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)

The neuropeptide galanin potently inhibits insulin release, hippocampal acetylcholine release and firing of locus coeruleus cells, and stimulates feeding and release of growth hormone. Galanin regulates K+ channels, adenylyl cyclase and phospholipase C by acting at Gi/Go protein-coupled high-affinity receptors. Galanin receptor agonists such as the N-terminal fragment galanin1-16 act synergistically with morphine in the somatosensory system and have potential analgetic application. Galanin antagonists may be useful therapeutic agents in endocrinology, neurology and psychiatry. The enhancing effect of such agents on hippocampal cholinergic function would be useful in treatment of Alzheimer's disease. Recent synthesis of a series of high-affinity galanin antagonists, reviewed, along with galanin's actions, by Tamas Bartfai and colleagues, opens the possibility of examining the functions of endogenous galanin and test the pharmacological usefulness of antagonism of galanin function in the endocrine, somatosensory and central nervous systems.
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PMID:Galanin and galanin antagonists: molecular and biochemical perspectives. 138 14

The activity of phospholipase C (PLC) which hydrolyzes exogenous phosphatidylinositol (PI), was investigated in samples prepared from postmortem normal human brains and Alzheimer disease brains. The enzyme activity did not change significantly after rat brains were left for 24 h at room temperature. The PI-specific PLC activity in the Alzheimer cytosolic and particulate fractions was not significantly different from that in the control fractions. The PI-specific PLC activity as a function of the free Ca2+ concentration was also similar between control and Alzheimer brains. These results suggest that the PI-specific PLC activity is not altered in Alzheimer's disease.
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PMID:Phosphatidylinositol-specific phospholipase C activity in the postmortem human brain: no alteration in Alzheimer's disease. 162 21

The potential usefulness of cholinergic replacement therapy for Alzheimer disease (AD) is dependent upon retention of postsynaptic muscarinic receptors and their transduction mechanisms long after the degeneration of cholinergic nerves. The receptors most clearly associated with cholinergic cerebral excitation are m1 muscarinic receptors, which work via a G protein to activate phospholipase C. The ability of these receptors to couple to their associated G protein was assessed in the middle temporal gyrus of postmortem brains from persons with and without AD. A low concentration of [3H]-pirenzepine (1 nM) was used to label m1 receptors preferentially. The affinity of the agonist, oxotremorine-M, for labeled receptors and the ability of these receptors to couple with G protein were assessed by competition between the agonist and 1 nM [3H]-pirenzepine in the presence and absence of guanine nucleotide. Brain tissue from 7 patients with AD and five age-matched controls showed very similar levels of labeled receptors, agonist affinities for the high- and low-affinity states of m1 receptors, and guanine nucleotide-sensitive high-affinity binding. It is concluded that the coupling of m1 receptors to G protein is adequate to permit responses to exogenous muscarinic drugs in AD.
Alzheimer Dis Assoc Disord 1991
PMID:Coupling of m1 muscarinic receptors to G protein in Alzheimer disease. 177 36

Since phosphoinositide-specific phospholipase C (PLC) is one of the key molecules in signal transduction, the authors assessed its involvement in Alzheimer's disease (AD). Immunostaining of a specific antibody against the PLC isozyme, PLC-delta, demonstrated that this enzyme was abnormally accumulated in neurofibrillary tangles (NFT), the neurites surrounding senile plaque (SP) cores, and neuropil threads in AD brains. Western blot analysis confirmed that PLC-delta was concentrated in the paired helical filament (PHF)-rich fraction of AD brains. Antibodies to other PLC isozymes did not produce positive immunostaining of these pathologic structures. Moreover, diffuse and amorphous deposits of PLC-delta were found to precede the accumulation of fibrillary deposits. These results suggest that PLC-delta accumulation is a crucial event that ultimately may contribute to the formation of PHF.
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PMID:Aberrant accumulation of phospholipase C-delta in Alzheimer brains. 192 98

