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)

Since it was suggested in our previous study that ATP newly synthesized from ADP and phosphocreatine (PCr) by creatine kinase had an important role in Ca2+-induced phasic contraction in alpha-toxin permeabilized smooth muscle of rat proximal colon, we studied the role of newly synthesized ATP on myosin ATPase activity, by assessing a rate of force development as an index of myosin ATPase activity. The alpha-toxin-permeabilized preparations were thiophosphorylated by treatment with ATPgammaS. After the thiophosphorylation, the contraction induced by ATP plus PCr in the absence of Ca2+ reached the maximum at 30 s. When PCr was omitted from the bathing solution, the initial rate of the contraction was significantly slower, while the level of myosin light chain thiophosphorylation remained unchanged. An inhibitor of creatine kinase slowed the initial contractile rate to a rate similar to that induced by ATP alone. ADPbetaS had no effect on ATP plus PCr-induced contraction, suggesting that accumulation of ADP does not affect the initial rate of the contraction. PCr alone did not contract the thiophosphorylated-preparations. However, in the presence of ADP, PCr induced contraction at the initial rate which was slower than that induced by ATP plus PCr. These results indicate that newly synthesized ATP together with preexisting ATP is utilized as a substrate for myosin ATPase.
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PMID:The site where newly synthesized ATP is necessary for tension development in alpha-toxin permeabilized preparations of rat proximal colon. 1271 56

The role of ATP newly synthesized from ADP and phosphocreatine (PC) by creatine kinase (CK) in the contraction of tonic type smooth muscle, rat femoral artery was studied, since its necessity for phasic type smooth muscle was previously shown. In alpha-toxin-permeabilized preparations obtained from rat femoral artery, Ca(2+) induced a tonic type contraction in the presence of ATP and PC. Omission of PC inhibited significantly the contraction. Treatment of the preparations with 2,4-dinitrofluorobenzene, an inhibitor of CK, also inhibited the contraction. In the presence of ADP and PC, Ca(2+) also induced the contraction to a level comparable to that in the presence of ATP and PC. The extent of phosphorylated myosin light chain was fairly consistent with that of Ca(2+)-induced contraction under all experimental conditions planned above. These results suggest that ATP newly synthesized by CK essentially participates in the whole of the contraction in tonic type smooth muscle, although it participates only in a rapid phasic contraction in phasic type muscle as previously shown.
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PMID:Essential role of ATP synthesized by creatine kinase in contraction of alpha-toxin permeabilized preparations of tonic type smooth muscle. 1293 22

Previously, we have described differences between the rat proximal colon and femoral artery with respect to the role of ATP newly synthesized by creatine kinase. In the present study the role of newly synthesized ATP was studied in the guinea-pig femoral artery to examine species differences. In the alpha-toxin-permeabilized preparation of the guinea-pig femoral artery, the rapid Ca(2+)-induced contraction was suppressed when creatine kinase activity was inhibited. The contraction was restored completely by treatment with NaN(3), an inhibitor of ecto-ATPase, the enzyme that breaks down exogenous ATP. Thus, ATP newly synthesized by creatine kinase may have no role in contraction of the guinea-pig femoral artery. This is in marked contrast to the rat femoral artery, in which Ca(2+)-induced contractions are almost completely inhibited by inhibition of creatine kinase activity but only partly restored by NaN(3). To characterize the difference between the guinea-pig and rat tissue, the origin of ATP required for contraction was determined in intact preparations. Monoiodoacetic acid, an inhibitor of glycolysis, inhibited the high K(+)-induced contraction in the guinea-pig femoral artery more potently than in the rat tissue. In contrast, an inhibitor of mitochondrial respiration, carbonylcyanide p-(trifluoromethoxy)phenylhydrazone (FCCP), inhibited contraction in femoral arteries from rats, but not from guinea-pigs. These results suggest that contraction in the rat femoral artery is dependent largely on oxidative phosphorylation, while contraction in the guinea-pig tissue is dependent only on glycolysis. Because oxidative phosphorylation generates ATP and phosphocreatine, while glycolysis generates only ATP, the strong dependence of the contraction of the rat femoral artery on the oxidative phosphorylation is consistent with its dependence on ATP newly synthesized by creatine kinase from ADP and phosphocreatine, as previously shown. Thus, it is proposed that ATP, newly synthesized by creatine kinase, in addition to ATP generated by oxidative phosphorylation, is utilized for contraction in the rat femoral artery, while glycolysis produces sufficient ATP for contraction in the guinea-pig femoral artery.
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PMID:Origin of ATP for Ca2+-induced contraction in the guinea-pig femoral artery. 1473 Apr 18

