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)

Cholinergic pathways serve important functions in learning and memory processes, and deficits in cholinergic transmission occur in Alzheimer disease (AD). A subset of muscarinic cholinergic receptors are linked to G-proteins that activate phospholipase C, resulting in the liberation of inositol trisphosphate and Ca2+ release from intracellular stores. We now report that amyloid beta-peptide (Abeta), which forms plaques in the brain in AD, impairs muscarinic receptor activation of G proteins in cultured rat cortical neurons. Exposure of rodent fetal cortical neurons to Abeta25-35 and Abeta1-40 resulted in a concentration and time-dependent attenuation of carbachol-induced GTPase activity without affecting muscarinic receptor ligand binding parameters. Downstream events in the signal transduction cascade were similarly attenuated by Abeta. Carbachol-induced accumulation of inositol phosphates (IP, IP2, IP3, and IP4) was decreased and calcium imaging studies revealed that carbachol-induced release of calcium was severely impaired in neurons pretreated with Abeta. Muscarinic cholinergic signal transduction was disrupted with subtoxic levels of exposure to AP. The effects of Abeta on carbachol-induced GTPase activity and calcium release were attenuated by antioxidants, implicating free radicals in the mechanism whereby Abeta induced uncoupling of muscarinic receptors. These data demonstrate that Abeta disrupts muscarinic receptor coupling to G proteins that mediate induction of phosphoinositide accumulation and calcium release, findings that implicate Abeta in the impairment of cholinergic transmission that occurs in AD.
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PMID:Amyloid beta-peptide disrupts carbachol-induced muscarinic cholinergic signal transduction in cortical neurons. 869 90

Phosphoinositide-specific phospholipase C (PLC) is a key enzyme in signal transduction. We have previously demonstrated that a PLC isozyme is abnormally accumulated in the brain tissue in Alzheimer's disease (AD). AD has been suggested to be a systemic disease in which the expression of abnormalities is most prominent in neuronal tissues. In a recent study, we have revealed the increase of the cytosolic protein kinase C (PKC) concentration in platelets of AD patients, suggesting the change of PLC, which is upstream to PKC in phosphoinositide metabolism. In this study, we examined phosphatidylinositol-specific PLC activity in platelets from patients with AD and age-matched controls by measuring the formation of radioactive inositol phosphate. The PLC activity was significantly lower in the AD platelets than in the controls. These findings suggest that aberrant phosphoinositide metabolism is present in nonneuronal tissues as well as the brain in AD.
Alzheimer Dis Assoc Disord 1995
PMID:Reduction of platelet phospholipase C activity in patients with Alzheimer disease. 874 10

alpha-Secretase cleaves the full-length Alzheimer's amyloid precursor protein (APP) within the amyloid beta peptide sequence, thus precluding amyloid formation. The resultant soluble truncated APP is constitutively secreted. This nonamyloidogenic processing of APP is increased on stimulation of the phospholipase C/protein kinase C pathway by phorbol esters. Here we used C6 cells transfected with APP751 to examine whether the alpha-secretase cleavage is regulated by the adenylate cyclase signal transduction pathway. Forskolin, an activator of adenylate cyclase, inhibited both the constitutive and phorbol ester-stimulated secretion of nexin II (NXII), the secreted product of the alpha-secretase cleavage of APP751. At 1 microM, forskolin inhibited secretion of NXII by approximately 50% without affecting either the intracellular levels of total APP or the secretion of secretory alkaline phosphatase. In contrast, 1,9-dideoxyforskolin, an inactive analogue of forskolin, did not affect secretion of NXII. These results indicated that forskolin specifically inhibited the alpha-secretase cleavage of APP751. Forskolin treatment increased the intracellular concentration of cyclic AMP (cAMP), suggesting that the forskolin effects on APP cleavage may be mediated by cAMP. In support of this suggestion, both dibutyryl cAMP, a cAMP analogue, and isoproterenol, an activator of adenylate cyclase, also inhibited secretion of NXII. These data indicate that forskolin inhibition of the nonamyloidogenic cleavage of APP is mediated by the second messenger cAMP, which together with the protein kinase C signal transduction pathway modulates the secretory cleavage of APP.
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PMID:Intracellular cyclic AMP inhibits constitutive and phorbol ester-stimulated secretory cleavage of amyloid precursor protein. 876 18

