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)

The effects of global ischaemia and pentobarbital upon lipid metabolism were studied in the rat brain. Brain ischaemia was evoked by rat decapitation. Pentobarbital (60 mg/kg) was administered i.p. for 15 min prior to decapitation. The removed brains were incubated for 1, 5, 15 or 30 min at 37 degrees C and then quickly frozen in liquid nitrogen. After extraction of lipids from the brains, neutral lipid and phospholipid compositions were analysed by thin-layer and gas-liquid chromatography. The results demonstrated that free fatty acids (FFAs), either unsaturated or saturated, rapidly accumulated in the brain during the early period of ischaemia but attenuated significantly with pentobarbital pretreatment. Pentobarbital repressed the accumulations of stearate and arachidonate, with little effect on palmitate and oleate liberation. Diacylglycerols (DG) also were produced in the ischaemic brain, and their acyl chain composition was similar to that of liberated FFAs. However, the increase of DG was inhibited by pentobarbital anaesthesia. In particular, pentobarbital attenuated the formation of DG enriched in arachidonate and stearate. The fatty acyl composition of DG resembled that of phosphatidylinositol. These observations suggest that pentobarbital somehow may alter phospholipase C activity and influence inositol phospholipid breakdown during ischaemia, and this effect would be a membrane stabilizing action of pentobarbital.
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PMID:Attenuation by pentobarbital of free fatty acid and diacylglycerol liberation during global ischaemia in rat brain. 287 7

A murine corneal scratch model has been used extensively to study various aspects of the pathogenesis of Pseudomonas aeruginosa, a common etiologic agent of corneal infections. This model uses mild inhalation anesthetics which keep the animals immobile for a relatively short time and promote the interaction between the infecting organisms and the corneal wound. Under these circumstances, only a small number of P. aeruginosa isolates delivered at inocula of > 10(7) CFU are infectious. We determined that this model is useful for studying other P. aeruginosa strains given at lower doses if injectable anesthetics are administered prior to infection to keep the animals immobile for 15 to 30 min. Under these conditions, eight clinical isolates of P. aeruginosa tested at doses of 10(8) CFU per eye induced corneal perforation and/or phthisis in C3H/HeN mice. The 50% infective doses of several strains were between 3 x 10(2) and 1 x 10(5) CFU per mouse eye. When this modified anesthetic procedure was used to evaluate the roles of different P. aeruginosa virulence factors in eye infections, pathology was not observed when eyes were inoculated with 10(8) CFU of strains deficient in production of a complete lipopolysaccharide or the RpoN sigma factor. A strain with a point mutation in the fur gene, involved in production of iron-regulated factors, showed decreased virulence, while a mutant deficient in both hemolytic and nonhemolytic phospholipase C was fully virulent. By modifying the anesthesia procedure, the corneal scratch model allows rapid evaluations of the roles of P. aeruginosa virulence factors in corneal infections.
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PMID:Rapid and sensitive method for evaluating Pseudomonas aeruginosa virulence factors during corneal infections in mice. 764 83

We recently noted the association of carnitine palmitoyltransferase (CPT) activity with a 54 kDa microsomal protein [Murthy and Pande (1993) Mol. Cell Biochem. 122, 133-138] that, based on amino-acid-sequence identity, seemed to be the protein previously described as a 'glucose-regulated protein-58' (GRP58), phosphoinositide-specific phospholipase C, hormone-induced protein-70, endoplasmic-reticulum protein-61 (ERp61), protein disulphide-isomerase, thiol protease, a protein affected in halothane anaesthesia and one that affects renal-tubular functions and the transcriptional activation of the interferon-alpha inducible genes. To ascertain the catalytic identity of this protein unambiguously, we have expressed the corresponding cDNA transiently and stably in human kidney 293 cells as well as in HeLa cells. In each case we found that expression led to an increase in assayable and immunoreactive 54 kDa CPT activity, whereas the protein disulphide-isomerase activity was not increased. In vitro expression in a cell-free transcription and translation system led to the synthesis of a approximately 57 kDa (precursor) protein that was processed to a approximately 54 kDa (mature) protein when microsomes were present; in both these experiments again a large increase in CPT activity was seen. Thus the present data provide compelling evidence that the 54 kDa protein in question is a CPT isoenzyme. It remains to be seen now how the ability of this protein to interconvert acyl-CoA and acylcarnitine would relate to the diverse functions indicated for this protein in vivo.
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PMID:A stress-regulated protein, GRP58, a member of thioredoxin superfamily, is a carnitine palmitoyltransferase isoenzyme. 799 51

