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

---

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

Whole-cell patch clamp experiments were carried out in rat striatal brain slices. In a subset of striatal neurons (70-80%), NMDA-induced inward currents were inhibited by the adenosine A2A receptor selective agonist CGS 21680. The non-selective adenosine receptor antagonist 8-(p-sulphophenyl)-theophylline and the A2A receptor selective antagonist 8-(3-chlorostyryl)caffeine abolished the inhibitory action of CGS 21680. Intracellular GDP-beta-S, which is known to prevent G protein-mediated reactions, also eliminated the effect of CGS 21680. Extracellular dibutyryl cAMP, a membrane permeable analogue of cAMP, and intracellular Sp-cAMPS, an activator of cAMP-dependent protein kinases (PKA), both abolished the CGS 21680-induced inhibition. By contrast, Rp-cAMPS and PKI 14-24 amide, two inhibitors of PKA had no effect. Intracellular U-73122 (a phospholipase C inhibitor) and heparin (an inositoltriphosphate antagonist) prevented the effect of CGS 21680. Finally, a more efficient buffering of intracellular Ca2+ by a substitution of EGTA (11 mM) by BAPTA (5.5 mM) acted like U-73122 or heparin. Hence, A2A receptors appear to negatively modulate NMDA receptor channel conductance via the phospholipase C/inositoltriphosphate/Ca2+ pathway rather than the adenylate cyclase/PKA pathway.
...
PMID:Adenosine A2A receptors inhibit the conductance of NMDA receptor channels in rat neostriatal neurons. 987 38

In recent years there have been remarkable developments toward the understanding of the molecular and/or cellular changes in the neuronal second-messenger pathways during ethanol dependence. In general, it is believed that the cyclic adenosine 3',5'-monophosphate (cAMP) and the phosphoinositide (PI) signal-transduction pathways may be the intracellular targets that mediate the action of ethanol and ultimately contribute to the molecular events involved in the development of ethanol tolerance and dependence. Several laboratories have demonstrated that acute ethanol exposure increases, whereas protracted ethanol exposure decreases, agonist-stimulated adenylate cyclase activity in a variety of cell systems, including the rodent brain. Recent studies indicate that various postreceptor events of the cAMP signal transduction cascade (i.e., Gs protein, protein kinase A [PKA], and cAMP-responsive element binding protein [CREB]) in the rodent brain are also modulated by chronic ethanol exposure. The PI signal-transduction cascade represents another important second-messenger system that is modulated by both acute and chronic ethanol exposure in a variety of cell systems. It has been shown that protracted ethanol exposure significantly decreases phospholipase C (PLC) activity in the cerebral cortex of mice and rats. The decreased PLC activity during chronic ethanol exposure may be caused by a decrease in the protein levels of the PLC-beta 1 isozyme but not of PLC-delta 1 or PLC-gamma 1 isozymes in the rat cerebral cortex. Protein kinase C (PKC), which is a key step in the PI-signaling cascade, has been shown to be altered in a variety of cell systems by acute or chronic ethanol exposure. It appears from the literature that PKC plays an important role in the modulation of the function of various neurotransmitter receptors (e.g., gamma-aminobutyrate type A [GABAA], N-methyl-D-aspartate [NMDA], serotonin2A [5-HT2A], and 5-HT2C, and muscarinic [m1] receptors) resulting from ethanol exposure. The findings described in this review article indicate that neuronal-signaling proteins represent a molecular locus for the action of ethanol and are possibly involved in the neuro-adaptational mechanisms to protracted ethanol exposure. These findings support the notion that alterations in the cAMP and the PI-signaling cascades during chronic ethanol exposure could be the critical molecular events associated with the development of ethanol dependence.
...
PMID:Neuronal signaling systems and ethanol dependence. 988 43

