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PubMed1989

The inhibitory effect of GR32191, a thromboxane receptor blocking drug, on human platelet aggregation, adhesion and secretion.

GR32191, a potent selective thromboxane receptor antagonist, has been shown to inhibit completely prostaglandin endoperoxide and thromboxane A2 (TxA2)-induced platelet aggregation, [14C]-serotonin secretion and beta-thromboglobulin secretion. Deposition of human platelets onto damaged rabbit aorta in vitro is reduced in the presence of GR32191 which appears to inhibit aggregation of platelets but not direct adhesion of platelets to subendothelium. The effects of non-prostanoid platelet activating agents whose mode of action requires the biosynthesis of TxA2 are also inhibited by GR32191. Prostanoids which inhibit platelet function, such as prostacyclin or PGD2, retain their inhibitory properties in the presence of GR32191 which does not inhibit phospholipase A2, prostaglandin cyclooxygenase, thromboxane synthase, 12-lipoxygenase or cAMP phosphodiesterase activity. The inhibitory action of GR32191 on platelet aggregation, mural thrombus formation and platelet protein storage granule secretion suggests that it has potential in treating thrombotic disease in man.

Biphenyl Compounds↗
PubMed1996

Agrin binding to alpha-dystroglycan. Domains of agrin necessary to induce acetylcholine receptor clustering are overlapping but not identical to the alpha-dystroglycan-binding region.

The synaptic basal membrane protein agrin initiates the aggregation of acetylcholine receptors at the postsynaptic membrane of the developing neuromuscular junction. Recently, alpha-dystroglycan was found to be a major agrin-binding protein on the muscle cell surface and was therefore considered a candidate agrin receptor. Employing different truncation fragments of agrin, we determined regions of the protein involved in binding to alpha-dystroglycan and to heparin, an inhibitor of alpha-dystroglycan binding. Deletion of a 15-kDa fragment from the C terminus of agrin had no effect on its binding to alpha-dystroglycan from rabbit muscle membranes, even though this deletion completely abolishes its acetylcholine receptor aggregating activity. Conversely, deletion of a central region does not affect agrin's clustering activity, but reduced its affinity for alpha-dystroglycan. Combination of these two deletions resulted in a fragment of approximately 35 kDa that weakly bound to alpha-dystroglycan, but displayed no clustering activity. All of these fragments bound to heparin with high affinity. Thus, alpha-dystroglycan does not show the binding specificity expected for an agrin receptor. Our data suggest the existence of an additional component on the muscle cell surface that generates the observed ligand specificity.

Agrin↗
PubMed1987

The actions of Ca2+ ionophores on rat basophilic (2H3) cells are dependent on cellular ATP and hydrolysis of inositol phospholipids. A comparison with antigen stimulation.

Calcium-specific ionophores are used widely to stimulate Ca2+-dependent secretion from cells on the assumption that permeabilization of the cell membranes to Ca2+ ions leads to a rise in concentration of cytosolic Ca2+ ([Ca2+]i), which in turn serves as a signal for secretion. In this way, events that precede mobilization of Ca2+ ions via receptor stimulation are bypassed. One such event is thought to be the rapid hydrolysis of membrane inositol phospholipids to form inositol phosphates and diacylglycerol. Accordingly, rat leukemic basophil (2H3) cells can be stimulated to secrete histamine either with the ionophores or by aggregation of receptors for IgE in the plasma membrane. We find, however, that ionophore A23187 stimulates secretion of histamine only at concentrations (200-1000 nM) that stimulate hydrolysis of membrane inositol phospholipids. The extent of hydrolysis of inositol phospholipids was dependent on the concentration of ionophore and the presence of external Ca2+ ions and correlated with the magnitude of the secretory response. A similar correlation between secretion and hydrolysis of inositol phospholipids was observed in response to the Ca2+-specific ionophore, ionomycin. Although this hydrolysis (possibly a consequence of elevated [Ca2+]i) was less extensive than that induced by aggregation of receptors, it may govern the secretory response to A23187. The studies revealed one paradox. The rise in [Ca2+]i depended on intracellular ATP levels, when either an ionophore or antigen was used as a stimulant irrespective of whether hydrolysis of inositol phospholipids was stimulated or not. The concept of how the ionophores act, therefore, requires critical reevaluation.

Adenosine Triphosphate↗
PubMed1997

Activation of Jak2 catalytic activity requires phosphorylation of Y1007 in the kinase activation loop.

