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)

The mechanism by which cicletanine (3-(4-chlorophenyl)-1,3-dihydro-7-hydroxy-6-methylfuro-[3,4-c]pyri dine) induces vasodilatation was examined in isolated vascular smooth muscle. Cicletanine inhibited the contraction induced by high K+, norepinephrine (NE) and prostaglandin F2alpha in a concentration-dependent manner in rat aorta. High K+ (15.8-72.7 mM) elicited elevation of cytosolic Ca2+ level ([Ca2+]i) and contraction in a concentration-dependent manner. Cicletanine (300 microM) inhibited the high K+-induced contractions without changing the [Ca2+]i/tension relationship. NE (3-300 nM) elicited greater contractions than high K+ at a given [Ca2+]i, suggesting that NE increased Ca2+ sensitivity of the contractile elements. Cicletanine inhibited the NE-induced contractions without changing the slope of the [Ca2+]i/tension relationship. Cicletanine inhibited the transient increases in both [Ca2+]i and muscle tension elicited by NE but not the transient increase in [Ca2+]i elicited by caffeine in Ca2+-free solution. Cicletanine did not inhibit contraction induced by Ca2+ in the permeabilized rabbit mesenteric artery with alpha-toxin. These results suggest that cicletanine inhibits vascular smooth muscle contraction by multiple mechanisms: 1) inhibition of Ca2+ influx via voltage-dependent Ca2+ channel and 2) inhibition of Ca2+ release mediated by the alpha-adrenoceptors, but not by caffeine.
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PMID:Cicletanine-induced decreases in cytosolic Ca2+ level and contraction in vascular smooth muscle. 951 5

Pituitary adenylate cyclase-activating polypeptide (PACAP) causes both Ca2+ release and Ca2+ influx in bovine adrenal chromaffin cells. To elucidate the mechanisms of PACAP-induced Ca2+ release, we investigated expression of PACAP receptors and measured inositol trisphosphates (IP3), cyclic AMP, and the intracellular Ca2+ concentration in bovine adrenal medullary cells maintained in primary culture. RT-PCR analysis revealed that bovine adrenal medullary cells express the PACAP receptor hop, which is known to couple with both IP3 and cyclic AMP pathways. The two naturally occurring forms of PACAP, PACAP38 and PACAP27, both increased cyclic AMP and IP3, and PACAP38 was more potent than PACAP27 in both effects. Despite the effects of PACAP on IP3 production, the Ca2+ release induced by PA-CAP38 or by PACAP27 was unaffected by cinnarizine, a blocker of IP3 channels. The potencies of the peptides to cause Ca2+ release in the presence of cinnarizine were similar. The Ca2+ release induced by PACAP38 or by PACAP27 was strongly inhibited by ryanodine and caffeine. In the presence of ryanodine and caffeine, PACAP38 was more potent than PACAP27. PACAP-induced Ca2+ release was unaffected by Rp-adenosine 3',5'-cyclic monophosphothioate, an inhibitor of protein kinase A. Ca2+ release induced by bradykinin and angiotensin II was also inhibited by ryanodine and caffeine, but unaffected by cinnarizine. Although IP3 production stimulated by PACAP38 or bradykinin was abolished by the phospholipase C inhibitor, U-73122, Ca2+ release in response to the peptides was unaffected by U-73122. These results suggest that PACAP induces Ca2+ release from ryanodine/caffeine stores through a novel intracellular mechanism independent of both IP3 and cyclic AMP and that the mechanism may be the common pathway through which peptides release Ca2+ in adrenal chromaffin cells.
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PMID:Pituitary adenylate cyclase-activating polypeptide causes Ca2+ release from ryanodine/caffeine stores through a novel pathway independent of both inositol trisphosphates and cyclic AMP in bovine adrenal medullary cells. 952 83