Dopamine, acting at a D1-like receptor, depresses the release of glutamate in the nucleus accumbens (NAcc) in brain slices, thereby reducing the amplitude of the excitatory postsynaptic current (EPSC). This effect depends upon an inhibitory feedback action of adenosine, liberated following facilitation of postsynaptic NMDA receptors by D1 receptor activation, an action independent of adenylyl cyclase stimulation or cyclic AMP-dependent protein kinase (PKA; Harvey, J., Lacey, M.G., 1997. J. Neurosci. 17, 5271). Using whole-cell recording from NAcc neurones, the dopamine depression of the EPSC was blocked by pre-treatment of brain slices with the selective protein kinase C (PKC) inhibitor Ro 32-0432, but only minimally attenuated by intracellular dialysis of single cells with Ro 32-0432 in the recording pipette. With synaptic transmission blocked by tetrodotoxin, inward currents caused by application of NMDA were enhanced by the D1 receptor agonist SKF 81297A in half the cells tested. In a separate population of cells dialysed intracellularly with Ro 32-0432, SKF 81297A was without effect on NMDA current amplitude. These findings indicate a functional role for phospholipase C-coupled D1-like receptors in both modulating synaptic transmission in NAcc and potentiating NMDA receptors on a subset of NAcc neurones, via PKC activation.
...
PMID:Modulation by dopamine D1-like receptors of synaptic transmission and NMDA receptors in rat nucleus accumbens is attenuated by the protein kinase C inhibitor Ro 32-0432. 1021 63

The molecular mechanisms underlying the cerebral symptoms of ethanol withdrawal syndrome are poorly understood. In addition to ethanol's effect on GABA and NMDA receptors, ethanol affects muscarinic acetylcholine signaling. This interaction has attracted attention because of the importance of muscarinic signaling in consciousness. Chronic ethanol exposure increases muscarinic receptor binding. Increased transcription of receptor message has been suggested as the underlying mechanism, but this hypothesis has not been tested directly. Therefore, we studied the effects of ethanol on muscarinic signaling in a model that bypasses transcription of muscarinic receptor genes. We expressed rat m1 muscarinic receptors by cRNA microinjection in Xenopus oocytes. Cells were voltage-clamped at -70 mV and effects of prolonged (24, 48, and 72 hr) exposure to ethanol (25, 50, and 100 mM) on methylcholine-induced calcium-activated Cl- currents were determined. Effects of prolonged ethanol exposure on currents induced by stimulation of lysophosphatidate receptors, direct G protein activation, or inositol trisphosphate receptor activation were studied as well. Prolonged ethanol exposure enhanced methylcholine (or lysophosphatidate-)-induced currents in a time- and concentration-dependent manner. Thus, enhanced muscarinic gene transcription is not required for ethanol enhancement of muscarinic signaling. Lack of ethanol effect on inositol trisphosphate-induced signaling suggests that intracellular signaling systems downstream of phospholipase C are not involved. In contrast, currents induced by direct G protein stimulation were enhanced significantly. Therefore, one potential site of ethanol's action on muscarinic signaling is upregulation of the associated G protein or enhancement of its functioning.
...
PMID:Chronic ethanol exposure enhances signaling through muscarinic receptors expressed by cRNA injection in Xenopus oocytes: implications for mechanism of action. 1037 97

Imidazoline binding sites are now generally accepted as being receptors. Despite this acceptance, the molecular structure and signal transduction mechanisms of these receptors are still poorly understood. The I1-imidazoline binding site (I1-receptor) is localized to the plasma membrane, but it is not clear if this represents a conventional receptor. It is also not clear if there are multiple forms of the I1-receptor. The signal transduction mechanisms of I1-receptors are similarly unclear, but much progress has been made. Evidence clearly indicates that ligands with high affinity for I1-receptors stimulate a novel signal transduction pathway, phosphatidylcholine-selective phospholipase C, in the rat adrenal medullary tumor cell line PC-12. However, this may not be the case in all cell types as microphysiometry, a novel technique for determining cellular activation, could not detect receptor activation in cultured bovine adrenal medullary cells exposed to a number of imidazolines considered to be agonists at the I1-receptor. This suggests that there is no I1-receptor-mediated stimulation of phosphatidylcholine-specific phospholipase C in these cells. By contrast, nicotine-stimulated increases in ion entry were blocked by clonidine. Ion channels have been suggested as another possible I1-imidazoline "receptor" family and may represent the low affinity I1-receptor. I1-Receptor ligands can be shown to bind to, or block, the following members of the ligand-gated ion channel super family, the 5HT3, K+ATP, NMDA, and nicotinic acetylcholine receptors. The site of action appears to be the phencyclidine binding site in these channels, but other possibilities cannot be excluded. Molecular modeling suggests that I1-receptor-selective ligands share a common three-dimensional structure with phencyclidine, providing a basis for these actions. This suggests that a phencyclidine-binding site motif may represent a novel site of action for I1-receptor ligands and that searches for receptors based on this motif may reveal novel imidazoline "receptors."
...
PMID:Novel targets and techniques in imidazoline receptor research. 1041 31

