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)

1. The adenosine receptor in mouse pinealocytes was identified and characterized using pharmacological and physiological approaches. 2. Expression of the two adenosine receptor subtypes A2B and A3 was detected in mouse pineal glands and PGT-beta cells by polymerase chain reaction and nucleotide sequencing. 3. Adenosine and 5'-N-ethylcarboxamidoadenosine (NECA) evoked cyclic AMP generation but the A2)-selective agonist 2-(4-(2-carboxyethyl)phenylethylamino)adenosine-5'-N-ethylcarboxamideadenosine (CGS 21680) and the A1-specific agonists R-N(6)-(2-phenylisopropyl)adenosine (R-PIA) and N(6)-cyclopentyladenosine (CPA) had little effect on intracellular cyclic AMP levels. The A2B receptor selective antagonists alloxazine and enprofylline completely blocked NECA-mediated cyclic AMP accumulation. 4. Treatment of cells with the A3-selective agonist N(6)-(3-iodobenzyl)-5'-(N-methylcarbamoyl)adenosine (IB-MECA) inhibited the elevation of the cyclic AMP level induced by NECA or isoproterenol in a concentration-dependent manner with maximal inhibition of 40 - 50%. These responses were blocked by the specific A3 adenosine receptor antagonist MRS 1191. Pretreatment of the cells with pertussis toxin attenuated the IB-MECA-induced responses, suggesting that this effect occurred via the pertussis toxin-sensitive inhibitory G proteins. 5. IB-MECA also caused a concentration-dependent elevation in [Ca(2+)]i and IP3 content. Both the responses induced by IB-MECA were attenuated by treatment with U73122 or phorbol 12-myristate 13-acetate. 6. These data suggest the presence of both A2B and A3 adenosine receptors in mouse pineal tumour cells and that the A2B receptor is positively coupled to adenylyl cyclase whereas the A3 receptor is negatively coupled to adenylyl cyclase and also coupled to phospholipase C.
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PMID:Pharmacological characterization of adenosine receptors in PGT-beta mouse pineal gland tumour cells. 1152 5

Adenosine exerts a potent cardioprotective effect that is mediated by adenosine A1 and A3 receptors. The signaling pathways activated by the A1 and A3 receptors are distinct and involve selective coupling to phospholipases C and D, respectively. The objective of our study was to elucidate the signaling mechanism that mediates the coupling of each receptor to its respective phospholipase and to test the role of RhoA as a novel mediator leading from adenosine receptors to cardioprotection. C3 transferase and dominant negative RhoA (RhoAT19N) blocked the A3 receptor-mediated phospholipase D activation and cardioprotection but had no effect on A1 receptor-mediated phospholipase C activation or cardioprotection. In contrast, pertussis toxin treatment caused a greater inhibition of the diacylglycerol accumulation induced by the A1 agonist than by the A3 agonist, and it completely abrogated the A1 agonist-mediated cardioprotection. Thus, adenosine A1 and A3 receptors are linked to different G-proteins. The A3 receptor is coupled via RhoA to activate phospholipase D in exerting its cardioprotective effect, whereas the A1 receptor is linked via Gi to phospholipase C to produce cardioprotective responses. The present study identifies a novel role for RhoA and further suggests its importance in regulating cardiac cellular function.
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PMID:A novel cardioprotective role of RhoA: new signaling mechanism for adenosine. 1153 68

tk;1Adenosine plays a role in the control of water and electrolyte reabsorption in the distal tubule. As the distal convoluted tubule is important in the regulation of renal Mg(2+) balance, we determined the effects of adenosine on cellular Mg(2+) uptake in this segment. The effect of adenosine was studied on immortalized mouse distal convoluted tubule (MDCT) cells, a model of the intact distal convoluted tubule. The rate of Mg(2+) uptake was measured with fluorescence techniques using mag-fura 2. To assess Mg(2+) uptake, MDCT cells were first Mg(2+) depleted to 0.22 +/- 0.01 mM by being cultured in Mg(2+)-free media for 16 h and then placed in 1.5 mM MgCl(2); next, changes in intracellular Mg(2+) concentration ([Mg(2+)](i)) were determined. [Mg(2+)](i) returned to basal levels, 0.53 +/- 0.02 mM, with a mean refill rate, d([Mg(2+)](i))/dt, of 137 +/- 16 nM/s. Adenosine stimulates basal Mg(2+) uptake by 41 +/- 10%. The selective A(1) purinoceptor agonist N(6)-cyclopentyladenosine (CPA) increased intracellular Ca(2+) and decreased parathyroid hormone (PTH)-stimulated cAMP formation and PTH-mediated Mg(2+) uptake. On the other hand, the selective A(2) receptor agonist 2-[p-(2-carbonyl-ethyl)-phenylethylamino]-5'-N-ethylcarboxamidoadenosine (CGS) stimulated Mg(2+) entry in a concentration-dependent fashion. CGS increased cAMP formation and the protein kinase A inhibitor RpcAMPS inhibited CGS-stimulated Mg(2+) uptake. Selective inhibition of phospholipase C, protein kinase C, or mitogen-activated protein kinase enzyme cascades with U-73122, Ro-31-8220, and PD-98059, respectively, diminished A(2) agonist-mediated Mg(2+) entry. Aldosterone potentiated CGS-mediated Mg(2+) entry, and elevation of extracellular Ca(2+) diminished CGS-responsive cAMP formation and Mg(2+) uptake. Accordingly, MDCT cells possess both A(1) and A(2) purinoceptor subtypes with intracellular signaling typical of these respective receptors. We conclude that adenosine has dual effects on Mg(2+) uptake in MDCT cells through separate A(1) and A(2) purinoceptor pathways.
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PMID:Adenosine modulates Mg(2+) uptake in distal convoluted tubule cells via A(1) and A(2) purinoceptors. 1170 66