The Janus protein tyrosine kinases (Jaks) play critical roles in transducing growth and differentiation signals emanating from ligand-activated cytokine receptor complexes. The activation of the Jaks is hypothesized to occur as a consequence of auto- or transphosphorylation on tyrosine residues associated with ligand-induced aggregation of the receptor chains and the associated Jaks. In many kinases, regulation of catalytic activity by phosphorylation occurs on residues within the activation loop of the kinase domain. Within the Jak2 kinase domain, there is a region that has considerable sequence homology to the regulatory region of the insulin receptor and contains two tyrosines, Y1007 and Y1008, that are potential regulatory sites. In the studies presented here, we demonstrate that among a variety of sites, Y1007 and Y1008 are sites of trans- or autophosphorylation in vivo and in in vitro kinase reactions. Mutation of Y1007, or both Y1007 and Y1008, to phenylalanine essentially eliminated kinase activity, whereas mutation of Y1008 to phenylalanine had no detectable effect on kinase activity. The mutants were also examined for the ability to reconstitute erythropoietin signaling in gamma2 cells, which lack Jak2. Consistent with the kinase activity, mutation of Y1007 to phenylalanine eliminated the ability to restore signaling. Moreover, phosphorylation of a kinase-inactive mutant (K882E) was not detected, indicating that Jak2 activation during receptor aggregation is dependent on Jak2 and not another receptor-associated kinase. The results demonstrate the critical role of phosphorylation of Y1007 in Jak2 regulation and function.

Amino Acid Sequence↗
PubMed2001

The activation of platelet aggregation by human cholangiocarcinoma cells is mediated through thrombin receptor.

Tumor cell induced platelet aggregation (TCIPA) played an importance role in early state of thrombosis in cancer patients. In addition, TCIPA was recognized as one important step in metastatic cascade. Cholangiocarcinoma, one of the most common cancers in the north-eastern part of Thailand, associated with thrombosis was reported. The authors investigated the effects of cholangiocarcinoma cells on platelet function as measured by platelet aggregation. Primary human cholangiocarcinoma (HuCCA) cells were established in our laboratory. Cells were cultured as standard techniques and grown to confluence until used, after which cells were replaced with fresh medium (Dulbeco Modified Eargle's Medium, DMEM) without serum for 24, 48 and 72 h. Then, the conditioned medium (CM) was collected. CM (24, 48 and 72 h) from HuCCA failed to induce platelet aggregation, whereas, HuCCA pellets induced platelet aggregation and potentiated platelet aggregation induced by submaximal concentration of thrombin. Interestingly, platelet aggregation induced by HuCCA was inhibited by hirudin (thrombin receptor antagonist; 10, 20 and 40 U) in a dose dependent manner. Thus, cholangiocarcinoma cells can induce platelet aggregation in a direct tumor cell-platelet contact via thrombin receptor. Therefore, the use of antiplatelet agents especially via thrombin receptors may help to prevent TCIPA or metastasis by CCA.

Adult↗
PubMed1993

Human platelet aggregation by murine monoclonal antiplatelet antibodies is subtype-dependent.

Twenty murine monoclonal antibodies (MoAbs) generated against different human platelet antigens induced clumping of human platelets in plasma and buffer. Whereas one MoAb could agglutinate platelets, clumping for 19 MoAbs was blocked by metabolic inhibitors, indicating that these induce platelet activation. Fifteen MoAbs were of IgG1, two of IgG2a, and two of IgG2b subtype. F(ab')2 fragments of these did not evoke an aggregatory response, but specifically inhibited aggregations by and binding of their respective intact MoAbs to platelets. Single-platelet counting technology indicated that the MoAbs bind through their antigen-binding and Fc domains mainly to the surface of the same platelet, rather than cause interplatelet-binding. Despite these similarities, the mechanism of action was nevertheless subtype-dependent. Aggregation induced by all IgG1 antibodies could consistently be prevented by blocking the Fc gamma II-receptor, whereas aggregations induced by all IgG2 antibodies still occurred with blocked Fc-receptor, provided functional complement was present. We therefore conclude that platelet activation by MoAb-binding is initiated by antigen recognition followed by an Fc domain-dependent step, which involves the Fc gamma II-receptor for IgG1-type MoAbs and complement-binding for IgG2-type MoAbs. Thus, antibodies of different subtypes can aggregate platelets via different pathways.

Animals↗
PubMed2005

The platelet P2 receptors as molecular targets for old and new antiplatelet drugs.