Recent work has indicated that there is a major difference in the Ca2+ store of smooth muscle from rat and guinea-pig ureter; with the rat store being agonist-sensitive but ryanodine insensitive and the guinea-pig store being ryanodine sensitive but agonist insensitive [Th. V. Burdyga, M.J. Taggart, S. Wray, J. Physiol. 489 (1995) 327-335]. We have therefore examined directly the mechanism of Ca2+ release from the internal Ca2+ store (SR). Following permeabilisation with alpha-toxin or beta-escin the SR was Ca(2+)-loaded before application of carbachol or caffeine. Only carbachol evoked a transient contraction in rat ureter. The carbachol-induced contraction was blocked by heparin and cyclopiazonic acid (CPA) but not ryanodine. Only caffeine produced contraction in guinea-pig ureter, and this was blocked by ryanodine. Direct application of IP3 caused a small transient contraction in rat but not guinea-pig ureter. We conclude that rat ureter possesses only an IP3 sensitive store while guinea-pig ureter only has a ryanodine sensitive store.
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PMID:The mechanism of Ca2+ release from the SR of permeabilised guinea-pig and rat ureteric smooth muscle. 955 Oct 92

Changes in contractile force were measured during isometric contraction of the bovine middle cerebral artery caused by stimulation of various receptors and by application of high K+, caffeine, and protein kinase C (PKC)-activators. The protein tyrosine kinase (PTK)-inhibitors, such as genistein and tyrphostin, were applied before testing the effect on the contractions or during the maximal plateau of the contraction. The contractions induced by serotonin, prostaglandin F2 alpha, endothelin-1, and thromboxane A2 were significantly and dose-dependently depressed by the PTK-inhibitors (IC50 2-15 microM). In contrast, contractions were significantly augmented by 1 microM pervanadate, an inhibitor of phosphoprotein tyrosine phosphatase. Lineweaver-Burk plotting of the dose-response curves with an increase in inhibitor concentration indicated that the receptor affinity for each agonist remained unchanged in spite of marked depression of the responses. Although the effect was not significant, contractions induced by both high K+ and caffeine were also depressed slightly by PTK-inhibitors in the same range of concentrations used for receptor-induced contractions. Contractions induced by PKC-activators, such as 1-oleoyl-2-acetyl-sn-glycerol and phorbol-12,13-diacetate, were significantly depressed by PTK-inhibitors at concentrations similar to those used for receptor-induced contractions. The results suggest that receptor stimulations which produce sequential activation of phospholipase C and PKC can activate PTK and trigger the so-called "PTK-cascade" causing a sustained or long-lasting contraction similar to the cerebral vasospasm observed clinically.
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PMID:Modulatory role of protein tyrosine kinase activation in the receptor-induced contractions of the bovine cerebral artery. 955 33

The characteristics of adenosine receptors found in glial fibrillary acid protein (GFAP)-positive astrocytes acutely isolated from the cerebral cortices of 4- to 12-day old rats were examined by evaluating the effects of adenosine and its analogues on intracellular calcium levels. First, these effects were compared with those seen in primary astrocytic cultures, and it was found that acutely isolated astrocytes showed much greater sensitivity to adenosine than their cultured counterparts. Then, the adenosine evoked calcium responses in acutely isolated cells were evaluated under various conditions. The responses to adenosine were not inhibited by papaverine, an uptake blocker, or by removal of extracellular calcium. U73122, a phospholipase C inhibitor, was able to completely inhibit the adenosine response. The receptor inhibitor 3-isobutyl-1-methylxanthine inhibited the calcium response to adenosine, providing evidence that the response is not coupled to the xanthine-insensitive A3 receptor. The stimulatory action of NECA, a non-selective analogue, was blocked neither by the A2A-selective receptor antagonist 8-(3-chlorostyryl) caffeine nor by the A1-selective receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine. The A2B receptor antagonist alloxazine, however, was able to completely inhibit the increase in intracellular calcium produced by NECA. Taken together, these data suggest that the adenosine-evoked calcium response in acutely isolated astrocytes is coupled to the A2B receptor.
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PMID:Adenosine receptor mediated stimulation of intracellular calcium in acutely isolated astrocytes. 966 51