We investigated what adenosine receptor type exists and the signaling pathways on the contraction of circular muscle cells isolated by enzymatic digestion from the cat esophagus. Adenosine or the selective A1 receptor agonist R-PIA causes a concentration-dependent contraction. After pretreatment with A1 receptor antagonist, DPCPX, adenosine-mediated contraction was abolished. Adenosine-induced contraction was significantly increased when A1 receptors were preserved by pretreatment with DPCPX followed by inactivation of all unprotected receptors with N-ethylmaleimide. Adenosine- or R-PIA-induced contraction was significantly augmented in the preserved cells and the increase was abolished in the presence of the A1 receptor antagonist DPCPX. PTX abolished contraction induced by adenosine or R-PIA, implying that contraction activated by A1 receptor was coupled to a pertussis toxin (PTX)-sensitive G(i) protein. After permeabilization, contraction was inhibited by G(i2), but not by G(i1) and G(i3), antibodies. These data suggest that adenosine-induced contraction of esophagus depends on PTX-sensitive G(i2.) Adenosine- or R-PIA-induced contraction of esophageal smooth muscle cells was not affected by the phospholipase D (PLD) inhibitor rho-chloromercuribenzoic acid (rhoCMB), phospholipase A(2) (PLA(2)) inhibitor DEDA or PKC antagonist chelerythrine, but was significantly abolished by phospholipase C (PLC) inhibitor, neomycin. PLC-beta3 antibody inhibited R-PIA-induced contraction. R-PIA-induced contraction of esophageal muscle cells was inhibited by IP(3) receptor antagonist heparin, which suggests that the contraction of esophageal smooth muscle cells is dependent on phosphatidylinositol-specific phospholipase (PI-PLC) and IP(3). In conclusion, adenosine- and R-PIA-induced contraction in cat esophageal smooth muscle cell was mediated by A1 receptor. A1 receptor is coupled to PTX-sensitive G protein G(i2), which results in the activation of PI-PLC-beta3. PI hydrolysis by PI-PLC forms IP(3), which binds to IP(3) receptor on endoplasmic reticulum, resulting in the release of intracellular Ca(2+).
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PMID:Signal transduction mechanism via adenosine A1 receptor in the cat esophageal smooth muscle cells. 1185 44

Adenosine has been reported to stimulate or inhibit the release of angiogenic factors depending on the cell type examined. To test the hypothesis that differential expression of adenosine receptor subtypes contributes to endothelial cell heterogeneity, we studied microvascular (HMEC-1) and umbilical vein (HUVEC) human endothelial cells. Based on mRNA level and stimulation of adenylate cyclase, we found that HUVECs preferentially express A2A adenosine receptors and HMEC-1 preferentially express A2B receptors. Neither cells expressed A1 or A3 receptors. The nonselective adenosine agonist 5'-N-ethylcarboxamidoadenosine (NECA) increased expression of interleukin-8 (IL-8), basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF) in HMEC-1, but had no effect in HUVECs. In contrast, the selective A2A agonist 2-p-(2-carboxyethyl)phenylethylamino-NECA (CGS 21680) had no effect on expression of these angiogenic factors. Cotransfection of each type of adenosine receptors with a luciferase reporter in HMEC-1 showed that A2B receptors, but not A1, A2A, or A3, activated IL-8 and VEGF promoters. These effects were mimicked by constitutively active alphaG(q), alphaG12, and alphaG13, but not alphaG(s) or alphaG(i1-3). Furthermore, stimulation of phospholipase C indicated coupling of A2B receptors to G(q) proteins in HMEC-1. Thus, differential expression of adenosine receptor subtypes contributes to functional heterogeneity of human endothelial cells. A2B receptors, predominantly expressed in human microvascular cells, modulate expression of angiogenic factors via coupling to G(q), and possibly via G12/13.
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PMID:Differential expression of adenosine receptors in human endothelial cells: role of A2B receptors in angiogenic factor regulation. 1190 16