Information on the molecular biology of Alzheimer's disease (AD) pointing to new methods of diagnosis and drug therapies is explored. AD is the most common cause of dementia in the elderly and is characterized by senile plaques and neurofibrillary tangles in the brain and loss of cholinergic neurons in the basal forebrain. The disease has a strong genetic component. A definitive diagnosis can be made only by neuropathologic examination at autopsy or biopsy; however, the accuracy of diagnosis based on standard neuropsychological testing and inclusion criteria has improved considerably. Senile plaques consist of a central core of amyloid fibrils surrounded by dystrophic axons. The main component of senile plaque amyloid is a 39-to 42-amino-acid segment referred to as beta-amyloid, which is derived from amyloid precursor protein (APP). APP exists as multiple isoforms encoded by a single gene on chromosome 21. Factors that may influence APP metabolism include activation of phospholipase C, phosphorylation, and the cholinergic system. The microtubule-associated protein tau may contribute to the neurofibrillary tangles of AD. In AD all six adult isoforms of tau can become maximally phosphorylated and can, rather than binding to microtubules, bind to each other, destabilizing the neuronal cytoskeleton. One of the most important discoveries in AD research was the linking of apolipoprotein E phenotype to familial late-onset AD. Acetylcholinesterase inhibitors appear to improve cognitive function but may be limited in utility by adverse effects. Nicotinic agonists are also being investigated as symptomatic therapies. Other possible strategies include nerve growth factor, agents that potentiate the action of endogenous glutamate, antioxidants, nonsteroidal anti-inflammatory drugs, and estrogens. Research into the molecular biology of Alzheimer's disease has begun to point to possible causes of and treatments for this condition.
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PMID:Molecular basis of Alzheimer's disease. 880 75

Oxidative stress appears to contribute to neuronal dysfunction in a number of neurodegenerative conditions, notably including Alzheimer's disease, in which cholinergic receptor-linked signal transduction activity is severely impaired. To test whether oxidative stress could contribute to deficits in cholinergic signaling, responses to carbachol were measured in human neuroblastoma SH-SY5Y cells exposed to H2O2. DNA binding activities of two transcription factors that are respondent to oxidative conditions, AP-1 and NF kappa B, were measured in nuclear extracts. H2O2 and carbachol individually induced dose- and time-dependent increases in AP-1 and NF kappa B. In contrast, when given together, H2O2 concentration dependently (30-300 microM) inhibited the increase after carbachol in AP-1. Carbachol's stimulation of NF kappa B was not inhibited except with a high concentration (300 microM) of H2O2, which was associated with impaired activation of protein kinase C. Lower concentrations of H2O2 (30-300 microM) inhibited carbachol-induced [3H]phosphoinositide hydrolysis, and this inhibition correlated (r = 0.95) with the inhibition of carbachol-induced AP-1. Activation [3H]phosphoinositide hydrolysis by the calcium ionophore ionomycin was unaffected by H2O2, indicating that phospholipase C and phosphoinositides were impervious to this treatment. In contrast, activation with NaF of G-proteins coupled to phospholipase C was concentration dependently inhibited by H2O2, indicating impaired G-protein function. These effects of H2O2 are similar to signaling impairments reported in Alzheimer's disease brain, which involve deficits in receptor- and G-protein-stimulated phosphoinositide hydrolysis, but not phospholipase C activity. Thus, these findings indicate that oxidative stress may contribute to impaired phosphoinositide signaling in neurological disorders in which oxidative stress occurs, and that oxidative stress can differentially influence transcription factors activated by cholinergic stimulation.
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PMID:Cholinergic stimulation of AP-1 and NF kappa B transcription factors is differentially sensitive to oxidative stress in SH-SY5Y neuroblastoma: relationship to phosphoinositide hydrolysis. 881 74

