Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01185 (vasopressin)
 23,126 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The functional consequence of cyclic AMP-dependent phosphorylation of rap1B for stimulus-induced platelet activation is not known. Platelets were pretreated with the stable prostacyclin-analogue iloprost and resuspended in plasma without iloprost. Western blot analysis showed that rap1B was completely converted into its phosphorylated form in the iloprost-pretreated platelets. Surprisingly, the platelets that contained phosphorylated rap1B were found to respond fully to activation by a wide variety of stimuli: aggregation upon stimulation by collagen, phorbol ester, vasopressin, ADP, epinephrine, and ATP-secretion from dense granules induced by collagen, thrombin-receptor activating peptide, vasopressin and phorbol ester were unchanged as compared to control. The results indicate that cyclic AMP-dependent phosphorylation of rap1B does not play a role in the inhibition of the various signal transduction pathways that lead to platelet aggregation and dense granule secretion.
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PMID:Phosphorylation of rap1B by protein kinase A is not involved in platelet inhibition by cyclic AMP. 768

Platelet serotonin (5-HT) studies were conducted with 12 hyperserotonemic and 12 normoserotonemic age-, sex-, and relationship-matched relatives of autistic probands. Each group consisted of 7 mothers, 4 fathers, and 1 sister of autistic children and adolescents. The density (Bmax) of platelet 5-HT2 receptor binding sites, labelled with [3H]-lysergic acid diethylamide (LSD), was significantly lower in 11 hyperserotonemic subjects compared to 12 normoserotonemic subjects (40.9 +/- 13.5 fmol/mg protein, 59.6 +/- 13.2; p < 0.004). The affinity (Kd) for [3H]-LSD binding did not differ. Although the density (Bmax) of [3H]-paroxetine binding did not differ between groups, there was a small difference in the affinity (Kd) for [3H]-paroxetine binding (hyperserotonemic 47.6 +/- 9.0 pM, normoserotonemic 54.8 +/- 12.1; p < 0.05). There were no significant differences in platelet 5-HT uptake, or in thrombin-stimulated 5-HT release. Basal, 5-HT-stimulated, and arginine-vasopressin (AVP)-stimulated inositol phosphate production, as well as basal, prostaglandin E1 (PGE1)-, and forskolin-stimulated cAMP production did not differ. There were significant correlations between whole blood 5-HT levels and LSD Bmax (rs = -0.63, N = 23, p < 0.002) and whole blood 5-HT levels and 5-HT uptake Vmax (rs = 0.56, N = 18, p < 0.02). However, [3H]-LSD labelled 5-HT2 binding and 5-HT uptake were not correlated with each other. Hyperserotonemia of autism may be heterogeneous with one subgroup of subjects with increased 5-HT uptake and another subgroup with decreased 5-HT2 binding.
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PMID:Platelet serotonin studies in hyperserotonemic relatives of children with autistic disorder. 768 5