Phosphatidylinositol 4,5-bisphosphate (PIP2) affects profoundly several cardiac ion channels and transporters, and studies of PIP2-sensitive currents in excised patches suggest that PIP2 can be synthesized and broken down within 30 s. To test when, and if, total phosphatidylinositol 4-phosphate (PIP) and PIP(2) levels actually change in intact heart, we used a new, nonradioactive HPLC method to quantify anionic phospholipids. Total PIP and PIP2 levels (10-30 micromol/kg wet weight) do not change, or even increase, with activation of Galpha(q)/phospholipase C (PLC)-dependent pathways by carbachol (50 microM), phenylephrine (50 microM), and endothelin-1 (0.3 microM). Adenosine (0.2 mM) and phorbol 12-myristate 13-acetate (1microM) both cause 30% reduction of PIP2 in ventricles, suggesting that diacylglycerol (DAG)-dependent mechanisms negatively regulate cardiac PIP2. PIP2, but not PIP, increases reversibly by 30% during electrical stimulation (2 Hz for 5 min) in guinea pig left atria; the increase is blocked by nickel (2 mM). Both PIP and PIP2 increase within 3 min in hypertonic solutions, roughly in proportion to osmolarity, and similar effects occur in multiple cell lines. Inhibitors of several volume-sensitive signaling mechanisms do not affect these responses, suggesting that PIP2 metabolism might be sensitive to membrane tension, per se.
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PMID:Modulation of cardiac PIP2 by cardioactive hormones and other physiologically relevant interventions. 1205 91

Adenosine has a broad array of actions on neurons but astrocytes also possess adenosine receptors. We have previously shown that adenosine, by acting on astrocytes in the striatum, can modulate neuronal responses mediated by receptors coupled to phospholipase C through an astrocyto - neuronal interaction. In addition, adenosine was found to potentiate the alpha1-adrenergic production of inositol phosphates in astrocytes. The mechanism involved in this potentiation was further investigated by examining the effects of adenosine and alpha1-adrenergic receptor agonists on cytosolic Ca2+ in cultured striatal astrocytes from the embryonic mouse in primary culture. When used alone, methoxamine, a selective agonist of alpha-adrenergic receptors or 2-chloroadenosine, a stable analogue of adenosine, induced a transitory increase in cytosolic Ca2+, but their combined addition led to a sustained increase in cytosolic Ca2+, which seems to be due to a Ca2+ influx, because it was not observed in the absence of external Ca2+. Voltage independent Ca2+ channels contribute to this process and different blockers of voltage-operated calcium channels, such as dihydropyridines, phenylalkylamines, La3+ or Co2+ were ineffective in suppressing the sustained cytosolic Ca2+ elevation. Three observations suggest the implication of arachidonic acid in the observed potentiation: (i) arachidonic acid induced a sustained elevation of cytosolic Ca2+ similar to that evoked by the coapplication of methoxamine and 2-chloroadenosine; (ii) the addition of arachidonic acid during the calcic plateau produced by the combined application of the agonists did not increase further cytosolic Ca2+ levels; (iii) in the presence of methoxamine, 2-chloroadenosine induced a release of arachidonic acid. The stimulation of phospholipase C and the resulting activation of protein kinase C induced by methoxamine seem to be required for the potentiating effect of 2-chloroadenosine on cytosolic Ca2+. In fact, the direct activation of protein kinase C by an exogenous diacylglycerol analogue mimicked the effect of methoxamine because, in this condition, 2-chloroadenosine alone evoked a sustained elevation of cytosolic Ca2+. Therefore, methoxamine, through the successive activation of phospholipase C and protein kinase C, could allow a lipase, probably phospholipase A2, to be stimulated by 2-chloroadenosine. Arachidonic acid has already been shown to trigger the opening of K+ channels and the formation of inositol phosphates in other cell types. Therefore, in striatal astrocytes, 2-chloroadenosine, through an arachidonic acid-mediated hyperpolarization, could increase the Ca2+ driving force and thus improve Ca2+ influx through inositol phosphate-gated channels. This hypothesis is further supported by the suppressing effect of a 50 mM KCI-induced depolarization on the long lasting elevation of cytosolic Ca2+ seen in the combined presence of 2-chloroadenosine and methoxamine.
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PMID:Synergistic Regulation of Cytosolic Ca2+ Concentration by Adenosine and alpha1-Adrenergic Agonists in Mouse Striatal Astrocytes. 1210 86