Platelet activation by ADP and ATP plays a crucial role in haemostasis and thrombosis, and their so-called P2 receptors are potential targets for antithrombotic drugs. The ATP-gated channel P2X1 and the 2 G protein-coupled P2Y1 and P2Y12 ADP receptors selectively contribute to platelet aggregation. The P2Y1 receptor is responsible for ADP-induced shape change and weak and transient aggregation, while the P2Y12 receptor is responsible for the completion and amplification of the response to ADP and to all platelet agonists, including thromboxane A2 (TXA2), thrombin, and collagen. The P2X1 receptor is involved in platelet shape change and in activation by collagen under shear conditions. Due to its central role in the formation and stabilization of a thrombus, the P2Y12 receptor is a well-established target of antithrombotic drugs like ticlopidine or clopidogrel, which have proved efficacy in many clinical trials and experimental models of thrombosis. Competitive P2Y12 antagonists have also been shown to be effective in experimental thrombosis as well as in several clinical trials. Studies in P2Y1 and P2X1 knockout mice and experimental thrombosis models using selective P2Y1 and P2X1 antagonists have shown that, depending on the conditions, these receptors could also be potential targets for new antithrombotic drugs.

Animals↗
PubMed1997

Aggregation of low affinity IgG receptors induces mast cell adherence to fibronectin: requirement for the common FcR gamma-chain.

Mast cells have been reported to increase at sites of immune complex-induced inflammation where these cells appear to potentiate the inflammatory response. The mechanism by which mast cells accumulate at these sites is unknown. One possibility is that aggregation of low affinity IgG receptors could signal mast cells to adhere to components of the connective tissue matrix. To test this hypothesis, we first added aggregated IgG to a mast cell adhesion assay employing fibronectin as a matrix component and observed an increase in cell adhesion. Even a small amount of aggregated IgG (< 60 ng/ml) demonstrated by fast protein liquid chromatography in untreated IgG preparations was sufficient to increase mast cell adhesion by 100%. We next explored the Fc gamma receptors involved. Fc gammaRII/III, which are receptors for oligomeric IgG and were first verified as present on these mast cells by FACS analysis and immunoprecipitation, signaled mast cells to rapidly adhere to fibronectin when aggregated with the anti-receptor Ab2.4G2. The adhesion process mediated by Fc gammaRII/III was not associated with beta-hexosaminidase release. Bone marrow-cultured mast cells from common gamma-chain deficient mice, unlike mast cells cultured from +/+ mice, did not respond to Fc gammaRII/III aggregation. This demonstrated requirement for a gamma-chain implicates oligomeric Fc gammaRIII in the adhesion process. Thus, aggregation of Fc gammaRIII on mast cells leads to mast cell adhesion, demonstrating a previously unknown biological function for this receptor on mast cells and providing a mechanism for mast cell accumulation in immune complex-dependent inflammation.

Animals↗
PubMed1993

A review of the role of platelet membrane glycoproteins in the platelet-vessel wall interaction.

This review concerns our understanding of the molecular basis of platelet function in haemostasis. In particular, we indicate how research into platelet membrane glycoprotein (GP) receptors is yielding vital information on the mechanisms of platelet adhesion and aggregation. These receptors, nearly always complexes of two or more subunits, are now known to belong to distinct gene families, some of which are unique to platelets while others are widely distributed in mammalian tissues. GP Ib-IX complexes are responsible for the high-shear-rate-dependent adhesion of platelets to von Willebrand factor (vWF) exposed within the subendothelium of damaged vessels. Other adhesion receptors include members of the VLA subclass of the integrin family: VLA-2, VLA-5 and VLA-6, which mediate platelet adhesion to collagen, fibronectin and laminin, respectively. Platelet aggregation is initiated by distinct populations of receptors specific for each physiological agonist. Many of these receptors, including the highly important and recently cloned thrombin receptor, have seven transmembrane domains and possess highly selective agonist-binding determinants. Finally, we highlight platelet aggregation and the role of GP IIb-IIIa complexes which, following platelet activation, bind fibrinogen and other adhesive proteins. The latter, through being polyvalent for GP IIb-IIIa, then form the bridges linking adjoining platelets. The 'ligand-binding pocket' of GP IIb-IIIa contains at least three sequences essential for ligand binding; fibrinogen also binds to the activated complex through identified domains, one of which, the Arg-Gly-Asp (RGD) sequence, is also found in vWF and the other adhesive proteins able to support platelet aggregation. Finally, we further describe how these, and other glycoproteins in both surface and internal membrane systems, constitute a complex receptor network capable of translocation and reorganization after platelet activation. In cardiovascular disease, platelets accumulate within arteries whose luminal surface has been modified through atherosclerosis. Recent molecular advances are yielding exciting opportunities for the development of new, and more powerful, drugs acting as specific inhibitors of thrombotic processes.

Amino Acid Sequence↗
PubMed1995

How do multichain immune recognition receptors signal? A structural hypothesis.