Thrombin binds at least to two sites of the platelet surface; to the recently cloned thrombin receptor [Vu, T. K., Hung, D. T., Wheaton, V. I. & Coughlin, S. R. (1991) Cell 64, 1057-1068] and to glycoprotein Ib. In the present study, the decrease of pertussis-toxin-dependent ADP-ribosylation of membrane and soluble inhibitory guanine-nucleotide-binding alpha (Gi alpha) proteins was measured after platelet stimulation with a thrombin-receptor-activating peptide (TRAP), and compared to stimulation with thrombin. Stimulation of intact platelets with TRAP decreased the pertussis-toxin-dependent ADP-ribosylation of the major membrane 41-kDa Gi alpha protein and the minor soluble 40 kDa Gi alpha protein recently described in platelets [Gennity, J. M. & Siess, W. (1991) Biochem. J. 279, 643-650]. The kinetics and extent of the decrease of pertussis-toxin-dependent ADP-ribosylation after stimulation of TRAP were similar to the effect of thrombin. The decrease of pertussis-toxin-dependent ADP-ribosylation of the soluble Gi alpha protein was more pronounced and observed at lower agonist concentrations than the decrease of the membrane Gi alpha protein. Desensitization of the thrombin receptor by incubating platelets with a low concentration of TRAP reduced the subsequent decrease of pertussis-toxin-dependent ADP-ribosylation of Gi alpha proteins, evoked by TRAP or thrombin. Platelet stimulation with gamma-thrombin that does not bind to glycoprotein Ib also showed a decrease in the pertussis-toxin-dependent ADP-ribosylation of the soluble and membrane Gi alpha proteins. Treatment of platelets with the stable prostacyclin analog, iloprost, reduced the decrease of pertussis-toxin-dependent ADP-ribosylation of Gi alpha proteins induced by TRAP or thrombin. Among other platelet stimuli tested (endoperoxide/thromboxane analog U44619, collagen, ADP, vasopressin), only U44619 decreased the pertussis-toxin-dependent ADP-ribosylation of the soluble and membrane Gi alpha proteins to a degree comparable to TRAP. It is concluded that the thrombin-induced activation of both the membrane and soluble Gi alpha proteins in platelets occurs via stimulation of the recently cloned thrombin receptor and is independent of the binding of thrombin to glycoprotein Ib. Furthermore, the coupling thrombin receptor/Gi protein is reduced by intracellular cAMP.
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PMID:Activation of the cloned platelet thrombin receptor decreases the pertussis-toxin-dependent ADP-ribosylation of the membrane and soluble inhibitory guanine-nucleotide-binding-alpha proteins. Inhibition by the prostacyclin analog, iloprost. 768 67

Human blood platelets contain high levels of non-receptor protein tyrosine kinases of the Src family, particularly pp60c-src, suggesting an important role for these enzymes in platelet physiology. Indeed, in response to various agonists of platelet function, a number of proteins become phosphorylated at tyrosine residues. However, no enzymic activation of an Src-related tyrosine kinase has yet been shown in platelets. In searching for the kinase(s) responsible, we found that all agonists tested that directly or indirectly activate protein kinase C in platelets (phorbol 12-myristate, 13-acetate, thrombin, vasopressin, collagen, calcium ionophore A23187) increased the overall activity of pp60c-src determined by IgG phosphorylation in an immunocomplex assay in the presence of low ATP concentrations. On the other hand, elevation of cyclic AMP directly by forskolin or indirectly by prostaglandin E1, or elevation of cyclic GMP by sodium nitroprusside did not significantly affect the activity of the enzyme. To substantiate the differences in enzyme activity, we determined Km and Vmax, values of pp60c-src from resting and thrombin-stimulated platelets. Thrombin treatment increased substrate affinity of pp60c-src as indicated by a 2- to 3-fold decrease in the Km values for ATP and the exogenous protein substrate casein. Vmax. values were only slightly altered under the assay conditions used. To further rule out modifications of pp60c-src in phosphorylation as a probable cause of the changed substrate affinity, we analysed tryptic phosphopeptides of immunoprecipitated, 32P-labelled pp60c-src of unstimulated and stimulated platelets. The platelet agonists listed above induced an increase in pp60c-src phosphorylation at Ser-12, which is the amino acid phosphorylated by protein kinase C. Surprisingly, we found that elevation of cyclic AMP did not affect 32P labelling of pp60c-src. On the basis of our data, we suggest that phosphorylation at Ser-12 might be one of the signal-triggering events that cause the increase in substrate affinity of pp60c-src.
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PMID:Substrate affinity of the protein tyrosine kinase pp60c-src is increased on thrombin stimulation of human platelets. 769 43

