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)

Chronic blockade of opioid receptors by naltrexone increases opioid peptides in the striatum, and up-regulates brain opioid receptors resulting in functional supersensitivity. Striatal SP content was increased 3.5-fold after 8 days of naltrexone treatment relative to control animals. The present study was undertaken to determine whether SP receptors in the striatum and SP receptor-coupled second messenger system are modulated by increased striatal SP content induced by chronic opioid receptor blockade. The binding affinity and capacity of SP receptors, determined using [125I]Bolton-Hunter SP ([125I]BHSP) labeled at Lys3, in striatal synaptosomal membranes were not significantly altered by chronic blockade of opioid receptors. Although the concentrations of [Sar9,Met (O2)11]SP, a NK-1 receptor-specific agonist, and SP(1-7), an aminoterminal major metabolite of SP, required to inhibit half of [125I]BHSP binding (IC50) in striatal synaptosomal membranes were significantly decreased, the IC50s for SP and an NK-2 receptor-specific agonist, [Nle10]NK A (4-10), remained unchanged by chronic naltrexone treatment. The data suggest that naltrexone which has no SP receptor antagonistic action, not only indirectly acts on SP-ergic neurons but also causes a change in the apparent affinity of NK-1 receptor (as reflected by changes in IC50 values) in the striatum. Cellular inositol-1,4,5-trisphosphate [Ins(1,4,5)P3], quantified by a highly sensitive and selective radioreceptor mass assay, was increased in the striatum by 28% relative to control levels. With [3H]Ins(1,4,5)P3 as a ligand, Scatchard analyses of the concentration-dependent saturation curves showed that the density of striatal intracellular Ins(1,4,5)P3 receptors was increased by 53%. The levels of SP and cellular Ins(1,4,5)P3, and the density of Ins(1,4,5)P3 receptors in the cerebellum, used as a positive control, were unchanged by chronic naltrexone treatment. The findings of opiate antagonist-induced increases in SP striatal content and Ins(1,4,5)P3 receptor densities, appear to support the concept of a role of endogenous opioids in the regulation of SP receptor activity. The data also suggest that inter-regulatory mechanisms exist between phospholipase C/phosphoinositide-coupled receptors such as SP receptors, and adenylate cyclase-coupled inhibitory receptors, such as opioid receptors.
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PMID:Regulation of substance P receptor system in rat striatum by chronic naltrexone treatment. 750 77

The G protein-linked receptor for neurokinin A (NKA) couples to stimulation of phospholipase C and, in some cells, adenylyl cyclase. We have examined the function of the C-terminal cytoplasmic domain in receptor signaling and desensitization. We constructed C-terminal deletion mutants of the human NK-2 receptor (epitope tagged) to remove potential Ser/Thr phosphorylation sites, and expressed them in both mammalian and insect cells. When activated, truncated receptors mediate stronger and more prolonged phosphoinositide hydrolysis than wild-type receptor; however, the amplitude and kinetics of the NKA-induced rise in cytosolic Ca2+ remain unaltered. Protein kinase C (PKC)-activating phorbol ester abolishes wild-type receptor signaling but not mutant receptor signaling. Mutant receptors also mediate enhanced and prolonged cAMP generation, at least in part via PKC activation. When expressed in COS cells or Sf9 insect cells, the wild-type receptor is phosphorylated; receptor phosphorylation increases after addition of either NKA or phorbol ester. In contrast, mutant receptors are not phosphorylated by either treatment. Our results suggest that C-terminal Ser/Thr phosphorylation sites in the NK-2 receptor have a critical role in both homologous and heterologous desensitization. Removal of these phosphorylation sites results in a receptor that mediates sustained activation of signaling pathways and is insensitive to inhibition by PKC.
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PMID:C-terminal truncation of the neurokinin-2 receptor causes enhanced and sustained agonist-induced signaling. Role of receptor phosphorylation in signal attenuation. 772 3

We have used the neurokinin NK-2 receptor as a model to examine how receptor desensitization affects cellular responses. The liganded receptor transiently activates phospholipase C (PLC) and is rapidly phosphorylated on Ser/Thr residues in its C-terminal domain. Mutant receptors lacking this domain mediate persistent activation of PLC. We now show that, in transfected Rat-1 cells, mutant receptor mediates ligand-induced DNA synthesis, morphological transformation and growth in soft agar, whereas wild-type (wt) receptor does not. Wt receptor causes only transient MAP kinase activation. In contrast, MAP kinase activation by mutant receptor is sustained for >4 h. Neither wt nor mutant receptor couples to Ras activation. Downregulation of protein kinase C (PKC) has little effect on MAP kinase activation, DNA synthesis and transformation. Mutant receptors also promote stronger protein tyrosine phosphorylation and stress fibre formation than does wt receptor. Thus, C-terminal truncation allows the NK-2 receptor to signal sustained MAP kinase activation, cell growth and transformation by a Ras- and PKC-independent mechanism. Our results reveal the importance of the C-terminal 'desensitization domain' in suppressing the oncogenic potential of a prototypic PLC-coupled receptor.
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PMID:Truncated, desensitization-defective neurokinin receptors mediate sustained MAP kinase activation, cell growth and transformation by a Ras-independent mechanism. 867 Aug 36

Endothelin 1 (ET1) desensitizes endothelin A receptor for 90-110 min while neurokinin A (NKA) desensitizes neurokinin A receptor for 25-35 min in Xenopus laevis oocytes. In the present study, endothelin A receptor and neurokinin A receptor were coexpressed in Xenopus laevis oocytes in an effort to characterize heterologous desensitization of the receptors that activate phospholipase C-beta. ET1 desensitizes both the endothelin A receptor and the neurokinin A receptor for 90-110 min, whereas stimulation with NKA desensitizes the same two receptors for only 25-35 min. Homologous and heterologous desensitization experiments were also carried out with endothelin 3 (ET3), a ligand that exhibits lower affinity to the endothelin A receptor and a quicker dissociation rate than ET1. ET3 was unable to desensitize endothelin A receptor and the neurokinin A receptor; this is in contrast to ET1 that desensitizes both receptors. These results suggests that the receptors that undergo homologous desensitization are able to heterologously desensitize other receptors that activate PLC-beta. Furthermore, the agonist-specific dissociation constant dictates the extent of desensitization and time of recovery of the receptor-mediated response.
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PMID:Heterologous desensitization of the human endothelin A and neurokinin A receptors in Xenopus laevis oocytes. 901 65

Microdomains such as rafts are considered as scaffolds for phosphatidylinositol (4,5) bisphosphate (PIP2) signaling, enabling PIP2 to selectively regulate different processes in the cell. Enrichment of PIP2 in microdomains was based on cholesterol-depletion and detergent-extraction studies. Here we show that two distinct phospholipase C-coupled receptors (those for neurokinin A and endothelin) share the same, homogeneously distributed PIP2 pool at the plasma membrane, even though the neurokinin A receptor is localized to microdomains and is cholesterol dependent in its PIP2 signaling whereas the endothelin receptor is not. Our experiments further indicate that detergent treatment causes PIP2 clustering and that cholesterol depletion interferes with basal, ligand-independent recycling of the neurokinin A receptor, thereby providing alternative explanations for the enrichment of PIP2 in detergent-insoluble membrane fractions and for the cholesterol dependency of PIP2 breakdown, respectively.
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PMID:PIP2 signaling in lipid domains: a critical re-evaluation. 1586 Nov 30