Although adenosine exerts cardio-and vasculoprotective effects, the roles and signaling mechanisms of different adenosine receptors in mediating skeletal muscle protection are not well understood. We used a mouse hindlimb ischemia-reperfusion model to delineate the function of three adenosine receptor subtypes. Adenosine A(3) receptor-selective agonist 2-chloro-N(6)-(3-iodobenzyl)adenosine-5'-N-methyluronamide (Cl-IBMECA; 0.07 mg/kg ip) reduced skeletal muscle injury with a significant decrease in both Evans blue dye staining (5.4 +/- 2.6%, n = 8 mice vs. vehicle-treated 28 +/- 6%, n = 7 mice, P < 0.05) and serum creatine kinase level (1,840 +/- 910 U/l, n = 13 vs. vehicle-treated 12,600 +/- 3,300 U/l, n = 14, P < 0.05), an effect that was selectively blocked by an A(3) receptor antagonist 3-ethyl-5-benzyl-2-methyl-6-phenyl-4-phenylethynyl-1,4-(+/-)-dihydropyridine-3,5-dicarboxylate (MRS-1191; 0.05 mg/kg). The adenosine A(1) receptor agonist 2-chloro-N(6)-cyclopentyladenosine (CCPA; 0.05 mg/kg) also exerted a cytoprotective effect, which was selectively blocked by the A(1) antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 0.2 mg/kg). The adenosine A(2A) receptor agonist 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS-21680; 0.07 mg/kg)-induced decrease in skeletal muscle injury was selectively blocked by the A(2A) antagonist 2-(2-furanyl)-7-[3-(4-methoxyphenyl)propyl]-7H-pyrazolo[4,3-e] [1,2,4]triazolo[1,5-C]pyrimidin-5-amine (SCH-442416; 0.017 mg/kg). The protection induced by the A(3) receptor was abrogated in phospholipase C-beta2/beta3 null mice, but the protection mediated by the A(1) or A(2A) receptor remained unaffected in these animals. The adenosine A(3) receptor is a novel cytoprotective receptor that signals selectively via phospholipase C-beta and represents a new target for ameliorating skeletal muscle injury.
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PMID:Protective roles of adenosine A1, A2A, and A3 receptors in skeletal muscle ischemia and reperfusion injury. 1792 28

Choline kinase in mice is encoded by two genes, Chka and Chkb. Disruption of murine Chka leads to embryonic lethality, whereas a spontaneously occurring genomic deletion in murine Chkb results in neonatal bone deformity and hindlimb muscular dystrophy. We have investigated the mechanism by which a lack of choline kinase beta, encoded by Chkb, causes hindlimb muscular dystrophy. The biosynthesis of phosphatidylcholine (PC) is impaired in the hindlimbs of Chkb -/- mice, with an accumulation of choline and decreased amount of phosphocholine. The activity of CTP: phosphocholine cytidylyltransferase is also decreased in the hindlimb muscle of mutant mice. Concomitantly, the activities of PC phospholipase C and phospholipase A2 are increased. The mitochondria in Chkb -/- mice are abnormally large and exhibit decreased inner membrane potential. Despite the muscular dystrophy in Chkb -/- mice, we observed increased expression of insulin like growth factor 1 and proliferating cell nuclear antigen. However, regeneration of hindlimb muscles of Chkb -/- mice was impaired when challenged with cardiotoxin. Injection of CDP-choline increased PC content of hindlimb muscle and decreased creatine kinase activity in plasma of Chkb -/- mice. We conclude that the hindlimb muscular dystrophy in Chkb -/- mice is due to attenuated PC biosynthesis and enhanced catabolism of PC.
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PMID:Understanding the muscular dystrophy caused by deletion of choline kinase beta in mice. 1923 39