The role of external Na+ in agonist-evoked platelet Ca2+ response is poorly understood. This was explored in this study. Removal of external Na+ decreased both cytosolic Ca2+ mobilization and external Ca2+ entry, induced by thrombin but not by ADP or vasopressin. That external Na+ regulates thrombin activities was demonstrated by 1) Na+ dependency of the amidolytic activity of thrombin, 2) inhibition of thrombin binding to the high-affinity binding sites in Na(+)-free medium, and 3) attenuation of thrombin-induced inositol 1,4,5-trisphosphate production in Na(+)-free medium. Moreover, Ca2+ response to the thrombin receptor 6-amino acid peptide was independent of external Na+. The role of external Na+ in modifying agonist-evoked Ca2+ response through activation of Na+/H+ antiport and cytosolic alkalinization was then explored. Cytosolic alkalinization by monensin or NH4Cl enhanced thrombin, ADP, and thimerosal-induced external Ca2+ entry. Thimerosal-induced acceleration of external Ca2+ entry was diminished by the inhibition of Na+/H+ antiport. Thus external Na+ enhances thrombin activities, and cytosolic pH mediates store-regulated external Ca2+ entry. However, Na+/H+ antiport activation is not essential for agonist-evoked Ca2+ mobilization and external Ca2+ entry.
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PMID:Role of external Na+ and cytosolic pH in agonist-evoked cytosolic Ca2+ response in human platelets. 781 May 95

Platelets respond through discrete receptors to a number of physiological agonists and foreign surfaces with a sequence of measurable responses: shape change, aggregation, secretion and arachidonate liberation. Three secretory responses are distinguished: exocytosis of substances from (1) dense granules, (2) alpha-granules and (3) lysosomes. Free arachidonate, liberated from phospholipids by phospholipase A2, is rapidly converted (by oxygenation) to prostaglandins and thromboxanes which, together with secreted ADP and close cell contact, will cause further platelet activation through 'positive feedback' (autocrine stimulation). Some agonists are classified as 'weak' (ADP, vasopressin, platelet-activating factor [PAF], serotonin) because they depend on autocrine stimulation to promote the full sequence of responses, while others are 'strong' agonists (thrombin, collagen) and activate all responses directly without autocrine stimulation. Adrenaline, long thought to be a platelet agonist per se, most probably acts by amplifying the activation brought about by other, proper, agonists. Such synergistic interaction among agonists is very typical for platelet activation and most likely takes place in vivo. Shape change, aggregation and secretion(s) may be tested by flow cytometry or electron microscopy in vitro under conditions that probably reflect the in vivo situation. However, the aggregation response to weak agonists in vitro is dependent on the extracellular [Ca2+], with biphasic aggregation at the low [Ca2+] present when citrate is used as anticoagulant (or in suspension of washed platelets) but not at the physiological [Ca2+] present in platelet-rich plasma from heparinized blood.
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PMID:Significance of testing platelet functions in vitro. 801 28

The lectin wheat germ agglutinin (WGA) elicited a prompt and sharp increase in intracellular Ca2+ concentration in human platelets. The WGA-induced Ca2+ mobilization was markedly inhibited by a protein kinase inhibitor staurosporine, whereas Ca2+ mobilization by receptor-mediated agonists, including thrombin, platelet-activating factor, and arginine-vasopressin, was not. In contrast, the lectin-induced Ca2+ mobilization was resistant to cyclic AMP inhibition, compared with that induced by receptor-mediated agonists. These findings indicate that the mechanism of intracellular Ca2+ mobilization, or possibly phospholipase C activation, induced by WGA is different from that induced by receptor-mediated agonists in human platelets.
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PMID:Wheat germ agglutinin-induced intracellular calcium mobilization in human platelets: suppression by staurosporine and resistance to cyclic AMP inhibition. 838 40