Several cell surface receptors involved in cellular activation by antigen, such as the B-cell and T-cell antigen receptors, and receptors for IgE and IgG (Fc epsilon RI and Fc gamma RIII) show substantial similarities in structure and signaling pathways. An essential step in the activation of immune cells through these receptors is the phosphorylation of specific tyrosine residues within certain consensus sequences found in the cytoplasmic tails of different chains belonging to each of these receptors. The mechanism by which aggregation of the receptors triggers these phosphorylation is still unknown. In this paper, a mechanistic model for this key event is proposed. This model assumes that the kinase(s) responsible for catalysing these phosphorylations do exist associated with the receptors, but for steric reasons they cannot phosphorylate tyrosine residues on chains of the same receptor complex. Upon aggregation, these kinases phosphorylate the tyrosines of a distinct receptor complex (cross-phosphorylation), thus starting the signaling cascade.

Animals↗
PubMed2000

Reduced synaptic clustering of GABA and glycine receptors in the retina of the gephyrin null mutant mouse.

Clustering of neurotransmitter receptors in postsynaptic densities involves proteins that aggregate the receptors and link them to the cytoskeleton. In the case of glycine and GABA(A) receptors, gephyrin has been shown to serve this function. However, it is unknown whether gephyrin is involved in the clustering of all glycine and GABA(A) receptors or whether it interacts only with specific isoforms. This was studied in the retinae of mice, whose gephyrin gene was disrupted, with immunocytochemistry and antibodies that recognize specific subunits of glycine and GABA(A) receptors. Because homozygous (geph -/-) mutants die around birth, an organotypic culture system of the mouse retina was established to study the clustering of gephyrin and the receptors in vitro. We found that all gephyrin and all glycine receptor clusters (hot spots) were abolished in the geph (-/-) mouse retina. In the case of GABA(A) receptors, there was a significant reduction of clusters incorporating the gamma2, alpha2, and alpha3 subunits; however, a substantial number of hot spots was still present in geph (-/-) mutant retinae. This shows that gephyrin interacts with all glycine receptor isoforms but with only certain forms of GABA(A) receptors. In heterozygous geph (+/-) mutants, no reduction of hot spots was observed in the retina in vivo, but a significant reduction was found in the organotypic cultures. This suggests that mechanisms may exist in vivo that allow for the compensation of a partial gephyrin deficit.

Animals↗
PubMed1986

Syntheses and beta-adrenergic agonist and antiaggregatory properties of N-substituted trimetoquinol analogues.

Trimetoquinol [1-(3,4,5-trimethoxybenzyl)-6,7- dihydroxy-1,2,3,4-tetrahydroisoquinoline, TMQ] is a potent beta-adrenergic receptor agonist and inhibitor of human platelet aggregation. Selective cleavage of O-benzyl groups in the presence of an N-benzyl group using HCl and formation of a cyclic sulfite ester from the reaction of a catechol with thionyl chloride were achieved. The N-substituents included methyl, benzyl, and beta-hydroxy- and beta-chloroethyl groups. Each N-substituted TMQ caused a concentration-dependent stimulation of beta 2 (trachea) and beta 1 (atria) adrenoceptor tissues and inhibition of 15(S)-hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13(E)-dienoic acid (U46619, a thromboxane A2 mimetic) mediated human platelet activation. TMQ remained the most potent in the series. Structure-activity results indicated that the larger the N-substituent, the lower the beta-adrenergic activity but the higher the inhibition of platelet aggregatory activity. Thus, the structural requirements of these TMQ analogues for the two types of biological activity are different.

Adrenergic beta-Agonists↗
PubMed1986

Glycoprotein properties of muscarinic acetylcholine receptors from bovine cerebral cortex.

