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)

The amino acids L-glutamic and L-aspartic acids form the most widespread excitatory transmitter network in mammalian brain. The excitation produced by L-glutamic acid is important in the early development of the nervous system, synaptic plasticity and memory formation, seizures and neuronal degeneration. The receptors activated by L-glutamic acid are a target for therapeutic intervention in neurodegenerative diseases, brain ischaemia and epilepsy. There are two types of receptors for the excitatory amino acids, those that lead to the opening of cation-selective channels and those that activate phospholipase C (ref. 11). The receptors activating ion channels are NMDA (N-methyl-D-aspartate) and kainate/AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate)-sensitive receptors. The complementary DNAs for the kainate/AMPA receptor and for the metabotropic receptor have been cloned. We report here on the isolation and characterization of a protein complex of four major proteins that represents an intact complex of the NMDA receptor ion channel and on the cloning of the cDNA for one of the subunits of this receptor complex, the glutamate-binding protein.
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PMID:Cloning of cDNA for the glutamate-binding subunit of an NMDA receptor complex. 183 48

The effect of ionotropic excitatory amino acids and potassium on the formation of inositol phosphates elicited by the metabotropic glutamate receptor agonist (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (trans-ACPD) was studied in mouse cerebellar granule cells. In Mg(2+)-containing buffers, NMDA (50-100 microM), alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA; 10-1,000 microM), and high potassium (10-30 mM) enhanced synergistically the response to a maximally effective concentration of 500 microM trans-ACPD. Potentiation of the trans-ACPD response was blocked by higher concentrations of NMDA (> 500 microM) and potassium (> 35 mM) but not by AMPA (up to 1 mM). The potentiation by NMDA of the trans-ACPD-stimulated phosphoinositide hydrolysis was blocked by D,L-2-amino-5-phosphonopentanoic acid (APV), a competitive NMDA-receptor antagonist. Under Mg(2+)-free conditions, the accumulation of inositol phosphates in the presence of trans-ACPD alone was equal to that attained by trans-ACPD in Mg(2+)-containing buffers when costimulated with maximally enhancing concentrations of NMDA (50 microM). trans-ACPD potentiated synergistically the NMDA-evoked increases in cytosolic free-Ca2+ levels in Mg(2+)-containing but not in Mg(2+)-free solutions, and moreover did not enhance the AMPA-evoked increases in cytosolic free-Ca2+ levels. The calcium ionophore A23187 caused a dose-dependent increase in inositol phosphate accumulation but did not enhance the response stimulated by trans-ACPD alone. These results demonstrate the existence of cross talk between metabotropic and ionotropic glutamate receptors in cerebellar granule cells. The exact mechanism remains unclear but appears to involve interplay of G protein-coupled phospholipase C activation and regulated elevation of cytosolic free-Ca2+ levels. This study may provide a framework for future investigations at the cellular and molecular level that clarify the functional relevance and molecular mechanisms that are described.
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PMID:Modulation by ionotropic excitatory amino acids and potassium of (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid-stimulated phosphoinositide hydrolysis in mouse cerebellar granule cells. 759 41

Quisqualic acid (QA) is an excitatory amino acid analogue that binds to the glutamate ionotropic receptor subclass AMPA (alpha-amino-3 hydroxy-5 methyl-4 isoxazol propionic acid) and metabotropic receptor phospholipase C. To study its epileptogenic properties, we administered QA through an intraventricular cannula to 23-, 41-, and 60-day-old rats with recording electrodes implanted in amygdala, hippocampus, and neocortex. The frequency power spectra of the recorded EEG was computed by fast fourier transform (FFT), and coherence between anatomic sites was computed. Seizures occurred in all animals receiving QA. The behavioral manifestations of the seizures varied as a function of age, with younger rats demonstrating rigidity and immobility followed by circling activity and intermittent forelimb clonus and 60-day-old animals exhibiting severe, wild running followed by generalized clonus. Ictal electrical discharges occurred in all animals. Neocortical ictal discharges occurred more prominently in the younger animals, and amygdala ictal discharges were more prominent in the older animals. Marked increases in spectral power occurred during the seizures in all anatomic structures and at all frequencies. Our results demonstrate that the clinical manifestations of QA seizures vary during development; results of the neurophysiologic studies suggested that neocortex may play an important role in genesis of QA seizures in immature brain.
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PMID:Quisqualic acid-induced seizures during development: a behavioral and EEG study. 808 36