The cellular mechanisms underlying the clinical effects of volatile anaesthetics remain unknown, although the plasma membrane and its associated proteins are likely targets. One such protein is the enzyme phospholipase C (PLC), which catalyses the formation of the second messenger inositol(1,4,5)triphosphate [Ins(1,4,5)P3]. Using SH-SY5Y human neuroblastoma cells we have demonstrated that halothane (0.50, 0.75 and 1.00%) enhances basal Ins(1,4,5)P3 mass formation approximately 1.8-fold. Halothane also caused a dose-dependent enhancement of carbachol-stimulated biphasic Ins(1,4,5)P3 formation at both the peak (half-maximal stimulation, EC50 = 0.76%) and plateau (EC50 = 0.74%) phases. At 1%, halothane did not alter the affinity for carbachol at either the peak (IC50: air = 9.4 +/- 1.5, halothane = 12.7 +/- 1.0 microM) or plateau (EC50: air = 11.7 +/- 1.2, halothane = 11.6 +/- 1.0 microM) phase, but did increase the maximum Ins(1,4,5)P3 response at both phases (air vs halothane: peak, 79.9 +/- 0.5 vs 124.8 +/- 2.5; plateau, 33.2 +/- 0.5 vs 47.9 +/- 0.6 pmol/mg protein). Isoflurane (2%) also enhanced basal and carbachol-stimulated Ins(1,4,5)P3 formation 2-fold and 1.5-fold, respectively. In summary, clinically relevant doses of the volatile anaesthetics halothane and isoflurane enhance basal and carbachol-stimulated Ins(1,4,5)P3 formation. Thus, activation of PLC, and subsequent potential Ins(1,4,5)P3-mediated rises in intracellular calcium, could play a part in the cellular mechanisms of volatile agent-induced anaesthesia.
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PMID:Halothane and isoflurane enhance basal and carbachol-stimulated inositol(1,4,5)triphosphate formation in SH-SY5Y human neuroblastoma cells. 814 13

Anesthetics are believed to produce anesthesia through the reversible inhibition of synaptic transmission but how this is accomplished is unknown. Based on earlier studies of anesthetic-enzyme-phospholipid interaction, we surmised that anesthetics may inhibit synaptic transmission by increasing synaptic membrane lateral pressure thereby inhibiting phospholipid hydrolysis, membrane transduction and synaptic transmission. As a first approximation towards investigating this concept, we hypothesized that anesthetics modulate the rate of phospholipase C hydrolysis of a lipid monolayer through its effects on surface pressure. The relationship between the hydrolysis rate of a monolayer of dipalmitoylphosphatidylcholine [14C-choline] (DPPC) by phospholipase C (Plase C) and monolayer surface pressure (SP) as altered by either halothane, isoflurane, or by physical compression at 37 degrees C was studied. The decline in surface 14C-activity as the [14C]choline diffuses into the Krebs-Ringer bicarbonate buffer aqueous subphase is estimated as the rate of DPPC hydrolysis measured by the initial slope method. DPPC hydrolysis was about 300 cpm/min and constant between SP of 0 to 20 dynes/cm. Higher SP between 25 and 30 dyne/cm, whether induced by halothane, isoflurane or physical compression, increased the rate of hydrolysis by 5-fold to a peak rate of about 1600 cpm/min at 25-30 dynes/cm. At a SP above 32 dynes/cm, DPPC hydrolysis abruptly ceased. We conclude that anesthetics can reversibly inhibit synaptic transmission through their effects on synaptic membrane lateral pressure. We also speculate that membrane lateral pressure may be a highly sensitive means of controlling membrane function through alteration in membrane lipid composition, membrane enzyme activity, receptor affinity and ion channel permeability.
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PMID:Anesthetics modulate phospholipase C hydrolysis of monolayer phospholipids by surface pressure. 895 53