Muscarinic acetylcholine receptors from bovine cerebral cortex were solubilized in digitonin for the subsequent determination of several biochemical properties. The digitonin-solubilized receptors were representative of the entire membrane-bound population of muscarinic receptors with respect to carbohydrate content, isoelectric point, and molecular weight. The glycoprotein nature of the solubilized receptors was demonstrated by their quantitative binding to wheat germ agglutinin-agarose. The presence of a bound antagonist did not decrease the extent of receptor binding to this lectin. Treatment of receptors with neuraminidase to remove N-acetylneuraminic acid residues reduced binding to wheat germ agglutinin-agarose by 40%; further treatment with endoglycosidases D and H, to remove all N-linked carbohydrate, decreased binding by a total of 67%. Removal of N-acetylneuraminic acid residues had no effect on agonist binding properties of the membrane-bound receptors. The carbohydrate-specific enzymes were further used to assess the contribution of carbohydrate to the isoelectric point and molecular weight of the receptor. Muscarinic receptors solubilized in either digitonin or Triton X-100 focused as one major species with a pI of 4.3. Neuraminidase treatment resulted in an increase of 0.17 units in the pI of the receptor. Muscarinic receptors labeled with the covalent muscarinic antagonist propylbenzilylcholine mustard migrated as a single major polypeptide with a molecular weight of 73,000 on sodium dodecyl sulfate-urea-polyacrylamide gels. The exclusion of urea from these gels severely retarded receptor mobility, indicating a strong tendency for aggregation of receptors in SDS. Removal of N-linked carbohydrate by endoglycosidase treatment reduced the molecular weight of the antagonist binding polypeptide by no more than 5%. These results demonstrate the glycoprotein nature of muscarinic receptors from mammalian cerebral cortex and provide evidence for their heterogeneity with respect to carbohydrate content.

Animals↗
PubMed1988

Functional expression of the amplification reaction between serotonin and epinephrine on platelets.

Human platelet reactions are enhanced when a combination of serotonin and epinephrine is used as a stimulus. The amplification of the response operates through S2-serotonergic and alpha 2-adrenergic receptor subtypes. The first wave of platelet aggregation, which is independent of platelet release products, is enhanced while the latency period for the occurrence of release reaction and prostaglandin biosynthesis is shortened. Synergism between serotonin and epinephrine on the platelet occurs at low concentration of agonists and may contribute to the formation of an arterial thrombus in vivo.

Adenosine Triphosphate↗
PubMed1990

Transmembrane signaling in P815 mastocytoma cells by transfected IgE receptors.

In order to delineate structural-functional relationships of the mast cell receptor for IgE (Fc epsilon RI) by molecular-genetic analysis, a transfectable cell must be identified which resembles mast cells except for being deficient in receptors. We have found that the well known murine mastocytoma P815 is suitable. These cells express no Fc epsilon RI, lack mRNA for the alpha and beta subunits of the receptor, but contain some mRNA for gamma chains. After transfection with the cDNA for each of the subunits, stable clones could be isolated which expressed several hundred thousand normal Fc epsilon RI and synthesized large amounts of mRNA for alpha, beta, and gamma, the last at 3-fold higher levels than in the untransfected cells. Aggregation of the transfected receptors led to opening of presumptive calcium channels and to activation of phospholipase C, phospholipase A2, and protein kinase C. The kinetics and other characteristics of the signals were similar to those observed after stimulation of the rat tumor mast cells from which the receptor genetic material had been derived but were smaller in magnitude. These weaker signals most likely result from an overall reduced reactivity exhibited by the P815 cells since stimulation by other ligands led to weaker or even no responses. The cells failed to degranulate after either receptor aggregation or reaction with ionophores with or without phorbol ester. Both the transfected and untransfected P815 cells express Fc receptors for IgG (Fc gamma RII) which, interestingly, independently triggered similar responses despite their apparently simpler subunit structure.

Animals↗
PubMed1987

Binding of aggregated immunoglobulins to the human platelet Fc receptors: a mechanism of platelet to platelet bridging.

Aggregated immunoglobulins react with human platelets by occupying the Fc receptors present on their surface, inducing aggregation and the release reaction. We studied the effect of heat aggregated gammaglobulins (HAGG) on ADP-induced aggregation of platelets. We used the minimum concentration of ADP required to induce a reversible aggregation of platelets without any substantial amount of serotonin (14C-5HT) release. EDTA (5 mM) added at the peak of platelet aggregation resulted in rapid deaggregation of these platelets. However, incubation of platelets with HAGG at a dose that did not by itself induce any aggregation or release reaction, followed by ADP addition resulted in an irreversible platelet aggregation of greater magnitude accompanied by a substantial release of 14C-5HT. The addition of EDTA at the peak of platelet aggregation failed to deaggregate these platelets. To determine whether the augmented aggregation response and the inhibition of deaggregation was due to HAGG or a consequence of platelet release products, we used thrombin-degranulated platelets. The augmented aggregation response and the inhibition of deaggregation due to HAGG and ADP could be demonstrated using these platelets. To confirm that the binding of HAGG to the platelet Fc receptors was responsible for these observations, we incubated platelets with an excess of Fc fragments of IgG prior to the addition of HAGG and ADP. This abolished the aggregation response observed previously. From this study we conclude that interplatelet bridging by HAGG renders the platelets hyperaggregable and appears to be a mechanism involved in maintaining platelet aggregates.

Adenosine Diphosphate↗