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 clinical efficacy of dopamine (DA) replacement therapy for patients with Parkinson's disease (PD) depends on the preservation of postsynaptic DA receptors and their intracellular signalling mechanisms in the striatum long after degeneration of the nigrostriatal DA pathway. DA activates adenylyl cyclase (AC) and phospholipase C (PLC) via the D1 receptor, and inhibits through the D2 receptor, thereby regulating the production of intracellular second messengers, cyclic adenosine 3',5'-monophosphate (cAMP), 1,2-diacylglycerol (DAG) and Ca2+. Recent advances in molecular biology have made it possible to monitor the intracellular signal transduction cascade following receptor activation by various transmitters. The authors review the literature addressing this issue, summarized as follows: (1) striatal D1 and D2 receptor densities remain constant, at least in treated and non-demented patients; (2) DA-sensitive AC activity appears to be increased in the putamen of treated patients, although this remains to be confirmed; (3) levels of cAMP-dependent protein kinase (PKA) are normal in non-demented patients, consistent with unchanged levels of DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of M(r) 32,000); (4) levels of Ca2+/phospholipid-dependent protein kinase (PKC) and of inositol 1,4,5-trisphosphate (InsP3) receptor also remain unchanged in non-demented patients; (5) the above three second messenger sites as well as densities of D1 and D2 receptors are decreased in the striatum of demented PD patients (PDD). We tentatively conclude that postreceptor signalling function is intact in the striatum of non-demented PD patients and that there is a clear difference between non-demented patients and PDD, i.e. striatal dopaminoceptive neurons are affected in PDD.
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PMID:Transmembrane signalling systems in the brain of patients with Parkinson's disease. 795 88

Phosphatidylinositol 4-kinase (PI 4-kinase) and phosphatidylinositol 4-phosphate kinase (PIP kinase) were assayed in membranes prepared from samples of human frontal cortex initially frozen at autopsy. PI 4-kinase activity was significantly lower in Alzheimer's disease patients relative to age-matched controls or patients with Parkinson's disease. PIP kinase was not different in Alzheimer's versus age-matched controls. The beta amyloid protein fragment 1-40 inhibited PI 4-kinase activity in assays of control human or rat cortical membranes. Fragments 1-28 and 25-35 could not mimic the effects of fragment 1-40 while a reverse peptide 40-1 was equipotent. The inhibition of PI 4-kinase by fragment 1-40 was competitive with substrate. The beta amyloid protein fragments had diverse effects on phosphoinositide-specific phospholipase C (PI-PLC) as assayed in rat cortical membranes. Low concentrations of fragment 1-40 stimulated, while high concentrations of 1-40 or 40-1 inhibited PI-PLC activity. Fragment 25-35 stimulated PI-PLC nearly 3-fold, while fragment 1-28 had only minor effects on the enzyme. The results suggest alterations in phosphoinositide metabolism in Alzheimer's disease which could affect signal transduction and/or cytoskeletal organization.
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PMID:Effects of Alzheimer's disease-related beta amyloid protein fragments on enzymes metabolizing phosphoinositides in brain. 798 26

We have previously demonstrated that an antibody to phosphoinositide-specific phospholipase C (PLC) isozyme, PLC-delta, intensely stained neurofibrillary tangles (NFT) in the brain tissue of Alzheimer's disease (AD). This study was performed to determine if abnormal PLC-delta accumulation might be present in the filamentous inclusions of other neurodegenerative diseases. We found that the anti-PLC-delta antibody stained neuronal inclusions of Pick's disease, progressive supranuclear palsy and diffuse Lewy body disease while the inclusions of idiopathic Parkinson's disease lacked PLC-delta accumulation. These results suggest a possible role for PLC-delta interaction in the formation of intraneuronal filamentous inclusions in human neurodegenerative diseases.
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PMID:Abnormal accumulation of phospholipase C-delta in filamentous inclusions of human neurodegenerative diseases. 812 25

Stimulation of phosphoinositide-specific phospholipase C (PLC) by carbachol, dopamine and serotonin was measured by supplying exogenous [3H]phosphatidylinositol 4,5-bisphosphate to membranes prepared from human cortex dissected and frozen at autopsy. Subjects with Alzheimer's disease, Parkinson's disease or schizophrenia were compared to age-matched controls with no known neurological disorders. Stimulation of PLC by the neurotransmitters was dependent on the presence of GTP gamma S. Carbachol elicited the greatest stimulations of PLC followed by serotonin and then dopamine. The maximal stimulations of PLC evoked by a neurotransmitter were similar for the various categories of subjects except in Parkinson's patients, where dopamine failed to stimulate PLC beyond the activity attained with carbachol. In the presence of carbachol, the sensitivity of PLC to GTP gamma S was significantly increased in Alzheimer's membranes, but not in age-matched controls or Parkinson's. Overall, the experiments demonstrate the feasibility for using the exogenous substrate assay to study the functionality of the phosphoinositide transmembrane signaling system in human brain.
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PMID:Transmembrane signaling through phospholipase C in human cortical membranes. 838 29

