Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.3 (phospholipase C)
 18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have developed the coexpression system of both delta-opioid receptor (DOR1) and M2-muscarinic receptor (M2) which mediate agonist-evoked currents due to common post-receptor mechanisms including Gi1 and phospholipase C (PLC) activation in Xenopus oocytes reconstituted with Gi1 alpha. The DOR1-currents by 100 nM D-Ser2-leu-enkephalin-Thr6 (DSLET) were selectively desensitized by 10 nM phorbol 12-myristate 13-acetate (PMA). The PMA-desensitization of DSLET-currents was abolished in the presence of calphostin C, a protein kinase C inhibitor, or reversed by an intracellular injection of calcineurin, a protein phosphatase 2B. When a higher concentration (3 microM) of DSLET was used, DSLET-currents were rapidly desensitized by repeated challenges of DSLET itself. However, repeated challenges of 10 microM ACh caused no influence on such DSLET- or M2-currents. The desensitization of DSLET-currents was selectively reversed by protein kinase C inhibitors. Similar results were also obtained with various delta-opioid agonists. These results suggest that protein kinase C is involved in the homologous desensitization of delta-opioid receptors.
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PMID:Protein kinase C involvement in homologous desensitization of delta-opioid receptor coupled to Gi1-phospholipase C activation in Xenopus oocytes. 747

Abscisic acid (ABA) affects a number of ion transport mechanisms in guard cells. One effect of ABA is to inhibit inward K+ channels, an effect that can contribute to the inhibition of stomatal opening. One model of the signal transduction cascade mediating this response involves ABA-activation of a G-protein, which in turn activates phospholipase C, resulting in production of inositol 1,4,5-trisphosphate (IP3), elevation of cytosolic free Ca2+ levels (Cai), and activation of a Ca(2+)-dependent phosphatase (protein phosphatase 2B; PP2B) which mediates channel inhibition. A review of the literature reveals that several of the links in this putative signal transduction chain have been established. The G-protein activator, GTP gamma S, inhibits inward K+ currents. Exogenous IP3 inhibits inward K+ currents. Exogenous IP3 elevates Cai. Elevated Cai inhibits inward K+ currents, and the inhibition by ABA of inward K+ currents does require Ca2+. Exogenous PP2B inhibits inward K+ currents, and an endogenous Ca(2+)-dependent phosphatase activity is present in guard cells. However, significant gaps in the chain remain. There is no direct evidence that ABA activates a G-protein. The presence or absence of a G-protein-activated phospholipase C in guard cells has not been investigated. Elevation of Cai by ABA is variable, and the reasons for this variability remain to be established. It is not known whether or not activation of a guard-cell PP2B homolog is the exclusive mechanism by which Ca2+ inhibits the channels.
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PMID:Inhibition of guard-cell inward K+ channels by abscisic acid: links and gaps in the signal transduction chain. 759 43

Brush-border membrane vesicles (BBMV) were prepared from superficial rat renal cortex by a divalent(2+)-precipitation technique using either CaCl2 or MgCl2. The dependence of the initial [14C]-D-glucose (or [3H]-L-proline) uptake rate and the extent of the overshoot of D-glucose or L-proline uphill accumulation from solutions containing 100 mM Na+ salt, was found to be dependent upon the precipitating divalent cation. With Mg2+ precipitation the initial uptake and overshoot accumulation of either D-glucose or L-proline were enhanced compared to BBMV prepared by Ca2+ precipitation. When the anion composition of the media was varied (uptake in Cl- media in comparison to gluconate(-)-containing media) it was found that the Cl(-)-dependent component of the initial uptake was markedly depressed with Ca(2+)-prepared BBMV (104.99 +/- 33.31 vs. 13.83 +/- 1.44 pmoles/sec/mg protein for Mg2+ and Ca2+ prepared vesicles respectively). When Ca2+ was loaded into Mg2+ prepared BBMV using a freeze-thaw technique, it was found that the magnitude and Cl- enhancement of D-glucose transport was reduced in a dose-dependent manner. Neomycin, an inhibitor of phospholipase C, had no effect on the reduction of D-glucose uptake by Ca2+ in Mg2+ prepared vesicles. In contrast, phosphatase inhibitors such as vanadate and fluoride were able to partially reverse the Ca2+ inhibition of D-glucose uptake and restore the enhancement due to Cl- media. In addition, inhibitors of protein phosphatase 2B, deltamethrin (50 nM) and trifluoperazine (10 microM), caused partial reversal of Ca2(+)-dependent inhibition of D-glucose uptake. Direct measurement of changes in the bi-ionic (Cl-vs. gluconate-) transmembrane electrical potential differences using the cyanine dye, 3,3'-dipropylthiodicarbocyanine iodide DiSC3-(5) confirmed that Cl- conductance was reduced in Ca(2+)-prepared vesicles. We conclude that a Cl- conductance coexists with Na+ cotransport in rat renal BBMV and this may be subject to negative regulation by Ca2+ via stimulation of protein phosphatase (PP2B).
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PMID:An effect of Ca2+ on the Intrinsic Cl(-)-conductance of rat kidney cortex brush border membrane vesicles. 866 77