5-Hydroxytryptamine type 2A receptors (5-HT2A) are G protein-coupled receptors that increase intracellular Ca2+ concentrations via activation of phospholipase C-beta and elevation of myo-inositol-1,4,5-triphosphate levels. In the central nervous system, these receptors are involved in regulating sleep and alertness. We now report that ethanol inhibited (IC50 = 41 mM) 5-HT2A receptor-induced Ca2+-dependent Cl- currents in Xenopus laevis oocytes. Pharmacologically relevant concentrations of other n-alcohols (propanol to octanol) also inhibited 5-HT responses; however, longer-chain alcohols (decanol, undecanol and dodecanol) had little or no effect. The protein kinase C inhibitor GF109203X and the nonspecific protein kinase inhibitor staurosporine abolished the inhibitory effects of ethanol and octanol on 5-HT2A receptors. GF109203X enhanced 5-HT2A receptor function when administered alone. In addition, the volatile anesthetics halothane and 1-chloro-1,2,2-trifluorocyclobutane decreased 5-HT2A responses in a concentration-dependent manner. The inhibitory effects of the volatile anesthetics were also attenuated in oocytes treated with GF109203X. The intravenous anesthetics propofol, ketamine, pentobarbital and etomidate did not affect 5-HT2A receptor function. The modulation of 5-HT2A receptor-dependent current was also investigated using two novel halogenated compounds that do not produce anesthesia. The nonanesthetic compound 2,3-chloro-octafluorobutane had no effects on 5-HT-induced currents; however, the nonanesthetic compound 1,2-dichlorohexafluorocyclobutane had an inhibitory effect at lower concentrations than the predicted anesthetic concentration. Thus, 5-HT2A receptors are inhibited by alcohols and volatile anesthetics, and these actions are dependent on protein kinase C.
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PMID:Inhibition of 5-hydroxytryptamine type 2A receptor-induced currents by n-alcohols and anesthetics. 919 Aug 46

Rhythmic oscillatory activities at the theta frequency (4-12 Hz) in the hippocampus have long-attracted attention because they have been implicated in diverse brain functions, including spatial cognition. Although studies based on pharmacology and lesion experiments suggested heterogeneity of these rhythms and their behavioral correlates, controversies are abundant on these issues. Here we show that mice harboring a phospholipase C (PLC)-beta1(-/-) mutation (PLC-beta1(-/-) mice) lack one subset of theta rhythms normally observed during urethane anesthesia, alert immobility, and passive whole-body rotation. In contrast, the other subset of theta rhythms observed during walking or running was intact in these mutant mice. PLC-beta1(-/-) mice also have somewhat disrupted theta activity during paradoxical sleep but do have an atropine-resistant component of theta rhythm. In addition, carbachol-induced oscillations were obliterated in hippocampal slices of PLC-beta1(-/-) mice. Interestingly, PLC-beta1(-/-) mice showed deficits in a hidden platform version of the Morris water maze yet performed well in motor coordination tests and a visual platform version of the Morris water maze. The results genetically define the existence of at least two subtypes of theta rhythms and reveal their association with different behaviors.
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PMID:Genetic dissection of theta rhythm heterogeneity in mice. 1633 Jul 75

Arteries that develop vasospasm after subarachnoid hemorrhage (SAH) may have altered contractility and compliance. Whether these changes are due to alterations in the smooth muscle cells or the arterial wall extracellular matrix is unknown. This study elucidated the location of such changes and determined the calcium sensitivity of vasospastic arteries. Dogs were placed under general anesthesia and underwent creation of SAH using the double-hemorrhage model. Vasospasm was assessed by angiography performed before and 4, 7, or 21 days after SAH. Basilar arteries were excised from SAH or control dogs (n = 8-52 arterial rings from 2-9 dogs per measurement) and studied under isometric tension in vitro before and after permeabilization of smooth muscle with alpha-toxin. Endothelium was removed from all arteries. Vasospastic arteries demonstrated significantly reduced contractility to KCl with a shift in the EC(50) toward reduced sensitivity to KCl 4 and 7 days after SAH (P < 0.05, ANOVA). There was reduced compliance that persisted after permeabilization (P < 0.05, ANOVA). Calcium sensitivity was decreased during vasospasm 4 and 7 days after SAH, as assessed in permeabilized arteries and in those contracted with BAY K 8644 in the presence of different concentrations of extracellular calcium (P < 0.05, ANOVA). Depolymerization of actin with cytochalasin D abolished contractions to KCl but failed to alter arterial compliance. In conclusion, it is shown for the first time that calcium sensitivity is decreased during vasospasm after SAH in dogs, suggesting that other mechanisms are involved in maintaining the contraction. Reduced compliance seems to be due to an alteration in the arterial wall extracellullar matrix rather than the smooth muscle cells themselves because it cannot be alleviated by depolymerization of smooth muscle actin.
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PMID:Calcium sensitivity of vasospastic basilar artery after experimental subarachnoid hemorrhage. 1639 68