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

Tissue transglutaminase (tTG) belongs to the family of transglutaminase enzymes that catalyze the posttranslational modification of proteins via Ca(2+)-dependent cross-linking reactions. The catalytic action of tTG results in the formation of an isopeptide bond that is of great physiological significance since it is highly resistant to proteolysis and denaturants. Although tTG-mediated cross-linking reactions have been implicated to play a role in diverse biological processes, the precise physiological function of the enzyme remains unclear. Recent data, however, suggest that the protein polymers resulting from tTG-catalyzed reactions may play a role in commitment of cells to undergo apoptosis. On the same token, tTG-mediated formation of insoluble protein aggregates may underlie the markers of numerous pathological conditions, such as the senile plaques in Alzheimer's disease and the Lewy bodies in Parkinson's disease. In addition to catalyzing Ca(2+)-dependent cross-linking reactions, tTG can also bind and hydrolyze guanosine triphosphate and adenosine triphosphate. By virtue of this ability, tTG has been identified as a novel G-protein that interacts and activates phospholipase C following stimulation of the alpha-adrenergic receptor. The ability of tTG to mediate signal transduction may contribute to its involvement in the regulation of cell cycle progression. The following review summarizes the important features of this multifunctional enzyme that have emerged as a result of recent work from different laboratories.
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PMID:Tissue transglutaminase: an enzyme with a split personality. 1048 Dec 69

Cellular metabolism of dopamine (DA) generates H2O2, which is further reduced to hydroxyl radicals in the presence of iron. Cellular damage inflicted by DA-derived hydroxyl radicals is thought to contribute to Parkinson's disease. We have previously developed procedures for detecting proteins that contain H2O2-sensitive cysteine (or selenocysteine) residues. Using these procedures, we identified ERP72 and ERP60, two members of the protein disulfide isomerase family, creatine kinase, glyceraldehyde-3-phosphate dehydrogenase, phospholipase C-gamma1, and thioredoxin reductase as the targets of DA-derived H2O2. Experiments with purified enzymes identified the essential Cys residues of creatine kinase and glyceraldehyde-3-phosphate dehydrogenase, that are specifically oxidized by H2O2. Although the identified proteins represent only a fraction of the targets of DA-derived H2O2, functional impairment of these proteins has previously been associated with cell death. The oxidation of proteins that contain reactive Cys residues by DA-derived H2O2 is therefore proposed both to be largely responsible for DA-induced apoptosis in neuronal cells and to play an important role in the pathogenesis of Parkinson's disease.
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PMID:Oxidation of proteinaceous cysteine residues by dopamine-derived H2O2 in PC12 cells. 1179 2

Highly reactive transition metals, such as copper and iron play an obligatory role in generating of reactive oxygen species (ROS). Many neurodegenerative diseases including Alzheimer's disease (AD) and Parkinson's disease (PD) show increased accumulation of these metals. Phosphoinositide metabolism is altered in neurodegenerative diseases. In the present study, we examined the effect of CuSO(4) and FeCl(2) on phospholipase C (PLC) activity degrading phosphatidylinositol-4,5-bisphosphate (PIP(2)) and phosphatidylinositol (PI) in synaptic plasma membranes (SPM) from the rat brain cortex. We report that 25 microM CuSO(4) and FeCl(2) decreased PIP(2)-PLC activity by 60% and 75%, respectively. However, both compounds had no effect on PI-PLC activity. These data indicated that exclusively PIP(2)-PLC is sensitive to transition metal ions. We suggest that chelators of these metals may protect brain against alteration of phosphoinositide metabolism and might be beneficial in the treatment of neurodegenerative diseases.
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PMID:Transition metal ions significantly decrease phospholipase C activity degrading phosphatidylinositol-4,5-bisphosphate in the brain cortex. 1470 87

Acetylcholine, acting through muscarinic receptors, modulates the excitability of striatal medium spiny neurones. However, the underlying membrane conductances and intracellular signalling pathways have not been fully determined. Our aim was to characterize excitatory effects mediated by M1 muscarinic acetylcholine receptors in these neurones using whole-cell patch-clamp recordings in brain slices of postnatal rats. Under voltage-clamp, muscarine evoked an inward current associated with an increase in cell membrane resistance. The current, which reversed at -85 mV, was sensitive to the M1 receptor antagonist pirenzepine. Blocking the potassium conductance attenuated the response and the residual current was further reduced by ruthenium red (50 microm) and reversed at +15 mV. Simultaneous recordings from cholinergic interneurones and medium spiny neurones in conjunction with spike-triggered averaging revealed small unitary excitatory postsynaptic currents in four of 39 cell pairs tested. The muscarine-induced inward current was attenuated by a phospholipase C (PLC) inhibitor, U73122, but not by a protein kinase C inhibitor, chelerythrine, or by the intracellular calcium chelator 1,2-bis(2-aminophenoxy) ethane-N,N,N',N'-tetra-acetic acid, suggesting that the current was associated with PLC in a protein kinase C- and Ca2+ -independent manner. The phosphatidylinositol 4-kinase inhibitor wortmannin (10 microm) reduced the recovery of the inward current, indicating that the recovery process was dependent on the removal of diacylglycerol and/or inositol 1,4,5 triphosphate or resynthesis of phospholipid phosphatidylinositol 4,5-bisphophate. Ratiometric measurement of intracellular calcium after cell loading with fura-2 demonstrated a muscarine-induced increase in calcium signal that originated mainly from intracellular stores. Thus, the cholinergic excitatory effect in striatal medium spiny neurones, which is important in motor disorders associated with altered cholinergic transmission in the striatum such as Parkinson's disease, is mediated through M1 receptors and the PLC-dependent pathway.
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PMID:Effects of muscarinic acetylcholine receptor activation on membrane currents and intracellular messengers in medium spiny neurones of the rat striatum. 1534 94


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