The effect of aging on receptor- and G-protein-activated and on depolarization-induced phosphoinositide (PI) hydrolysis was examined in mechanically dissociated neurons from female NMRI mice. Additionally, age-dependent changes in Ca2+ homeostasis, i.e. changes in basal intracellular calcium ([Ca2+]i) and in depolarization-induced rise in [Ca2+]i were investigated. No age-related differences in PI hydrolysis were found after stimulation of muscarinic cholinergic, alpha 1, serotonin and quisqualate receptors coupled to the phosphoinositide-phospholipase C (PI-PLC) system. PI hydrolysis following stimulation with AMPA ((RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) revealed a significantly increased response in aged animals. Activation of G-proteins with NaF also induced a higher inositol monophosphate (InsP1) accumulation in aged mice. Moreover, InsP1 accumulation due to PLC activation by increased [Ca2+]i after depolarization with KCl was significantly increased in neurons from aged animals. Investigations about age-related changes in Ca2+ homeostasis revealed lower basal [Ca2+]i and lower rise in [Ca2+]i after depolarization with KCl. The data indicate that receptor-mediated and depolarization-induced PI hydrolysis are differentially affected by aging. Decreased availability of [Ca2+]i in aged animals may enhance the sensitivity of Ca(2+)-activated mechanisms. This may explain increased KCl- and AMPA-induced InsP1 accumulation whereas receptor-coupled PLC activation is less affected.
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PMID:Age-related changes in receptor-mediated and depolarization-induced phosphatidylinositol turnover in mouse brain. 824 88

The effects of L-glutamate, acetylcholine, and serotonin (5HT) were examined on generation of inositol 1,4,5-triphosphate [Ins(1,4,5)P3], in membrane preparations of the cestode Hymenolepis diminuta. Only L-glutamate and acetylcholine stimulated a significant elevation in Ins(1,4,5)P3. The response to L-glutamate was stereospecific; D-glutamate or L-aspartate were not as potent. A role for G-protein(s) was supported by the observations that sodium fluoride stimulated Ins(1,4,5)P3 generation, and the L-glutamate response was potentiated by GTP and GTP-S and was suppressed by GDPS. However, studies with pertussis and cholera toxins indicated that the putative G-protein(s) was not pertussis or cholera toxin sensitive. The pharmacological profile of the L-glutamate response was examined partially. Trans-ACPD was a very effective agonist at 10(-5)M. While 10(-3)M L-glutamate, NMDA, and AMPA significantly elevated Ins(1,4,5)P3 levels, quisqualate and kainate did not. The elevation of Ins(1,4,5)P3 levels by L-glutamate and NMDA was antagonized by the specific glutamatergic antagonists AP-5, AP-7, CNQX, and CPP. While the response to ACPD was antagonized by AP5, CPP and CPG, CNQX was without effect. Collectively, the data support the hypothesis that in the cestode H. diminuta, L-glutamate activation of a metabotropic (ACPD) and/or ionotropic-like AMPA/NMDA receptor subtypes proceeds via a G protein(s) to enhance phospholipase C activity, ultimately resulting in the elevation of Ins(1,4,5)P3 levels in the tissues.
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PMID:The stimulatory effect of L-glutamate and related agents on inositol 1,4,5-trisphosphate production in the cestode Hymenolepis diminuta. 869 99