A physiological role for cannabinoids in the CNS is indicated by the presence of endogenous cannabinoids and cannabinoid receptors. However, the cellular mechanisms of cannabinoid actions in the CNS have yet to be fully defined. In the current study, we identified a novel action of cannabinoids to enhance intracellular Ca2+ responses in CNS neurons. Acute application of the cannabinoid receptor agonists R(+)-methanandamide, R(+)-WIN, and HU-210 (1-50 nM) dose-dependently enhanced the peak amplitude of the Ca2+ response elicited by stimulation of the NMDA subtype of glutamate receptors (NMDARs) in cerebellar granule neurons. The cannabinoid effect was blocked by the cannabinoid receptor antagonist SR141716A and the Gi/Go protein inhibitor pertussis toxin but was not mimicked by the inactive cannabinoid analog S(-)-WIN, indicating the involvement of cannabinoid receptors. In current-clamp studies neither R(+)-WIN nor R(+)-methanandamide altered the membrane response to NMDA or passive membrane properties of granule neurons, suggesting that NMDARs are not the primary sites of cannabinoid action. Additional Ca2+ imaging studies showed that cannabinoid enhancement of the Ca2+ signal to NMDA did not involve N-, P-, or L-type Ca2+ channels but was dependent on Ca2+ release from intracellular stores. Moreover, the phospholipase C inhibitor U-73122 and the inositol 1,4,5-trisphosphate (IP3) receptor antagonist xestospongin C blocked the cannabinoid effect, suggesting that the cannabinoid enhancement of NMDA-evoked Ca2+ signals results from enhanced release from IP3-sensitive Ca2+ stores. These data suggest that the CNS cannabinoid system could serve a critical modulatory role in CNS neurons through the regulation of intracellular Ca2+ signaling.
...
PMID:Cannabinoids enhance NMDA-elicited Ca2+ signals in cerebellar granule neurons in culture. 1051 96

Extracellular single-unit recordings and iontophoresis were used to compare the effect of a single administration of pertussis toxin (PTX, 1 microg), into midbrain dopamine (DA) nuclei (A9 and A10 regions), on the muscarinic, NMDA and DA receptor responses of midbrain DA cells in the anesthetized rat. Iontophoretic applications of DA, or apomorphine (50 microg/kg, i.v.), markedly reduced the firing of DA cells in control rats. In PTX-treated animals, these inhibitory responses were totally abolished, indicating that, in both DA nuclei, the inhibitory DA receptors are coupled to Gi/o proteins. In parallel, there was a significant decrease in the number of active DA cells per track which returned to baseline 5 weeks after the treatment. Applications of the muscarinic agonist oxotremorine M (OXO M) or of NMDA produced a potent increase in the firing of DA cells in control rats. DA neurons treated with PTX were still responsive to OXO M, although their sensitivity to the agonist was significantly reduced by 40%. In contrast, NMDA-induced activation remained unchanged, indicating that PTX did not non-selectively dampen all excitatory responses. Applications of cell-permeable cAMP derivatives did not change the basal firing of DA neurons. On the other hand, the phospholipase C inhibitors neomycin and ET-18-OCH3 (200 microg, i.c.v.), reduced significantly the activation of DA cells induced by OXO M. These data suggest that muscarinic activation of DA cells involves an M1-like receptor, possibly coupled to Gq/11 proteins, but also the participation of a PTX substrate.
...
PMID:Pertussis toxin treatment differentially affects cholinergic and dopaminergic receptor stimulation of midbrain dopaminergic neurons. 1060 85