Regulation of phospholipase D (PLD) activity was investigated in cultured monolayers of bovine pulmonary artery endothelial cells (BPAECs). Agonists such as bradykinin, histamine, vasopressin, alpha-thrombin, and adenosine triphosphate (ATP) stimulated up to 15-fold accumulation of phosphatidylethanol (PEt) in the presence of ethanol through PLD-catalyzed phosphatidyltransferase activity. To examine mechanisms of PLD regulation, we investigated the role of protein kinase C (PKC) and Ca2+ fluxes in agonist-induced PLD activation. The PKC activator 12-O-tetradecanoylphorbol-13-acetate (TPA, 100 nmol/L) produced up to a 25-fold increase in PEt formation in a time- and dose-dependent manner. PEt production was also stimulated by other cell-permeant PKC activators such as 1,2 dioctanoylglycerol and 1-oleyl-2-acetylglycerol, whereas inactive phorbol derivatives 4-alpha-phorbol-12,13-didecanoate and 4-beta-phorbol showed no effect. The effect of TPA on PEt accumulation was inhibited by the PKC inhibitors staurosporine (5 mumol/L, 95% inhibition) and sphingosine (10 mumol/L, 50% inhibition). TPA-induced PEt accumulation was almost completely abolished (> 95% inhibition) by PKC down-regulation accomplished by long-term treatment with 100 nmol/L TPA. In contrast, bradykinin- or ATP-induced phosphorus 32-labeled PA and [32P]-labeled PEt formation was only partially blocked (70% inhibition) by either staurosporine (10 mumol/L) or PKC down-regulation, suggesting that part of agonist-stimulated PLD activity may occur in the absence of PKC activation. An increase in Cai2+ appears to be involved in agonist-induced PLD activation as bradykinin-, ATP-, or Ca2+ ionophore-induced [32P]. PEt production was attenuated by either depletion of extra-cellular Ca2+ with EGTA or chelation of intracellular Ca2+ by BAPTA. TPA-mediated PEt accumulation was not affected by EGTA treatment, whereas BAPTA reduced TPA-mediated PEt formation by 50%. These results suggest that direct PKC activation is a potent stimulus for PLD activity and that the major pathway for agonist-induced PLD activation involves PKC activation and is dependent on an increase in intracellular Ca2+. Further, these studies suggest that agonist-induced PLD activation may also involve a PKC-independent mechanism.
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PMID:Agonist-induced activation of phospholipase D in bovine pulmonary artery endothelial cells: regulation by protein kinase C and calcium. 843 44

We studied the inhibitory effects of heparin on basal and agonist-induced endothelin-1 biosynthesis and release from cultured bovine endothelial cells. Heparin dose-dependently and similarly inhibited endothelin-1 release, inositol trisphosphate production, and intracellular free Ca2+ levels stimulated by thrombin. Hirudin fragment had an inhibitory effect on thrombin-induced endothelin-1 release, whereas anti-thrombomodulin antibody had no effect. Heparin completely blocked phorbol ester-induced endothelin-1 release, whereas it had a partial inhibitory effect on endothelin-1 release stimulated by angiotensin and vasopressin. Northern blot analysis using complementary DNA for bovine preproendothelin-1 as a probe revealed that heparin reduced not only the basal but also the stimulated expression of preproendothelin-1 messenger RNA by thrombin and phorbol ester. These data suggest that heparin, in addition to its antithrombin effect, has an inhibitory effect on the biosynthesis and release of endothelin-1, possibly by inhibiting protein kinase C-dependent pathway.
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PMID:Heparin has an inhibitory effect on endothelin-1 synthesis and release by endothelial cells. 847 44

Bleeding may become a major impediment to accurate and safe dissection by laparoscopy. The traditional maneuvers of pressure, dumping, irrigation, and aspiration frequently applied during open procedures to maintain a clear field of dissection are cumbersome through laparoscopy. Several pharmacologic agents have been used topically or by local injection to stop bleeding or to prevent excessive blood loss during surgical procedures. They include calcium alginate, aluminum salts, silver nitrate, formalin, and coagulating agents like thrombin and collagens, all of which leave a layer of damaged tissue or foreign material on the surface. Epinephrine and vasopressin have been employed mostly by local injections. We report the use of topical epinephrine applied before and during the dissection of the cystic duct and artery area in the course of laparoscopic cholecystectomy. A 3/8-inch gauze sponge, impregnated with a 1:10,000 epinephrine solution, was used to blanch the tissues and to bluntly dissect the cystic duct and artery. It was also used to control minor bleeding in the gallbladder fossa. The prophylactic bleeding control with topical epinephrine proved to be an easy and safe maneuver, and greatly facilitated the dissection of the most critical areas during laparoscopic cholecystectomy. This technique may be applicable to laparoscopic dissection for other procedures.
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PMID:Pharmacologic hemostasis in laparoscopy: topical epinephrine facilitates cholecystectomy. 848 94


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