Excitatory amino acids (EAA) became known as neurotransmitters of the central nervous system (CNS) in the last decade. The most studied EAA are glutamate and aspartate. Both are synthetized by the same mechanism as gamaaminobutyric acid. (Fig. 1). Glutamate is widely distributed in the CNS and the spinal cord, being the areas of higher concentration the cerebral cortex, the hypocampus and the cerebellum. There have been identified two type of receptors for glutamate: ionotropic and metabotropic. The former includes three different types: NMDA, AMPA and KA. NMDA receptor is coupled to a Na+ and Ca2+ channel being the second ion the most important one. This receptor has several sites of binding for various substances. Along with the site for N-methyl-D-aspartate, which binds glutamate and/or aspartate, there have been identified a site for the binding of glycine (which is different from the strychnine sensitive one), a site for poliamines such as spermine and spermidine, and a site for the binding of Zn2+ (Table 1). AMPA receptor is associated to a Ca(2+)-Na+ channel, being in this case the Na+ the most important ion. There are two metabotropic type receptors: L-AP4 and trans-ACPD. Both are coupled to a G protein and agonists exert their action increasing phospholipase C activity which in turn induces an increment of IP3 and diacyl-glicerol, and a consecutive releasing of Ca2+ from intracellular stores. EAA play a role in some physiological processes. One of them is long-term potentiation (LTP), an electrochemical phenomenon involved in memory consolidation. Antagonists of NMDA and AMPA receptor prevent the development of LTP, and conversely, the agonist of glycine site of NMDA receptor--D-cycloserine--facilitates memory consolidation. Since 1957, EAA are considered neurotoxic substances and there are many indirect evidences to support this statement. Pathogenesis of neuronal damage elicited by EAA involves the events shown in Fig. 3. Prevention of the cascade of events that provokes neurotoxicity may be achieved by NMDA antagonists, but once it has begun it may be only aborted subtracting the Ca2+ from the medium, using nifedipine or blocking AMPA receptor with an antagonist (CNQX). EAA have been shown to play a toxic role in neuronal damage induced by ischemia. Research using various experimental models demonstrated that NMDA receptor antagonists (i.e. MK 801) blocks postischemic damage. Interventions at various levels of the pathogenic cascade shown in Fig. 4 provoke the same results. There is enough evidence to suspect that NMDA and AMPA receptors are altered in epilepsy. NMDA antagonists (i.e. MK801 or AP5) prevent the development of epileptic seizures induced by kindling; CNQX, an AMPA antagonist, blocks the increase in electrical activity induced by K+ in slices of hypocampus; felbamate, an antiepileptic drug, blocks the glycine site (not strychnine sensitive) decreasing NMDA receptor activity. Several neurodegenerative disorders have been associated with exogenous administration or accidental intake of EAA. (i.e. neurolatirism, Guam disease). Similarities between these diseases and lateral aminotrophic sclerosis indicate that in the latter EAA may play a pathogenic role. Finally, the psychotomimetic effect of phencyclidine (an antagonist of NMDA receptor) suggests that in schizophrenia, together with dopaminergic neurotransmission impairment, some dysfunction of glutamate pathways may be present.
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PMID:[Role of excitatory amino acids in neuropathology]. 872 78

