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)

l-Glutamate elicits the umami taste sensation, now recognized as a fifth distinct taste quality. A characteristic feature of umami taste is its potentiation by 5'-ribonucleotides such as guanosine-5'-monophosphate and inosine 5'-monophosphate, which also elicit the umami taste on their own. Recent data suggest that multiple G protein-coupled receptors contribute to umami taste. This review will focus on events downstream of the umami taste receptors. Ligand binding leads to Gbetagamma activation of phospholipase C beta2, which produces the second messengers inositol trisphosphate and diacylglycerol. Inositol trisphosphate binds to the type III inositol trisphosphate receptor, which causes the release of Ca(2+) from intracellular stores and Ca(2+)-dependent activation of a monovalent-selective cation channel, TRPM5. TRPM5 is believed to depolarize taste cells, which leads to the release of ATP, which activates ionotropic purinergic receptors on gustatory afferent nerve fibers. This model is supported by knockout of the relevant signaling effectors as well as physiologic studies of isolated taste cells. Concomitant with the molecular studies, physiologic studies show that l-glutamate elicits increases in intracellular Ca(2+) in isolated taste cells and that the source of the Ca(2+) is release from intracellular stores. Both Galpha gustducin and Galpha transducin are involved in umami signaling, because the knockout of either subunit compromises responses to umami stimuli. Both alpha-gustducin and alpha-transducin activate phosphodiesterases to decrease intracellular cAMP. The target of cAMP in umami transduction is not known, but membrane-permeant analogs of cAMP antagonize electrophysiologic responses to umami stimuli in isolated taste cells, which suggests that cAMP may have a modulatory role in umami signaling.
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PMID:Umami taste transduction mechanisms. 1957 Dec 14

Phosphorylation of ionotropic glutamate receptors in the brain plays a crucial role in the regulation of synaptic plasticity. In this study, we investigated the regulation of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor phosphorylation by the stimulation of group I metabotropic glutamate receptors (mGluRs) in the dorsal striatum in vivo. The results showed that intrastriatal infusion of the group I mGluR agonist, (RS)-3,5-dihydroxyphenylglycine (DHPG, 250 nmol), enhanced the sensitivity of GluR2 subunit in its phosphorylation at serine 880 (S880) in the dorsal striatum. This enhancement of the sensitivity of GluR2-S880 phosphorylation was reduced by blocking group I mGluRs and N-methyl-D-aspartate (NMDA) receptors. Similar reduction of the enhancement was also induced by inhibiting phospholipase C (PLC), calcium/calmodulin-dependent protein kinase (CaMK), c-Jun N-terminal kinase (JNK), and protein kinase C (PKC). Inhibition of protein phosphatase (PP) 1/2A and calcineurin (PP2B) alone enhanced GluR2-S880 phosphorylation in the dorsal striatum, whereas inhibition of these phosphatases did not further enhance the S880 phosphorylation by DHPG stimulation. In addition, inhibition of PP1/2A or PP2B also enhanced the phosphorylation of CaMKII, JNK and PKC. These data suggest that the phosphorylation of AMPA receptor GluR2 subunit at S880 is subject to the upregulation by the stimulation of group I mGluRs. Interactions among glutamate receptors, protein kinases, and PPs participate in this upregulation.
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PMID:Alterations in GluR2 AMPA receptor phosphorylation at serine 880 following group I metabotropic glutamate receptor stimulation in the rat dorsal striatum. 1990 85