Aluminum (Al) is believed to exert a primary role in the neurotoxicity associated with dialysis encephalopathy and has been suggested to be involved in a number of other neurological disorders, including Alzheimer's disease. Al, complexed with fluoride to form fluoroaluminate (AlF4-), can activate the GTP-binding (G) proteins of the adenylate cyclase and retinal cyclic GMP phosphodiesterase systems. Since an involvement of G-proteins with cerebral phosphoinositide (PtdIns) metabolism has also been suggested, in this study we investigated the interaction of the stable GTP analogue GTP(S), Al salts and NaF with this system. In rat cerebral cortical membranes, GTP(S) dose-dependently stimulated [3H]inositol phosphates ([3H]InsPs) accumulation. This effect was potentiated by carbachol and was partially prevented by the GTP-binding antagonist GDP(S), indicating that CNS muscarinic receptor activation is coupled to PtdIns hydrolysis via putative G-protein(s). GTP(S) stimulation was also inhibited by phorbol 12-myristate 13-acetate (PMA), an activator of protein kinase C, which is known to exert a negative feedback control on agonist-stimulated PtdIns metabolism. Both Al salts and NaF mimicked the action of GTP(S) in stimulating PtdIns turnover. Their actions were highly synergistic, suggesting that AlF4- could be the active stimulatory species. However, the stimulatory effects of AlCl3 and/or NaF were not potentiated by carbachol and were not inhibited by GDP(S) and PMA, suggesting that separate sites of action might exist for GTP(S) and AlF4-. In the nervous tissue, activation of PtdIns hydrolysis by Al (probably as AlF4-) may be mediated by activating a regulatory G-protein at a location distinct from the GTP-binding site or by a direct stimulation of phospholipase C.
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PMID:Interaction of aluminum ions with phosphoinositide metabolism in rat cerebral cortical membranes. 194 39

Phosphoinositide-specific phospholipase C (PLC) is a key enzyme in signal transduction. It was previously demonstrated that an antibody to an isozyme of PLC, PLC-delta, produces intense staining of neurofibrillary tangles (NFT), the neurites surrounding senile plaque (SP) cores and neuropil threads in the brains of patients with Alzheimer's disease (AD). Although the etiology of neuronal degeneration in AD is still to be defined, excitotoxic glutamate might be a candidate. In the present study, an anti-PLC-delta antibody was used to examine the influence of glutamate on PLC-delta immunoreactivity in cultured rat cortical neurons. Exposure to glutamate caused the death of cultured cortical neurons and exhibited increased immunostaining with the anti-PLC-delta antibody. Subtoxic doses of glutamate also increased PLC-delta immunoreactivity in a dose-dependent manner. Both glutamate-induced neuronal degeneration and the increases in PLC-delta immunoreactivity were prevented by removal of extracellular Ca2+ or the application of an N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801. The glutamate-induced increase in PLC-delta immunoreactivity was also prevented by N omega-nitro-L-arginine, a nitric oxide (NO) synthase inhibitor. These results suggest that NO formation secondary to Ca2+ influx by NMDA receptor activation leads to similar modifications of PLC-delta to those seen in AD.
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PMID:Glutamate-induced antigenic changes of phospholipase C-delta in cultured cortical neurons. 756 35

The ability of beta-amyloid peptides to activate the classical complement cascade and the presence of various complement proteins including the membrane attack complex (C5b-9) on dystrophic neurites in Alzheimer's disease brains, raises the possibility that the complement system may contribute to this neurodegenerative disorder. To address this issue, we have studied the effect of complement activation on nerve growth factor (NGF)-differentiated rat pheochromocytoma PC12 cells, and on retinoic acid (RA)-differentiated human neuroblastoma SH-SY5Y cells. Although incubation of both cell types with human serum resulted in activation of complement, as indicated by iC3b formation, only PC12 but not SH-SY5Y cells were killed by human serum treatment. In contrast, heat-inactivated serum (56 degrees C, 45 min) was not neurotoxic. On SH-SY5Y cells, both PCR amplification and immunocytochemistry demonstrated the presence of CD59, a glycosylphosphatidylinositol-anchored protein that restricts homologous complement activation by inhibiting the formation of the membrane attack complex. The presence of CD59 probably accounts for the inability of human complement to lyse the human cell lines. Indeed, removal of glycosylphosphatidylinositol (GPI)-anchored proteins with phosphatidylinositol-specific phospholipase C (PI-PLC) rendered SH-SY5Y cells vulnerable to complement attack and eventually led to serum-medicated cell death. Reconstituted C5b-9 was also toxic to both PC12 and PI-PLC-pretreated SH-SY5Y cells. These observations suggest that complement activation can cause neuronal cell death and that this process is regulated by homologous restriction.
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PMID:Complement-mediated neurotoxicity is regulated by homologous restriction. 774 16

