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)

Seizures induced by three convulsant treatments produced differential effects on the concentration of acetylcholine in rat brain. Status epilepticus induced by (i) coadministration of lithium and pilocarpine caused massive increases in the concentration of acetylcholine in the cerebral cortex and hippocampus, (ii) a high dose of pilocarpine did not cause an increase of acetylcholine, and (iii) kainate increased acetylcholine, but the magnitude was lower than with the lithium/pilocarpine model. The finding that the acetylcholine concentration increases in two models of status epilepticus in the cortex and hippocampus is in direct contrast with many in vitro reports in which excessive stimulation causes depletion of acetylcholine. The concentration of choline increased during seizures with all three models. This is likely to be due to calcium- and agonist-induced activation of phospholipase C and/or D activity causing cleavage of choline-containing lipids. The excessive acetylcholine present during status epilepticus induced by lithium and pilocarpine was responsive to pharmacological manipulation. Atropine tended to decrease acetylcholine, similar to its effects in controls. The N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801, reduced the excessive concentration of acetylcholine, especially in the cortex. Inhibition of choline uptake by hemicholinium-3 (HC-3) administered icv reduced the acetylcholine concentration in controls and when given to rats during status epilepticus. These results demonstrate that the rat brain concentrations of acetylcholine and choline can increase during status epilepticus. The accumulated acetylcholine was not in a static, inactive compartment, but was actively turning-over and was responsive to drug treatments. Excessive concentrations of acetylcholine and/or choline may play a role in seizure maintenance and in the neuronal damage and lethality associated with status epilepticus.
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PMID:Seizures increase acetylcholine and choline concentrations in rat brain regions. 181 38

Acetylcholine (ACh) is a powerful excitotoxic neurotransmitter in the brain. By stimulating Ca(2+)-mobilizing receptors, ACh, through G-protein(s), stimulates phospholipase C and causes the hydrolysis of a membrane phospholipid, phosphatidylinositol-4,5-bisphosphate to two second messengers, inositol-1,4,5-trisphosphate (ins-(1,4,5)-P3), and diacylglycerol. Ins-(1,4,5)-P3 is important in cholinergic neuronal stimulation, and injury. Cholinergic agonists cause tonic-clonic convulsions which may be either transient or persistent. Even short-term cholinergic convulsions may be associated with neuronal injury, especially in the basal forebrain and the hippocampus. Cholinergic-induced convulsions also elevate levels of brain Ca2+ which precede neuronal injury. Female sex and senescence increase the sensitivity of rats to cholinergic excitotoxicity. Even if cholinergic-induced brain phosphoinositide signalling is likely to trigger cholinergic excitotoxicity, several other processes may be involved in the ensuing neuronal injury. Once initiated, cholinergic convulsions cannot be stopped with cholinergic antagonists such as atropine even though they are effective when given prior to a cholinergic agonist. However, glutaminergic antagonists, and GABAergic agonists, are effective in the attenuation of ongoing cholinergic status epilepticus. Cholinergic brain stimulation may be, in fact, under a partial control of brain GABAergic tonus, but also cause the release of glutamate. Glutamate stimulates inositol lipid signalling in several neuronal cells and, therefore, underlines the significance of inositol lipid signalling in cholinergic-induced excitotoxicity. Moreover, the anatomical distribution of cholinergic brain damage correlates well with that of glutaminergic neurons. Furthermore, glutamate increases neuronal oxidative stress, i.e. it increases the levels of free intracellular calcium, the production of reactive oxygen species, and causes the depletion of neuronal glutathione. The role of excitatory amino acids as common mediators of cholinergic excitotoxicity may offer new insights into the neurotoxic consequences of cholinergic neuronal stimulation.
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PMID:Phosphoinositide second messengers in cholinergic excitotoxicity. 785 83

While it is generally accepted that phospholipase C (PLC) and protein kinase C (PKC) are down-stream proteins involved in metabotropic glutamate receptor 5 (mGluR5)-related signal transduction, we still do not know which subtype of PLC or PKC is specifically regulated after mGluR5 activation. In the present study in mGluR5 wild-type (mGluR5+/+) mice, we showed induced PKCbeta2 or PKCgamma expression at the border between the stratum oriens and alveus (O/A border) at 2h during pilocarpine induced status epilepticus (SE), and in the stratum pyramidale in CA1 area at 1 day after pilocarpine induced SE; at 1 day, induced expression of PLCbeta4 in the stratum pyramidale of CA1 area was observed. Furthermore, double labeling revealed the co-localization of induced PKCbeta2 or PKCgamma with mGluR5 or with induced PLCbeta4 in the stratum pyramidale of CA1 area. These induced expression, however, were not found in mGluR5 mutant (mGluR5-/-) mice. It suggests that induced PLCbeta4-PKCbeta2/PKCgamma at 1 day after pilocarpine induced SE in pyramidal neurons or PKCbeta2 or PKCgamma in interneurons at O/A border at 2h during pilocarpine induced SE may be specifically linked to the activation of mGluR5. When compared to mGluR5+/+ mice, significant shorter latency (from pilocarpine injection to the occurrence of status epilepticus) and maintenance period (from beginning to the end of status epilepticus) for status epilepticus in mGluR5-/- mice were also demonstrated. It is possible that mGluR5 may play a negative role in initiation of status epilepticus by interacting with muscarinic acetylcholine receptor in mGluR5+/+ mice.
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PMID:mGluR5-PLCbeta4-PKCbeta2/PKCgamma pathways in hippocampal CA1 pyramidal neurons in pilocarpine model of status epilepticus in mGluR5+/+ mice. 1877 62

Prostaglandin E2 (PGE2) regulates membrane excitability, synaptic transmission, plasticity, and neuronal survival. The consequences of PGE2 release following seizures has been the subject of much study. Here we demonstrate that the prostaglandin E2 receptor 1 (EP1, or Ptger1) modulates native kainate receptors, a family of ionotropic glutamate receptors widely expressed throughout the central nervous system. Global ablation of the EP1 gene in mice (EP1-KO) had no effect on seizure threshold after kainate injection but reduced the likelihood to enter status epilepticus. EP1-KO mice that did experience typical status epilepticus had reduced hippocampal neurodegeneration and a blunted inflammatory response. Further studies with native prostanoid and kainate receptors in cultured cortical neurons, as well as with recombinant prostanoid and kainate receptors expressed in Xenopus oocytes, demonstrated that EP1 receptor activation potentiates heteromeric but not homomeric kainate receptors via a second messenger cascade involving phospholipase C, calcium and protein kinase C. Three critical GluK5 C-terminal serines underlie the potentiation of the GluK2/GluK5 receptor by EP1 activation. Taken together, these results indicate that EP1 receptor activation during seizures, through a protein kinase C pathway, increases the probability of kainic acid induced status epilepticus, and independently promotes hippocampal neurodegeneration and a broad inflammatory response.
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PMID:The prostaglandin EP1 receptor potentiates kainate receptor activation via a protein kinase C pathway and exacerbates status epilepticus. 2495 62