L-glutamate is the principal excitatory neurotransmitter at fast synapses in the mammalian central nervous system, and signals though a number of ionotropic and metabotropic receptors. Among the latter are the group I metabotropic glutamate (mGlu1 and mGlu5) receptors that upon activation elevate intracellular calcium levels through activation of the phospholipase C pathway. The role of glutamatergic transmission in both the development of addiction and the phenomenon of relapse that may occur after prolonged abstinence, has come under intense scrutiny in recent times. While both mGlu1 and mGlu5 receptors have been implicated in certain aspects of the addictive state, the exact roles these receptors play in this process is, as yet, unclear. This review will introduce contemporary theories on drug addiction, including neural circuitry, before critically assessing the current body of knowledge on group I metabotropic glutamate receptors in this regard. This will involve an in-depth discussion of the distribution of these receptors in the brain, their presence in neural pathways known or postulated to be involved in addiction and their involvement in drug-related behavioral paradigms. The effect of acute and chronic drug administration on the activity and expression of group I metabotropic glutamate receptors will be investigated, as will the effect these receptors have on behavioral and biochemical responses to drugs of abuse. Finally, there will be a brief discussion on current and future therapeutic applications using our knowledge of these receptors, and the direction that future studies will need to take to close the gaps in our understanding.
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PMID:Group I metabotropic glutamate receptors: involvement in drug-seeking and drug-induced plasticity. 2002 49

Endogenous ghrelin and its synthetic counterpart hexarelin are peptide GH secretagogues (GHS) that exert a positive ionotropic effect in the cardiovascular system. The mechanism by which GHS modulate cardiac electrophysiology properties to alter myocyte contraction is poorly understood. In the present study, we examined whether GHS regulates the transient outward potassium current (I(to)) as well as the putative intracellular signaling cascade responsible for such regulation. GHS and experimental agents were applied locally onto freshly isolated adult Sprague-Dawley rat ventricular myocytes and action potential morphology and I(to) was recorded using nystatin-perforated whole-cell patch-clamp recording technique. Under current clamp, ghrelin and hexarelin (10 nm) significantly prolonged action potential duration. Under voltage clamp, hexarelin and ghrelin inhibited I(to) in a concentration-dependent manner. This inhibition was abolished in the presence of the GHS receptor (GHS-R) antagonist [D-Lys(3)]GH-releasing peptide-6 (10 microm) and GHS-R1a-specific antagonist BIM28163 (1 microm). GHS-induced I(to) inhibition was totally reversed by the phospholipase C inhibitor U73122 (5 microm) and protein kinase C inhibitors GO6983 (1 microm) and calphostin C (0.1 microm) but not by the cAMP antagonist Rp-cAMP (100 microm) or the PKA inhibitor H89 (1 microm). We conclude that hexarelin and ghrelin activate phospholipase C and protein kinase C signaling cascade through the stimulation of the GHS-R, resulting in a decrease in the I(to) current and subsequent prolongation of action potential duration.
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PMID:Growth hormone secretagogues reduce transient outward K+ current via phospholipase C/protein kinase C signaling pathway in rat ventricular myocytes. 2005 29

Presynaptic kainate receptors (KARs) exert a modulatory action on transmitter release. This effect can be switched from facilitation to inhibition by an increased concentration of KAR agonists. We here report that activation of presynaptic GluK1-containing KARs facilitates GABA release on oxytocin and vasopressin neurons in the supraoptic nucleus of the hypothalamus. Increase in ambient levels of glutamate associated with the physiological reduction of astrocytic coverage of oxytocin neurons in lactating rats switches this KAR-mediated facilitation to inhibition of GABAergic transmission. This effect was reproduced in both oxytocin and vasopressin neurons of virgin rats when glutamate transporters were blocked pharmacologically, thereby establishing that enhanced levels of extracellular glutamate induce the switch in KAR-mediated action. The facilitation of GABA release was inhibited with philanthotoxin, a Ca(2+)-permeable KAR antagonist, suggesting that this effect was associated with an ionotropic mode of action. Conversely, KAR-mediated inhibition was compromised in the presence of U73122, a phospholipase C inhibitor, in agreement with the involvement of a metabotropic pathway. We thus reveal that physiological astrocytic plasticity modifies the mode of action of presynaptic KARs, thereby inversing their coupling with GABA release.
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PMID:Glia-dependent switch of kainate receptor presynaptic action. 2008 7