Using an isolated non-working rat heart model, this study investigated the mechanisms of pharmacological pre-conditioning (PC) induced by P2Y receptor stimulation with pyridoxal-5'-phosphate (PLP). After 6-hydroxydopamine pretreatment and a 15-min stabilization period, isolated rat hearts were perfused for 25 min then subjected to 40 min of global ischemia and 30 min of reperfusion (I/R); exposed for 15 min to 0.05 microM PLP bracketed for 25 min with broad-spectrum P2 antagonists (suramin or PPADS) or with more specific P2Y antagonists (AMPalphaS or MRS2578), 1 microM each, followed by a 5-min PLP-free perfusion before I/R; treated during 25 min with either glybenclamide (GLY, 1 microM), 5-hydroxydecanoic acid (5-HD, 100 microM), U73122 (0.5 microM), H89 (1 microM), or KN93 (1 microM), with an infusion starting 5 min before PLP. The main endpoints were the rate-pressure product (RPP), creatine kinase (CK) release and area necrosis. Recovery of RPP, measured 5 min after reperfusion, was rapidly improved by PLP, blocked by the P2 antagonists, and decreased with the different inhibitors. Fifteen minutes after the end of ischemia, CK release reached maximal values in all groups. PLP provided significant protection, whereas the P2 antagonists, 5-HD, a mitochondrial selective K(ATP) antagonist and GLY a non-selective K(ATP) channel blocker, suppressed the protective effect on myocardial injury. The suppression of the cardioprotective effects of PLP by AMPalphaS, the PKA inhibitor (H89), and phospholipase C blocker (U73122) is in agreement with the P2Y11 receptor as a receptor for PLP-induced PC. The suppression of the cardioprotective effects of PLP by MRS2578 and U73122 is in agreement with the P2Y6 receptor as a receptor for PLP-induced PC. Pre-ischemic exposure to nanomolar concentrations of PLP is protective against I/R. P2Y11 and P2Y6 represents the most likely candidate receptors for PLP-induced cardiac PC.
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PMID:Involvement of P2Y receptors in pyridoxal-5'-phosphate-induced cardiac preconditioning. 1945 60

Regular alcohol consumption decreases the incidence of myocardial infarction (MI) and improves post-MI survival. It has previously been reported that chronic ethanol exposure induces long-term protection against cardiac ischemia/reperfusion injury, which improves myocardial recovery after MI. Chronic cardioprotection by ethanol requires the activation of myocyte adenosine A1 receptors and sustained intramyocyte translocation of epsilon protein kinase C. A1 receptors activate phospholipase C (PLC). In the present paper, the role of PLC in mediating ethanol's protective effect against ischemia/reperfusion injury is investigated. Isolated hearts from guinea pigs fed 2.5% ethanol in their water for four months were subjected to ischemia/reperfusion. Hearts from ethanol-treated animals showed improved recovery of left ventricular developed pressure compared with controls (61% versus 38% of baseline, respectively; P<0.05) and decreased necrosis, assessed by the release of creatine kinase (263+/-18 U/mL x g dry weight versus 360+/-24 U/mL x g dry weight, respectively; P<0.05). Ethanol protection was abolished by the PLC antagonist, U-73122 (50 nM). These findings suggest that PLC activation is required for ethanol cardioprotection against ischemia/reperfusion injury.
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PMID:Phospholipase C activation is required for cardioprotection by ethanol consumption. 1964 18

Effective therapy to reduce skeletal muscle injury associated with severe or eccentric exercise is needed. The purpose of this study was to determine whether adenosine receptor stimulation can mediate protection from eccentric exercise-induced muscle injury. Downhill treadmill exercise (-15 degrees ) was used to induce eccentric exercise-mediated skeletal muscle injury. Experiments were conducted in both normal wild-type (WT) mice and also in beta-sarcoglycan knockout dystrophic mice, animals that show an exaggerated muscle damage with the stress of exercise. In the vehicle-treated WT animals, eccentric exercise increased serum creatine kinase (CK) greater than 3-fold to 358.9 +/- 62.7 U/l (SE). This increase was totally abolished by stimulation of the A(3) receptor. In the dystrophic beta-sarcoglycan-null mice, eccentric exercise caused CK levels to reach 55,124 +/- 5,558 U/l. A(3) receptor stimulation in these animals reduced the CK response by nearly 50%. In the dystrophic mice at rest, 10% of the fibers were found to be damaged, as indicated by Evans blue dye staining. While this percentage was doubled after exercise, A(3) receptor stimulation eliminated this increase. Neither the A(1) receptor agonist 2-chloro-N(6)-cyclopentyladenosine (0.05 mg/kg) nor the A(2A) receptor agonist 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine (0.07 mg/kg) protected skeletal muscle from eccentric exercise injury in WT or dystrophic mice. The protective effect of adenosine A(3) receptor stimulation was absent in mice, in which genes for phospholipase C beta2/beta3 (PLCbeta2/beta3) and beta-sarcoglycan were deleted. The present study elucidates a new protective role of the A(3) receptor and PLCbeta2/beta3 and points to a potentially effective therapeutic strategy for eccentric exercise-induced skeletal muscle injury.
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PMID:Adenosine A(3) receptor stimulation induces protection of skeletal muscle from eccentric exercise-mediated injury. 2042 27


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