In airway smooth muscle cells (SMCs) from mouse lung slices, > or =10 microM ATP induced Ca2+ oscillations that were accompanied by airway contraction. After approximately 1 min, the Ca2+ oscillations subsided and the airway relaxed. By contrast, > or =0.5 microM adenosine 5'-O-(3-thiotriphosphate) (nonhydrolyzable) induced Ca2+ oscillations in the SMCs and an associated airway contraction that persisted for >2 min. Adenosine 5'-O-(3-thiotriphosphate)-induced Ca2+ oscillations occurred in the absence of external Ca2+ but were abolished by the phospholipase C inhibitor U-73122 and the inositol 1,4,5-trisphosphate receptor inhibitor xestospongin. Adenosine, AMP, and alpha,beta-methylene ATP had no effect on airway caliber, and the magnitude of the contractile response induced by a variety of nucleotides could be ranked in the following order: ATP = UTP > ADP. These results suggest that the SMC response to ATP is impaired by ATP hydrolysis and mediated via P2Y(2) or P2Y(4) receptors, activating phospholipase C to release Ca2+ via the inositol 1,4,5-trisphosphate receptor. We conclude that ATP can serve as a spasmogen of airway SMCs and that Ca2+ oscillations in SMCs are required to sustain airway contraction.
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PMID:ATP stimulates Ca2+ oscillations and contraction in airway smooth muscle cells of mouse lung slices. 1238 70

Studies of regulated mucin secretion from goblet cells in primary cultures of human bronchial epithelial (HBE) cells have suffered, generally, from poor signal-to-noise ratios, with reported secretory responses of <100% (less than onefold) relative to baseline. Using, instead, HBE cells grown as xenografts in the backs of nude mice, we found that UTP (100 micro M) stimulated strong mucin secretory responses from isolated, luminally perfused preparations. The peak response (10 min) for 11 control experiments (37 xenografts) was 3.3 +/- 0.05-fold relative to baseline, and the time-integrated response (60 min) was 23.4 +/- 0.5-fold. Because responses to ATP and UTP were approximately equal, an apical membrane P2Y(2)-receptor (R) is suggested. Additionally, ADP activated mucin release from HBE xenografts, whereas UDP and 2-methlythio-ADP did not, a pattern of response inconsistent with known purinoceptors. Hence, either a novel receptor to ADP is suggested or there is significant conversion of ADP to ATP by ecto-adenylate kinase activity. Adenosine and a nitric oxide donor were without effect. Consistent with P2Y(2)-R coupling to phospholipase C, HBE xenografts responded to ionomycin and PMA; however, they were recalcitrant to forskolin and chlorophenylthio-cAMP, and to 8-bromo-cGMP. Hence, human airway goblet cells, like those of other species, appear to be regulated primarily via phospholipase C pathways, activated particularly by apical membrane P2Y(2)-R agonists.
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PMID:Regulation of mucin secretion from human bronchial epithelial cells grown in murine hosted xenografts. 1253 43

The effect of extracellular ATP (10-100 microM) on intracellular Ca2+ concentration ([Ca2+]i) and firing rate has been studied in single pacemaker cells isolated from the sinus venosus of cane toads. In spontaneously firing cells, ATP initially increased peak [Ca2+]i by 43 +/- 5 %, increased diastolic [Ca2+]i by 20 + 3 % and increased the firing rate by 58 +/- 8 %. These early effects were followed by a late phase in which both the peak [Ca2+]i and the firing rate declined. Adenosine, and UTP (respectively, P1- and P2Y2,4,6-selective agonists) caused no significant change in [Ca2+]i or firing rate, while alphabeta-methylene ATP (a P2X1,3 agonist) caused a small increase in firing rate but no changes in [Ca2+]i. In contrast the P2Y1-selective agonist 2-MesADP (1 microM) mimicked the biphasic effects of ATP and these effects were inhibited by the purinoceptor antagonists suramin and PPADS and by the P2Y1-selective antagonist MRS 2179. Immunohistochemistry established that P2Y1 purinoceptors were present on the cell surface. Western blotting analysis demonstrated that the P2Y1 antibody recognised a 57 kDa protein. After sarcoplasmic reticulum Ca2+ release was prevented with caffeine or ryanodine, ATP no longer had any effect on [Ca2+]i or firing rate. Furthermore, the SR Ca2+ store content was decreased during the late phase of 2-MesADP application. The effect of ATP was coupled to phospholipase C (PLC) activity because the PLC inhibitor U-73122 eliminated the effects of ATP. Our study shows that in toad pacemaker cells, the biphasic effects of ATP on pacemaker activity are mainly through P2Y1 purinoceptors, which are able to modulate Ca2+ release from the SR Ca2+ store.
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PMID:ATP modulates intracellular Ca2+ and firing rate through a P2Y1 purinoceptor in cane toad pacemaker cells. 1294 18


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