles of these receptors in the CNS. In addition to mediating glutamatergic neurotransmission, Group I mGluRs can modulate other neurotransmitter receptors, including GABA and the ionotropic glutamate receptors. Group I mGluRs are involved in many CNS functions and may participate in a variety of disorders such as pain, epilepsy, ischemia, and chronic neurodegenerative diseases. This class of receptor may provide important pharmacological therapeutic targets and elucidating its functions will be relevant to develop new treatments for neurological and psychiatric disorders in which glutamatergic neurotransmission is abnormally regulated. In this review anatomical, physiological and pharmacological results are presented with a special emphasis on the role of Group I mGluRs in functional and pathological processes.
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PMID:Group I metabotropic glutamate receptors: implications for brain diseases. 1041 61


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