There is general agreement that activation of the N-methyl-D-aspartate receptor is involved in thermal hyperalgesia. However, there is less agreement on the specific intracellular events subsequent to receptor activation and the involvement of other excitatory amino acid receptors in thermal hyperalgesia. In the present study, we found that the intrathecal administration of N-methyl-D-aspartate produced a dose- (1 fmol-1 pmol) and time-dependent thermal hyperalgesia. In contrast, over the dose range tested, intrathecal administration of either alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionate (AMPA; 10 fmol-100 pmol), 1,3-trans-1-aminocyclopentyl-1,3-dicarboxylate (10 fmol-100 pmol), quisqualate (10 pmol-5 nmol) or a 1:1 combination of AMPA and 1,3-trans-1-aminocyclopentyl-1,3-dicarboxylate (total dose 20 fmol-200 pmol) did not produce any evidence of thermal hyperalgesia; greater doses produced a caudally-directed biting and scratching behavior that precluded testing in the paradigm used. A fixed dose of 1,3-trans-1-aminocyclopentyl-1,3-dicarboxylate (100 pmol) did, however, potentiate the effects of N-methyl-D-aspartate (1-100 fmol). Thermal hyperalgesia produced by N-methyl-D-aspartate (1 pmol) was attenuated by intrathecal administration of the N-methyl-D-aspartate receptor-selective antagonist 2-amino-5-phosphonopentanoate (100 pmol), but not by the AMPA receptor-selective antagonist 6,7-dinitroquinoxaline-2,3-dione (1 nmol) or the metabotropic receptor antagonist 2-amino-3-phosphonoproprionate (10 nmol). In a second series of experiments, we examined the role of different signal transduction systems in acute N-methyl-D-aspartate-produced thermal hyperalgesia. N-Methyl-D-aspartate-produced thermal hyperalgesia (1 pmol) was attenuated by intrathecal hemoglobin (1-100 pmol) and dose-dependently by intrathecal N(G)-nitro-L-arginine methyl ester (10 pmol-l nmol), Methylene Blue (10 pmol-l nmol) and chelerythrine (1-100 pmol), suggesting that acute N-methyl-D-aspartate-mediated thermal hyperalgesia involves activation of nitric oxide synthase and protein kinase C. In contrast, N-methyl-D-aspartate-produced thermal hyperalgesia was unaffected by intrathecal administration of the phospholipase A2 inhibitor mepacrine (10 nmol) or the phospholipase C inhibitor neomycin (10 nmol). While prostaglandins and leukotrienes have been suggested to play a role in hyperalgesia, N-methyl-D-aspartate-produced thermal hyperalgesia (1 pmol) was unaffected by the non-selective eicosanoid inhibitor nordihydroguaiarate (1 nmol), the cyclo-oxygenase selective inhibitor indomethacin (10 nmol) or the lipoxygenase selective inhibitor baicalein (1 nmol). The results of the present study suggest that acute thermal hyperalgesia can be produced by activation of N-methyl-D-aspartate receptors. Activation of AMPA, metabotropic or co-activation of AMPA and metabotropic glutamate receptors, at the doses tested, did not produce an acute thermal hyperalgesia. The thermal hyperalgesia produced by N-methyl-D-aspartate is mediated by activation of nitric oxide synthase and protein kinase C, but not by phospholipase C, phospholipase A2, cyclo-oxygenase or lipoxygenase. Collectively, the results are consistent with a role for spinal N-methyl-D-aspartate receptors, nitric oxide and protein kinase C in thermal hyperalgesia.
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PMID:Acute thermal hyperalgesia in the rat is produced by activation of N-methyl-D-aspartate receptors and protein kinase C and production of nitric oxide. 905 88

Somatostatin (SST), a regulatory peptide, is produced by neuroendocrine, inflammatory, and immune cells in response to ions, nutrients, neuropeptides, neurotransmitters, thyroid and steroid hormones, growth factors, and cytokines. The peptide is released in large amounts from storage pools of secretory cells, or in small amounts from activated immune and inflammatory cells, and acts as an endogenous inhibitory regulator of the secretory and proliferative responses of target cells that are widely distributed in the brain and periphery. These actions are mediated by a family of seven transmembrane (TM) domain G-protein-coupled receptors that comprise five distinct subtypes (termed SSTR1-5) that are endoded by separate genes segregated on different chromosomes. The five receptor subtypes bind the natural SST peptides, SST-14 and SST-28, with low nanomolar affinity. Short synthetic octapeptide and hexapeptide analogs bind well to only three of the subtypes, 2, 3, and 5. Selective nonpeptide agonists with nanomolar affinity have been developed for four of the subtypes (SSTR1, 2, 3, and 4) and putative peptide antagonists for SSTR2 and SSTR5 have been identified. The ligand binding domain for SST ligands is made up of residues in TMs III-VII with a potential contribution by the second extracellular loop. SSTRs are widely expressed in many tissues, frequently as multiple subtypes that coexist in the same cell. The five receptors share common signaling pathways such as the inhibition of adenylyl cyclase, activation of phosphotyrosine phosphatase (PTP), and modulation of mitogen-activated protein kinase (MAPK) through G-protein-dependent mechanisms. Some of the subtypes are also coupled to inward rectifying K(+) channels (SSTR2, 3, 4, 5), to voltage-dependent Ca(2+) channels (SSTR1, 2), a Na(+)/H(+) exchanger (SSTR1), AMPA/kainate glutamate channels (SSTR1, 2), phospholipase C (SSTR2, 5), and phospholipase A(2) (SSTR4). SSTRs block cell secretion by inhibiting intracellular cAMP and Ca(2+) and by a receptor-linked distal effect on exocytosis. Four of the receptors (SSTR1, 2, 4, and 5) induce cell cycle arrest via PTP-dependent modulation of MAPK, associated with induction of the retinoblastoma tumor suppressor protein and p21. In contrast, SSTR3 uniquely triggers PTP-dependent apoptosis accompanied by activation of p53 and the pro-apoptotic protein Bax. SSTR1, 2, 3, and 5 display acute desensitization of adenylyl cyclase coupling. Four of the subtypes (SSTR2, 3, 4, and 5) undergo rapid agonist-dependent endocytosis. SSTR1 fails to be internalized but is instead upregulated at the membrane in response to continued agonist exposure. Among the wide spectrum of SST effects, several biological responses have been identified that display absolute or relative subtype selectivity. These include GH secretion (SSTR2 and 5), insulin secretion (SSTR5), glucagon secretion (SSTR2), and immune responses (SSTR2).
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PMID:Somatostatin and its receptor family. 1043 61