Presynaptic kainate receptors regulate synaptic transmission in several brain areas but are not known to have this action at immature mossy fiber (MF) terminals, which during the first week of postnatal life release GABA, which exerts into targeted cells a depolarizing and excitatory action. Here, we report that, during the first week of postnatal life, endogenous activation of GluK1 receptors by glutamate present in the extracellular space severely depresses MF-mediated GABAergic currents [GABA(A)-mediated postsynaptic currents (GPSCs)]. Activation of GluK1 receptors was prevented by treating the slices with enzymatic glutamate scavengers that enhanced the clearance of glutamate from the extracellular space. The depressant effect of GluK1 on MF-GPSCs was mediated by a metabotropic process sensitive to pertussis toxin. In the presence of U73122 (1-[6-[[(17b)-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione), a selective inhibitor of phospholipase C, along the transduction pathway downstream to G-protein, GluK1 activation increased the probability of GABA release, thus unveiling the ionotropic action of this receptor. In line with this type of action, we found that GluK1 enhanced MF excitability by directly depolarizing MF terminals via calcium-permeable cation channels. Furthermore, GluK1 dynamically regulated the direction of spike time-dependent plasticity occurring by pairing MF stimulation with postsynaptic spiking and switched spike time-dependent potentiation into depression. The GluK1-induced depression of MF-GPSCs would prevent excessive activation of the CA3 associative network by the excitatory action of GABA and the emergence of seizures in the immature brain.
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PMID:In the developing rat hippocampus, endogenous activation of presynaptic kainate receptors reduces GABA release from mossy fiber terminals. 2013 Jan 84

Protein kinase D (PKD) is a family of serine/threonine kinases that can be activated by many stimuli via protein kinase C in a variety of cells. This is the first report where PKD activation and localization is studied in glial cells. Herein, we demonstrate that P2Y(2) and P2X7 receptor stimulation of primary rat cerebellar astrocytes rapidly increases PKD1/2 phosphorylation and activity. P2Y(2) receptor response evokes a PKD1/2 activation that is dependent on a pertussis toxin-insensitive G protein, phospholipase C (PLC)-mediated generation of diacylglycerol, and protein kinase C. This mechanism is similar to the one described for other G-protein coupled receptors. In contrast, the way the ionotropic P2X7 receptor activates PKD1/2 is significantly different. Importantly, this response is not dependent on calcium entry, but depends on the activity of several phospholipases, including phosphoinositide-phospholipase C (PI-PLC), phosphatidylcholine-phospholipase C (PC-PLC) and also phospholipase D (PLD). Immunoblot and confocal microscopy analysis show that PKD1/2 activation by nucleotides is transient. The active kinase first moves to and concentrates in certain plasma membrane domains. Then, phosphorylated-PKD1/2 translocates to intracellular vesicles, where it remains active. All together, our results open the perspective of PKD1/2 being involved in many physiological functions where nucleotides play important roles not only in astrocytes but in other cell types bearing these receptors.
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PMID:Mechanisms of protein kinase D activation in response to P2Y(2) and P2X7 receptors in primary astrocytes. 2022 45

Effects of activation of metabotropic glutamatergic receptors (mGluR) were investigated in mouse dopaminergic olfactory bulb neurons. After blockage of ionotropic receptors, focal application of glutamate or of group I/II mGluR agonist t-ACPD resulted in a depolarization, paralleled by an inward current in voltage-clamp conditions. The Group I agonist DHPG induced a depolarization, which could be largely blocked by mGluR1 antagonists. The DHPG action i) was prevented by buffering intracellular Ca(2+) with BAPTA and by a phospholipase C inhibitor; ii) was not affected by the block of Ca(2+) entry, and iii) was blocked by inhibitors of the Na(+)/Ca(2+) exchanger. These observations were interpreted as a mGluR1-mediated intracellular Ca(2+) release, followed by the activation of an electrogenic Na(+)/Ca(2+) exchanger. The mGluR5 agonist CHPG induced a hyperpolarization of membrane potential, resulting in a decrease of the spontaneous firing frequency. CHPG induced i) a decrease in membrane resistance; ii) an increase in the action potential repolarization rate, and iii) an increase in the amplitude of the afterhyperpolarization. This was interpreted as a mGluR5-mediated opening of a K(+) conductance. These data suggest that mGluR1 and mGluR5 play different and non-overlapping roles in the regulation of the excitability of bulbar dopaminergic neurons.
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PMID:Metabotropic glutamate receptors 1 and 5 differentially regulate bulbar dopaminergic cell function. 2069 42