Tachykinins belong to an evolutionarily conserved family of peptide neurotransmitters. The mammalian tachykinins include substance P, neurokinin A and neurokinin B, which exert their effects by binding to specific receptors. These tachykinin receptors are divided into three types, designated NK1, NK2 and NK3, respectively. Tachykinin receptors have been cloned and contain seven segments spanning the cell membrane, indicating their inclusion in the G-protein-linked receptor family. The continued development of selective agonists and antagonists for each receptor has helped elucidate roles for these mediators, ranging from effects in the central nervous system to the perpetuation of the inflammatory response in the periphery. Various selective ligands have shown both inter- and intraspecies differences in binding potencies, indicating distinct binding sites in the tachykinin receptor. The interaction of tachykinin with its receptor activates Gq, which in turn activates phospholipase C to break down phosphatidyl inositol bisphosphate into inositol trisphosphate (IP3) and diacylglycerol (DAG). IP3 acts on specific receptors in the sarcoplasmic reticulum to release intracellular stores of Ca2+, while DAG acts via protein kinase C to open L-type calcium channels in the plasma membrane. The rise in intracellular [Ca2+] induces the tissue response. With an array of actions as diverse as that seen with tachykinins, there is scope for numerous therapeutic possibilities. With the development of potent, selective non-peptide antagonists, there could be potential benefits in the treatment of a variety of clinical conditions, including chronic pain, Parkinson's disease, Alzheimer's disease, depression, rheumatoid arthritis, irritable bowel syndrome and asthma.
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PMID:Tachykinins: receptor to effector. 892 4

The phosphoinositide signal transduction system constitutes one of the primary means for intercellular communication in the central nervous system, but only recently has this system been studied in human brain. Although some investigations have studied phosphoinositide signaling in slices from biopsied human brain, due to the limited access to such material a greater number of studies have utilized membranes prepared from postmortem human brain. With membranes exposed to exogenous labeled phosphoinositides, activation of phospholipase C with calcium, with G-proteins stimulated by GTP gamma S or NaF, or with several receptor agonists, have demonstrated that all of the components of the phosphoinositide system are retained in human brain membranes and are responsive to appropriate stimuli. Investigators have begun to examine the effects of neurological (Alzheimer's disease, epilepsy, Parkinson's disease) and psychiatric (schizophrenia, major depression, bipolar affective disorder) diseases on the activity of the phosphoinositide system. Alzheimer's disease has been studied to the greatest extent and a severe deficit in phosphoinositide signaling has been identified in most studies. In addition, brain regionally selective deficits in G-protein function associated with phosphoinositide signaling have been reported in subjects with major depression or with bipolar affective disorder, and in the latter an ameliorative effect of the therapeutic drug lithium was identified. Although significant progress has been achieved in studying the phosphoinositide system in human brain, many issues remaining to be addressed are discussed in this review. With carefully controlled studies, it appears that much will be learned in the near future about the phosphoinositide signal transduction system in human brain and the effects of a variety of disorders on its function.
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PMID:Phosphoinositide signaling in human brain. 897 82