Glutamate is the major excitatory neurotransmitter in the brain. It acts at ligand-gated cationic channels (NMDA, AMPA and kainate receptors) and at G protein-coupled metabotropic glutamate receptors as well. The glutamatergic transmission is suggested to be involved in development, learning and memory. Its dysfunction can be detected in epilepsy, stroke, neurodegenerative disorders and drug abuse. This paper summarizes the present knowledge on the modulation of glutamate-gated ion channels in the central nervous system by phosphorylation. An inhibitory interaction between adenosine A2A receptors and NMDA receptors in the neostriatum is described as an example. mediated by the phospholipase C/inositol trisphosphate/calmodulin and calmodulin kinase II pathway.
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PMID:Modulation of ionotropic glutamate receptor channels. 1169 44

Emerging evidence indicates that group I metabotropic glutamate receptors (mGluRs) play a significant role in the addictive plasticity of striatal neurons. The plasticity is probably mediated by altered cellular gene expression in relation to stimulation of group I mGluRs and associative signaling proteins. In this study, we investigated the signaling linkage of surface group I mGluRs to the nuclear transcription factor cAMP response element-binding protein (CREB) in cultured primary striatal neurons. We found that selective activation of group I mGluRs (primarily the mGluR5 subtype) was able to up-regulate CREB phosphorylation in neurochemically identified gamma-aminobutyratergic neurons but not glia. The CREB phosphorylation was independent of kainate/AMPA receptors but partially dependent of concomitant NMDA receptor activation. Because L-type voltage-operated Ca(2+) channel inhibitors substantially blocked the CREB phosphorylation, group I receptors are believed to lead to activation of L-type Ca(2+) channels, resulting in the CREB phosphorylation. Indeed, further studies on signaling pathways showed that group I mGluRs, by activating phospholipase C, induced a rapid and transient Ca(2+) release from the 1,4,5-triphosphate-sensitive rather than ryanodine-sensitive Ca(2+) store. The transient Ca(2+) rise in turn triggered the opening of L-type Ca(2+) channels, resulting in a progressively larger increase in cytoplasmic Ca(2+) levels that is responsible for subsequent CREB phosphorylation. These results indicate that Ca(2+)-coupled group I mGluRs possess the ability to up-regulate CREB phosphorylation via the intracellular Ca(2+) release-induced activation of L-type Ca(2+) channels and, to a lesser extent, NMDA receptors in primary striatal neurons.
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PMID:Glutamate cascade to cAMP response element-binding protein phosphorylation in cultured striatal neurons through calcium-coupled group I metabotropic glutamate receptors. 1218 23


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