Phosphoinositide-specific phospholipase C (PLC) is a key enzyme in signal transduction. We have previously demonstrated that an antibody to an isozyme of PLC, PLC-delta, produced intense staining of neurofibrillary tangles in the brains of patients with Alzheimer's disease. In the present study, we investigated the protein level and activity of this enzyme in control and Alzheimer brains. Western blot analysis using a specific antibody for PLC-delta showed that the concentration of PLC-delta protein was significantly higher in the cytosolic fraction of Alzheimer disease cortical tissue than in control brains. The activity of PLC-delta, which hydrolyzes phosphatidylinositol, was also investigated, and we found that PLC-delta activity was not significantly different in the Alzheimer and control cytosolic fractions. These results indicate that the specific activity of PLC-delta is decreased in Alzheimer brains and suggest that inactivation of PLC-delta might be related to the pathophysiology of this disease.
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PMID:Alteration of phospholipase C-delta protein level and specific activity in Alzheimer's disease. 776 43

The effect of Alzheimer's disease (AD) on the activity of the phosphoinositide second messenger system was studied by measuring the hydrolysis of [3H]phosphatidylinositol (PI) by membranes from postmortem human prefrontal cortex. The activity of phospholipase C was similar in AD and control tissue. Activation with GTP gamma S and with carbachol demonstrated less [3H]PI hydrolysis in AD than control membranes. The concentration of Gq/11, the G-proteins most likely functional in phosphoinositide metabolism, was unchanged in AD compared with controls, indicating that function of the receptor-G-protein complex rather than the G-protein concentration was the site of the impairment in AD. These results indicate that postsynaptic muscarinic receptor responses are impaired in AD, a finding that may explain, in part, the limited therapeutic responses achieved by administration of cholinomimetics to patients with AD. Also, this assay provides a means to identify cholinomimetics that are most effective in activating muscarinic receptor-coupled phosphoinositide hydrolysis in human brain, agents which should have the greatest potential for providing therapeutic responses in AD.
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PMID:Impaired phosphoinositide hydrolysis in Alzheimer's disease brain. 783 95

The Alzheimer amyloid precursor protein (APP) undergoes complex processing resulting in the production of a 4-kDa amyloid peptide (A beta) which has been implicated in the pathogenesis of Alzheimer's disease. Recent studies have shown that cells can secrete carboxyl terminus truncated APP derivatives (APP-S) in response to physiological stimulus. We have used human central nervous system neurons (NT2N) derived from a teratocarcinoma cell line (NT2) to study the signal transduction pathways involved in APP-S secretion and A beta production. Muscarinic receptors (m2 and m3) as well as the heterotrimeric GTP-binding protein Gq and the beta 1 isoform of phospholipase C were present in NT2N neurons. Stimulation of the muscarinic receptor with carbachol resulted in phospholipase C activation as shown by a transient increase in the second messengers 1,2-diacyl-sn-glycerol and inositol 1,4,5-trisphosphate. Carbachol also caused an increase in intracellular Ca2+ levels measured in single NT2N neurons. Under these conditions, carbachol caused a time-dependent 2-fold increase in APP-S secretion into the medium. In contrast, prolonged treatment with carbachol caused a decrease in A beta production into the medium. These results suggest that APP-S secretion and A beta production in NT2N neurons are regulated by the muscarinic/phospholipase C signal transduction pathway. Furthermore, activation of this pathway results in dissociation of APP-S secretion and A beta production.
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PMID:Muscarinic regulation of Alzheimer's disease amyloid precursor protein secretion and amyloid beta-protein production in human neuronal NT2N cells. 787 66


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