Following cholinergic denervation of the hippocampal formation, via medial septal lesions, peripheral noradrenergic fibers, originating from the superior cervical ganglion, grow into the hippocampus. In previous studies, we have found that hippocampal sympathetic ingrowth and cholinergic denervation alone (animals with concurrent medial septal lesions and superior cervical ganglionectomy) alter phosphoinositide turnover and muscarinic cholinergic receptors in such a way as to suggest an alteration in coupling between the muscarinic cholinergic receptors and phosphoinositol turnover. To test this hypothesis we examined the effect of hippocampal sympathetic ingrowth and cholinergic denervation on phospholipase C activity, G-protein function and the whole receptor complex by measuring the amount of phosphoinositide hydrolysed in hippocampal membranes of the rat. Neither hippocampal sympathetic ingrowth nor cholinergic denervation was found to alter phospholipase C activity when activated by increasing concentrations of Ca2+. In dorsal hippocampus, cholinergic denervation, when compared to hippocampal sympathetic ingrowth and controls, was found to decrease the amount of phosphoinositol hydrolysed when stimulated with the GTP analog, guanosine-5'-O-(3-thiotriphosphate). When guanosine-5'-O-(3-thiotriphosphate) plus carbachol (1 mM) was utilized to stimulate the entire receptor complex, phosphoinositol hydrolysis was found to be decreased in the cholinergic denervation group as compared to both hippocampal sympathetic ingrowth and control groups. This effect was maximum at 3 microM guanosine-5'-O-(3-thiotriphosphate). These results suggest that both hippocampal sympathetic ingrowth and cholinergic denervation affect the efficiency of coupling between the muscarinic cholinergic receptors and phosphoinositol turnover, with cholinergic denervation decreasing and hippocampal sympathetic ingrowth "normalizing" efficiency. Further, they suggest that the G-protein is the site at which hippocampal sympathetic ingrowth and cholinergic denervation mediate their effects. The results of these experiments are also discussed within the context of recent findings demonstrating G-protein abnormalities in Alzheimer's disease.
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PMID:Effect of hippocampal sympathetic ingrowth and cholinergic denervation on hippocampal phospholipase C activity and G-protein function. 904 79

The amyloid-beta peptides (A beta) are produced in excess in Alzheimer's disease (AD) and may contribute to neuronal dysfunction and degeneration. This study provides strong evidence for a novel cellular target for the actions of A beta, the phospholipase C-coupled, extracellular Ca(2+)-sensing receptor (CaR). We demonstrate that A beta(s) produce a CaR-mediated activation of a Ca(2+)-permeable, nonselective cation channel (NCC), probably via elevation in cytosolic Ca2+ (Cai), in cultured hippocampal pyramidal neurons from normal rats and from wild type mice but not those from mice with targeted disruption of the CaR gene (CaR -/-). A beta(s) also activate NCC in CaR-transfected but not in nontransfected human embryonic kidney (HEK293) cells. Thus aggregates of A beta deposited on hippocampal neurons in AD could appropriately activate the CaR, stimulating Ca(2+)-permeable channels and causing sustained elevation of Cai with resultant neuronal dysfunction.
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PMID:Amyloid-beta proteins activate Ca(2+)-permeable channels through calcium-sensing receptors. 906 64

The amyloid beta protein (25-35) stimulated appearance of 3H-inositol phosphates from [3H]inositol-prelabeled LA-N-2 cells was investigated. This stimulation was unaltered by extra- and intracellular calcium chelators in a calcium-free medium or by several protein kinase inhibitors. This phospholipase C stimulation by amyloid beta protein appeared to be pertussis toxin sensitive. It is possible that this phospholipase C stimulation by amyloid beta protein is a receptor-mediated process. This possibility is based on two related observations. The stimulation is ablated by the presence of conventional antagonists for metabotropic, adrenergic, and bombesin agonists. The IC50 values were 12 microM for propranolol, 15 microM for AP-3, and 25 nM for [Tyr4,D-Phe12]bombesin. Additional support comes from results of desensitization and resensitization experiments. Amyloid beta protein stimulation of phospholipase C was absent from LA-N-2 cells previously treated with norepinephrine, trans-1-amino-1,3-cyclopentanedicarboxylic acid (t-ACPD), bombesin, or amyloid beta peptide. In a similar manner, LA-N-2 cells previously treated with amyloid beta protein were no longer responsive to norepinephrine, t-ACPD, or bombesin. The responsiveness to amyloid beta protein returned, subsequent to a period of resensitization for the individual agonists. It is suggested that this observed amyloid beta protein stimulation of phospholipase C may be responsible for the elevated quantity of inositol seen in the brains of Alzheimer's disease patients.
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PMID:Amyloid beta protein (25-35) stimulation of phospholipase C in LA-N-2 cells. 920 17


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