Measurement of the change in cell membrane capacitance (Cm) along with the change in IK(Ca) was used to investigate the effects of bradykinin and caffeine on the secretory process in rat adrenal chromaffin cells. In a Ca2+-free external solution, bradykinin (100 nM) caused a transient increase in Cm with a concurrent change in IK(Ca). Extracellular application of neomycin as an inhibitor of phospholipase C activity reversibly inhibited the bradykinin-activated event, implying an IP3-mediated increase of submembrane-free Ca2+. The increases in Cm and IK(Ca) caused by bradykinin were transient even with the sustained application of bradykinin. Caffeine also caused exocytosis in the Ca2+-free solution, and this was irreversibly blocked by ryanodine (1 microM) in a use-dependent manner. Caffeine-sensitive intracellular Ca2+ stores were also depleted in several seconds and recovered by an influx of external Ca2+. The sequential application of bradykinin and caffeine showed that these are likely to activate Ca2+ release from the same or distinct but rapidly equilibrating intracellular Ca2+ stores. The single cell assay of exocytosis and the increase in IK(Ca) revealed cell-to-cell variability in bradykinin- and caffeine-induced exocytotic response. Our results suggest that Ca2+ release from intracellular stores potentially increases submembrane Ca2+ concentration and modulates simultaneously two submembrane Ca2+-dependent processes, exocytosis and IK(Ca), in rat adrenal chromaffin cells.
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PMID:Relation of exocytosis and Ca2+-activated K+ current during Ca2+ release from intracellular stores in individual rat chromaffin cells. 967 79

1. To examine the contributions of the putative Ca2+ releasers, inositol 1,4,5-trisphosphate (InsP3), cyclic ADP ribose (cADPR), and nicotinate adenine dinucleotide phosphate (NAADP), to carbachol (CCh)-induced contraction in airway smooth muscle, we measured force development of permeabilized rabbit tracheal smooth muscle, human bronchial smooth muscle and guinea-pig ileum longitudinal smooth muscle. 2. In the presence of 50 microM GTP, CCh and InsP3 contracted alpha-toxin-permeabilized tracheal smooth muscle dose dependently; the EC50 values for CCh and InsP3 were 1.84 microM and 363 microM, and the maximum responses (normalized to the 30 mM caffeine response) to 100 microM CCh and to 800 microM InsP3 were 206 +/- 13.4 % (mean +/- S.E.M.) and 84.4 +/- 5.3 %, respectively. 3. However, cADPR (10-300 microM), beta-NAD+ (2.5 mM), FK506 (30 microM) and NAADP (100 microM) neither contracted the strip by themselves nor affected the subsequent CCh (1 microM) response. alpha-Toxin-permeabilized bronchial smooth muscle and ileum smooth muscle also responded to caffeine, InsP3 and CCh but not to cADPR. 4. Both 100 microM 8-amino-cADPR, a selective cADPR antagonist, and 100 microM thionicotinamide-NADP, a selective NAADP antagonist, failed to inhibit the CCh response, although procaine abolished the caffeine, InsP3 and CCh responses in the permeabilized tracheal smooth muscle. 5. Although inhibition of the caffeine response by 30 microM ryanodine was nearly complete, approximately 30 % of the InsP3 (300 microM) plus GTP (50 microM) response was retained, and the resultant response disappeared after the caffeine response was evoked in the presence of ryanodine. 6. Heparin (300 microg ml-1) blocked InsP3 (300 microM) and CCh (3 microM) responses in beta-escin-permeabilized tracheal smooth muscle, while Ruthenium Red (100 microM) partially inhibited the CCh response. 7. Collectively, InsP3 but not cADPR or NAADP plays a key role in CCh-initiated contraction, and InsP3 utilizes a single compartment of the caffeine/ryanodine-sensitive stored Ca2+ in airway smooth muscle.
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PMID:InsP3, but not novel Ca2+ releasers, contributes to agonist-initiated contraction in rabbit airway smooth muscle. 971 70