NMDA receptor (NMDAR)-dependent hippocampal synaptic plasticity underlying learning and memory coordinately regulates dendritic spine structure and AMPA receptor (AMPAR) postsynaptic strength through poorly understood mechanisms. Induction of long-term depression (LTD) activates protein phosphatase 2B/calcineurin (CaN), leading to dendritic spine shrinkage through actin depolymerization and AMPAR depression through receptor dephosphorylation and internalization. The scaffold proteins A-kinase-anchoring protein 79/150 (AKAP79/150) and postsynaptic density 95 (PSD95) form a complex that controls the opposing actions of the cAMP-dependent protein kinase (PKA) and CaN in regulation of AMPAR phosphorylation. The AKAP79/150-PSD95 complex is disrupted in hippocampal neurons during LTD coincident with internalization of AMPARs, decreases in PSD95 levels, and loss of AKAP79/150 and PKA from spines. AKAP79/150 is targeted to spines through binding F-actin and the phospholipid phosphatidylinositol-(4,5)-bisphosphate (PIP2). Previous electrophysiological studies have demonstrated that inhibition of phospholipase C (PLC)-catalyzed hydrolysis of PIP2 inhibits NMDAR-dependent LTD; however, the signaling mechanisms that link PLC activation to alterations in dendritic spine structure and AMPAR function in LTD are unknown. We show here that NMDAR stimulation of PLC in cultured hippocampal neurons is necessary for AKAP79/150 loss from spines and depolymerization of spine actin. Importantly, we demonstrate that NMDAR activation of PLC is also necessary for decreases in spine PSD95 levels and AMPAR internalization. Thus, PLC signaling is required for structural and functional changes in spine actin, PSD scaffolding, and AMPAR trafficking underlying postsynaptic expression of LTD.
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PMID:Phospholipase C is required for changes in postsynaptic structure and function associated with NMDA receptor-dependent long-term depression. 1739 68

The pharmacological desensitization of receptors is a fundamental mechanism for regulating the activity of neuronal systems. The TRPA1 channel plays a key role in the processing of noxious information and can undergo functional desensitization by unknown mechanisms. Here we show that TRPA1 is desensitized by homologous (mustard oil; a TRPA1 agonist) and heterologous (capsaicin; a TRPV1 agonist) agonists via Ca2+-independent and Ca2+-dependent pathways, respectively, in sensory neurons. The pharmacological desensitization of TRPA1 by capsaicin and mustard oil is not influenced by activation of protein phosphatase 2B. However, it is regulated by phosphatidylinositol-4,5-bisphosphate depletion after capsaicin, but not mustard oil, application. Using a biosensor, we establish that capsaicin, unlike mustard oil, consistently activates phospholipase C in sensory neurons. We next demonstrate that TRPA1 desensitization is regulated by TRPV1, and it appears that mustard oil-induced TRPA1 internalization is prevented by coexpression with TRPV1 in a heterologous expression system and in sensory neurons. In conclusion, we propose novel mechanisms whereby TRPA1 activity undergoes pharmacological desensitization through multiple cellular pathways that are agonist dependent and modulated by TRPV1.
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PMID:Transient receptor potential TRPA1 channel desensitization in sensory neurons is agonist dependent and regulated by TRPV1-directed internalization. 1758 31

In adult neostriatal projection neurons, the intracellular Ca(2+) supplied by Ca(V)2.1 (P/Q) Ca(2+) channels is in charge of both the generation of the afterhyperpolarizing potential (AHP) and the release of GABA from their synaptic terminals, thus being a major target for firing pattern and transmitter release modulations. We have shown that activation of muscarinic M(1)-class receptors modulates Ca(V)2.1 channels in these neurons in rats. This modulation is reversible, is not membrane delimited, is blocked by the specific M(1)-class muscarinic antagonist muscarine toxin 7 (MT-7), and is neither mediated by protein kinase C (PKC) nor by protein phosphatase 2B (PP-2B). Hence, the signaling mechanism of muscarinic Ca(V)2.1 channel modulation has remained elusive. The present paper shows that inactivation of phospholipase C (PLC) abolishes this modulation while inhibition of phosphoinositide kinases, PI-3K and PI-4K, prevents its reversibility, suggesting that the reconstitution of muscarinic modulation depends on phosphoinositide rephosphorylation. In support of this hypothesis, the supply of intracellular phosphatidylinositol (4,5) bisphosphate [PI(4,5)P(2)] blocked all muscarinic modulation of this channel. The results indicate that muscarinic M(1) modulation of Ca(V)2.1 Ca(2+) channels in these neurons involves phosphoinositide hydrolysis.
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PMID:CaV2.1 channels are modulated by muscarinic M1 receptors through phosphoinositide hydrolysis in neostriatal neurons. 1988 39