Kainate receptors (KARs) are members of the family of ionotropic glutamate receptors (iGluRs) which also include NMDA and AMPA receptors. As ionotropic receptors, KARs have been characterized, pre and postsynaptically, in several brain regions. In this chapter we review evidence that suggests that KARs mediate some of their effects without invoking ion-fluxes. Beginning with seminal experiments described some ten years ago, when the notion of a metabotropic action of KAR was first posited in the modulation of GABA release from hippocampal interneurons, increasingly, there have been reports indicating that some KAR functions overtly depend on G-protein activation and involve the participation of intracellular signalling cascades. Thus, KAR activation instigates a cascade involving G(i/o), phospholipase C and protein kinase C to suppress the release of GABA and therefore underpins disinhibition of pyramidal cells in the CA1 region of the hippocampus. This type of metabotropic function of KARs in controlling GABA release represents an additional level of activity-dependent control of synaptic inhibition which is independent of any ionotropic activity of KARs.
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PMID:Metabotropic actions of kainate receptors in the control of GABA release. 2171 62

Kainate receptors (KARs) are glutamate-gated ion channels assembled from various combinations of GluK1-GluK5 subunits with different physiological and pharmacological properties. In the hippocampus, KARs expressed at postsynaptic sites mediate a small component of excitatory postsynaptic currents while at presynaptic sites they exert a powerful control on transmitter release at both excitatory and inhibitory connections. KARs are developmentally regulated and play a key role in several developmental processes including neuronal migration, differentiation and synapse formation. Interestingly, they can signal through a canonical ionotropic pathway but also through a noncanonical modality involving pertussis toxin-sensitive G proteins and downstream signaling molecules.In this Chapter some of our recent data concerning the functional role of presynaptic KARs in regulation of transmitter release from immature mossy fiber terminals and in synaptic plasticity processes will be reviewed. Early in postnatal development, MFs release into their targeted neurons mainly GABA which is depolarizing and excitatory. Endogenous activation of GluK1 KARs localized on MF terminals by glutamate present in the extracellular space down regulates GABA release, leading sometimes to synapse silencing. The depressant effect of GluK1 on MF responses is mediated by a metabotropic process, sensitive to pertussis toxin and phospholipase C (PLC) along the transduction pathway downstream to G protein activation. Blocking PLC with the selective antagonist U73122, unmasks the potentiating effect of GluK1 on MF-evoked GABAergic currents, which probably depend on the ionotropic type of action of these receptors.In addition, GluK1 KARs dynamically regulate the direction of spike-time dependent plasticity, a particular form of Hebbian type of learning which consists in bidirectional modifications in synaptic strength according to the temporal order of pre and postsynaptic spiking. At immature MF-CA3 synapses pairing MF stimulation with postsynaptic spiking and vice versa induces long term depression of MF-evoked GABAergic currents. In the case of positive pairing synaptic depression can be switched into spike-time dependent potentiation by blocking GluK1 KARs with UBP 302. The depressant action exerted by GluK1 KARs on MF responses would prevent the excessive activation of the CA3 associative network by the excitatory action of GABA early in postnatal development.
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PMID:In the developing hippocampus kainate receptors control the release of GABA from mossy fiber terminals via a metabotropic type of action. 2171 63


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