Exposure of cardiac myocytes from adult rat ventricles to the highly selective, high affinity sigma receptor ligands 1S,2 R-cis-N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)-cycloh exylamine (BD-737) (0.1-100 nM) and N-[2-(3,4-dichlorophenyl)ethyl]-N,N',N'-trimethylethylenediamine (BD-1047) (0.01-10 nM), caused potentiation of electrically-evoked amplitudes of contraction and Ca2+ transients, while exposure to 100 nM BD-1047 caused attenuation of these amplitudes. In addition, BD-737 (1-100 nM) and BD-1047 (10-100 nM) caused an increase in the incidence of spontaneous twitches. These effects were inhibited when the incubation with BD-737 was done in the presence of the phospholipase C inhibitor, neomycin, or after pre-incubation with thapsigargin or caffeine which deplete the sarcoplasmic reticulum Ca2+ stores. Inositol 1,4,5-trisphosphate (IP3) production in cardiac myocytes was determined by the IP3 binding protein assay. Both substances caused an increase in the intracellular concentration of IP3. BD-737 caused a rapid transient increase to 3.2-fold in 1 min and stabilization at 2.1-fold of control thereafter. BD-1047 caused a gradual increase reaching 4.4-fold after 5 min. The results suggest that the effects of these sigma receptor ligands on contractility and spontaneous contractions are mediated by activation of phospholipase C and elevation of intracellular IP3 level.
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PMID:Highly selective sigma receptor ligands elevate inositol 1,4,5-trisphosphate production in rat cardiac myocytes. 972 62

Whole-cell patch clamp experiments were carried out in rat striatal brain slices. In a subset of striatal neurons (70-80%), NMDA-induced inward currents were inhibited by the adenosine A2A receptor selective agonist CGS 21680. The non-selective adenosine receptor antagonist 8-(p-sulphophenyl)-theophylline and the A2A receptor selective antagonist 8-(3-chlorostyryl)caffeine abolished the inhibitory action of CGS 21680. Intracellular GDP-beta-S, which is known to prevent G protein-mediated reactions, also eliminated the effect of CGS 21680. Extracellular dibutyryl cAMP, a membrane permeable analogue of cAMP, and intracellular Sp-cAMPS, an activator of cAMP-dependent protein kinases (PKA), both abolished the CGS 21680-induced inhibition. By contrast, Rp-cAMPS and PKI 14-24 amide, two inhibitors of PKA had no effect. Intracellular U-73122 (a phospholipase C inhibitor) and heparin (an inositoltriphosphate antagonist) prevented the effect of CGS 21680. Finally, a more efficient buffering of intracellular Ca2+ by a substitution of EGTA (11 mM) by BAPTA (5.5 mM) acted like U-73122 or heparin. Hence, A2A receptors appear to negatively modulate NMDA receptor channel conductance via the phospholipase C/inositoltriphosphate/Ca2+ pathway rather than the adenylate cyclase/PKA pathway.
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PMID:Adenosine A2A receptors inhibit the conductance of NMDA receptor channels in rat neostriatal neurons. 987 38

An unusual inward current which is slowly elicited in the Xenopus oocyte membrane during sustained depolarization is reportedly carried by Na+. It is thought that Na+ selective channels are in some way induced to become voltage-sensitive by the depolarization. Earlier studies report that the induction process involves a phospholipase C and a protein kinase C as well as calcium ions. The present work investigated the origins of this calcium in the oocyte. We show that injection of the powerful Ca2+ chelator (BAPTA) in the oocyte, before induction of the Na+ channels, prevented the appearance of the Na+ current, confirming an important role for [Ca2+]i. However, in oocytes perfused with Ca2+ -free medium, induction of the channels could still be obtained, indicating that induction did not depend upon the entry of external Ca2+. Downmodulation of Ca2+ release from inositol 1,4,5-trisphosphate (InsP3)-sensitive stores with caffeine and with a low molecular weight heparin resulted in decreased or no Na+ currents. The results are discussed in terms of the contributions from other endogenous calcium-dependent conductances which can influence the Na+ current amplitudes and time courses. The results presented support the idea that intracellular Ca2+ increase principally due to Ca2+ released from InsP3-sensitive stores is needed by the enzyme systems to produce the depolarization-induced activation of the Na+ conductance in the Xenopus oocyte.
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PMID:Induction of Na+ channel voltage sensitivity in Xenopus oocytes depends on Ca2+ mobilization. 1004 90


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