Potentiation of ionotropic glutamate receptor activity by metabotropic glutamate receptors (mGluRs) is thought to modulate activity at glutamatergic synapses in the hippocampus. However, the precise pathway by which this modulation occurs is not well understood. The present study tests the hypothesis that mGluR1-mediated potentiation of N-methyl-D-aspartate receptors (NMDARs) occurs via a phospholipase C (PLC)-initiated cascade. NMDAR functional activity was examined by whole-cell recording from Xenopus oocytes expressing recombinant NMDARs and mGluR1alpha. The mGluR1 agonist (1S,3R)-1-amino-cyclopentane-1,3-dicarboxylic acid (ACPD) significantly potentiated NMDA-elicited currents. mGluR1alpha-mediated potentiation of NMDA responses was eliminated by the PLC inhibitor U-73122. Buffering of intracellular Ca2+ by BAPTA-AM or depletion of intracellular Ca2+ by the Ca2+/ATPase inhibitor thapsigargin greatly reduced ACPD potentiation. ACPD potentiation was reduced by the specific protein kinase C (PKC) inhibitor Ro-32-0432 and eliminated by the broad spectrum kinase inhibitor staurosporine. ACPD produced no further potentiation after potentiation of NMDARs by the PKC-activating phorbol ester 12-O-tetradecanoyl phorbol-13-acetate (TPA). Thus, Group I mGluRs potentiate NMDA responses via activation of PLC; at least part of the potentiation is due to rise in intracellular Ca2+ and stimulation of PKC. Cytochalasin D, which disrupts the actin cytoskeleton, blocked ACPD-elicited chloride currents and ACPD-induced potentiation of NMDAR currents, consistent with a role for cytoskeletal protein(s) in the signaling pathway. As Group I mGluRs are localized to the perisynaptic region in juxtaposition to NMDARs at glutamatergic synapses, mGluR-mediated potentiation of NMDAR activity may play a role in synaptic transmission and plasticity including LTP.
...
PMID:mGluR1-mediated potentiation of NMDA receptors involves a rise in intracellular calcium and activation of protein kinase C. 1137 56

The neuroprotectant fructose-1,6-bisphosphate (FBP) preserves cellular [ATP] and prevents catastrophic increases in [Ca2+]i during hypoxia. Because FBP does not enter neurons or glia, the mechanism of protection is not clear. In this study, we show that FBP's capacity to protect neurons and stabilize [Ca2+]i during hypoxia derives from signaling by a phospholipase-C-intracellular Ca2+-protein kinases pathway, rather than Ca2+ chelation or glutamate receptor inhibition. FBP reduced [Ca2+]i changes in hypoxic hippocampal neurons, regardless of [Ca2+]e, and preserved cellular integrity as measured by trypan blue or propidium iodide exclusion and [ATP]. FBP also prevented hypoxia-induced increases in [Ca2+]i when glucose was absent and when [Ca2+]e was increased to negate Ca2+ chelation by FBP. These protective effects were observed equally in postnatal day 2 (P2) and P16 neurons. Inhibiting glycolysis with iodoacetate eliminated the protective effects of FBP in P16 neurons. FBP did not alter Ca2+ influx stimulated by brief applications of NMDA or glutamate during normoxia or hypoxia, but did reduce the increase in [Ca2+]i produced by 10 min of glutamate exposure during hypoxia. Because FBP increases basal [Ca2+]i and stimulates membrane lipid hydrolysis, we tested whether FBP's protective action was dependent on phospholipase C signaling. The phospholipase C inhibitor U73122 prevented FBP-induced increases in [Ca2+]i and eliminated FBP's ability to stabilize [Ca2+]i and increase survival during anoxia. Similarly, FBP's protection was eliminated in the presence of the mitogen/extracellular signal protein kinase (MEK) inhibitor U0126. We conclude that FBP may produce neuroprotection via activation of neuroprotective signaling pathways that modulate Ca2+ homeostasis.
...
PMID:Neuroprotection and intracellular Ca2+ modulation with fructose-1,6-bisphosphate during in vitro hypoxia-ischemia involves phospholipase C-dependent signaling. 1164 Sep 1

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.
...
PMID:Modulation of ionotropic glutamate receptor channels. 1169 44


<< Previous 1 2 3 4 5 6 7 Next >>

---