The emerging literature implicates a role for glia/cytokines in persistent pain. However, the mechanisms by which these non-neural elements contribute to CNS activity-dependent plasticity and pain are unclear. Using a trigeminal model of inflammatory hyperalgesia, here we provide evidence that demonstrates a mechanism by which glia interact with neurons, leading to activity-dependent plasticity and hyperalgesia. In response to masseter inflammation, there was an upregulation of glial fibrillary acidic proteins (GFAPs), a marker of astroglia, and interleukin-1beta (IL-1beta), a prototype proinflammatory cytokine, in the region of the trigeminal nucleus specifically related to the processing of deep orofacial input. The activated astroglia exhibited hypertrophy and an increased level of connexin 43, an astroglial gap junction protein. The upregulated IL-1beta was selectively localized to astrocytes but not to microglia and neurons. Local anesthesia of the masseter nerve prevented the increase in GFAP and IL-1beta after inflammation, and substance P, a prototype neurotransmitter of primary afferents, induced similar increases in GFAP and IL-1beta, which was blocked by a nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester. Injection of IL-1 receptor antagonist and fluorocitrate, a glial inhibitor, attenuated hyperalgesia and NMDA receptor phosphorylation after inflammation. In vitro application of IL-1beta induced NR1 phosphorylation, which was blocked by an IL-1 receptor antagonist, a PKC inhibitor (chelerythrine), an IP3 receptor inhibitor (2-aminoethoxydiphenylborate), and inhibitors of phospholipase C [1-[6-((17b-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl]-1H-pyrrole-2,5-dione] and phospholipase A2 (arachidonyltrifluoromethyl ketone). These findings provide evidence of astroglial activation by tissue injury, concomitant IL-1beta induction, and the coupling of NMDA receptor phosphorylation through IL-1 receptor signaling.
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PMID:Glial-cytokine-neuronal interactions underlying the mechanisms of persistent pain. 1753 72

Leptin, acting as a measure of metabolic fuel availability, exerts a powerful permissive influence on neurogenic thermogenesis. During starvation and an absence of leptin, animals cannot produce thermogenic reactions to cold stress. However, thermogenesis is rescued by restoring leptin. We have previously observed (Hermann, G.E., Barnes, M.J., Rogers, R.C., 2006. Leptin and thyrotropin-releasing hormone: cooperative action in the hindbrain to activate brown adipose thermogenesis. Brain Res. 1117, 118-124.) a highly cooperative interaction between leptin and thyrotropin-releasing hormone [TRH] to activate hindbrain generated thermogenic responses. Specifically, exposure to both leptin and TRH elicited a 3.5 degrees C increase in brown adipose tissue [BAT] thermogenesis, while leptin alone did not evoke any change, and TRH alone caused only approximately 1 degrees C increase. The present study shows that the leptin-TRH synergy in controlling brown adipose [BAT] thermogenesis is order-specific and dependent on the feeding status of the animal. That is, fourth ventricular [4V] application of leptin to the food-deprived animal, before TRH injection, yields a substantial increase in BAT; while the reverse order yields a significantly smaller effect. If the animal were fed within minutes of anesthesia, then exogenous leptin was not necessary for TRH to yield a large increase in BAT temperature. The leptin-TRH synergy was uncoupled by pretreatment with the phosphoinositol-tris phosphate kinase [PI3K] inhibitor, wortmannin and the Src-SH2 antagonist, PP2. The TRH transduction mechanism utilizes phospholipase C [PLC] potently regulated by the SH2 site. Previous work in culture systems suggests that the product of PI3K activity [PIP3] potently upregulates PLC by activating the SH2 domain of the PLC complex. Perhaps leptin "gates" the thermogenic action of TRH in the hindbrain by invoking this same mechanism.
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PMID:Leptin "gates" thermogenic action of thyrotropin-releasing hormone in the hindbrain. 1964 94


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