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PubMed1998

Heterogeneity of platelet aggregation and major surface receptor expression in patients with acute myocardial infarction.

BACKGROUND: Platelets play an important role in the natural history of acute myocardial infarction (AMI). METHODS AND RESULTS: Platelet aggregation and receptor expression were studied in 23 patients with AMI before reperfusion therapy and compared with 10 healthy control subjects. Platelet aggregation was induced with 5 micromol/L adenosine 5'-diphosphate, 10 micromol/L ADP, 1 microg/mL collagen, 1 mg/mL thrombin, and 1.25 mg/mL ristocetin. Receptor expression was measured by flow cytometry with monoclonal antibodies to p24 (CD9), Ib (CD42b), IIb (CD41b), IIIa (CD61), IIb/IIIa (CD41b/CD61), very late antigen-2 (CD49b), P-selectin (CD62p), platelet/endothelial cell adhesion molecule-1 (CD31); and vitronectin (CD51/CD61). The percentage of platelet aggregation was higher in patients with AMI when induced by 5 micromol/L ADP (64.1+/-12.7 vs 52.0+/-6.7; P=.04), by 10 micromol/L ADP (71.7+/-13.0 vs 59.2+/-7.2, P=.003), by thrombin (75.8+/-10.9 vs 60.5+/-6.9, P=.01), and by ristocetin (92.5+/-7.8 vs 71.3+/-7.4, P=.0001). Collagen-induced platelet aggregation did not differ between groups. Expression of P-selectin (log amplification of fluorescence intensity) (31.5+/-5.0 vs 25.1+/-2.6, P=.003) and platelet/endothelial cell adhesion molecule-1 (56.8+/-17.7 vs 44.5+/-3.7, P=.04) were significantly increased in patients with AMI. The expression of IIb (28.4+/-2.5 vs 37.2+/-1.7, P=.0001) and Ib (103.6+/-29.9 vs 133.8+/-8.0, P=.007) were reduced in patients with AMI. CONCLUSIONS: Platelets are not necessarily systemically activated during the prereperfusion phase of AMI. For each agonist used and surface antigen measured, there was a cohort of patients with AMI within the normal or even below normal range of platelet status.

Adenosine Diphosphate↗
PubMed1982

Interaction of verapamil with human platelet alpha-adrenergic receptors.

Platelet aggregation induced by epinephrine is an alpha-adrenergic event and is inhibited in vitro by the calcium-channel blocker, verapamil. We wondered whether this inhibition might be mediated by an interaction of verapamil with platelet alpha-adrenergic receptors. Verapamil inhibited the specific binding of [3H]dihydroergocryptine ([3H]DHE), a nonselective alpha-adrenergic antagonist, to intact platelets in a concentration-dependent and competitive manner. At 10 microM verapamil caused a fivefold decrease in the affinity of binding of [3H]DHE to platelet alpha-adrenergic receptors (P less than 0.001) with no change in the number of receptors per platelet. The inhibition of binding was not reversed by excess calcium. Verapamil also inhibited the binding of a selective alpha 2-adrenergic antagonist, [3H]yohimbine, to intact platelets, and inhibited the binding of an alpha 2-partial agonist, [3H]clonidine, to platelet membranes. Moreover there was a strong correlation between verapamil's effect on [3H]DHE binding and its effect on epinephrine-induced aggregation (r = 0.98). Although verapamil is commonly used as an inhibitor of calcium flux across cell membranes, the present studies demonstrate that verapamil also inhibits epinephrine-induced aggregation at the level of the platelet alpha-adrenergic receptor.

Binding, Competitive↗
PubMed2005

Fc{epsilon}RI-mediated mast cell degranulation requires calcium-independent microtubule-dependent translocation of granules to the plasma membrane.

The aggregation of high affinity IgE receptors (Fcepsilon receptor I [FcepsilonRI]) on mast cells is potent stimulus for the release of inflammatory and allergic mediators from cytoplasmic granules. However, the molecular mechanism of degranulation has not yet been established. It is still unclear how FcepsilonRI-mediated signal transduction ultimately regulates the reorganization of the cytoskeleton and how these events lead to degranulation. Here, we show that FcepsilonRI stimulation triggers the formation of microtubules in a manner independent of calcium. Drugs affecting microtubule dynamics effectively suppressed the FcepsilonRI-mediated translocation of granules to the plasma membrane and degranulation. Furthermore, the translocation of granules to the plasma membrane occurred in a calcium-independent manner, but the release of mediators and granule-plasma membrane fusion were completely dependent on calcium. Thus, the degranulation process can be dissected into two events: the calcium-independent microtubule-dependent translocation of granules to the plasma membrane and calcium-dependent membrane fusion and exocytosis. Finally, we show that the Fyn/Gab2/RhoA (but not Lyn/SLP-76) signaling pathway plays a critical role in the calcium-independent microtubule-dependent pathway.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Positive and negative regulation of mast cell activation by Lyn via the FcepsilonRI.

Aggregation of the high affinity receptor for IgE (FcepsilonRI) induces activation of mast cells. In this study we show that upon low intensity stimulation of FcepsilonRI with monomeric IgE, IgE plus anti-IgE, or IgE plus low Ag, Lyn (a Src family kinase) positively regulates degranulation, cytokine production, and survival, whereas Lyn works as a negative regulator of high intensity stimulation with IgE plus high Ag. Low intensity stimulation suppressed Lyn kinase activity and its association with FcepsilonRI beta subunit, whereas high intensity stimulation enhanced Lyn activity and its association with FcepsilonRI beta. The latter induced much higher levels of FcepsilonRI beta phosphorylation and Syk activity than the former. Downstream positive signaling molecules, such as Akt and p38, were positively and negatively regulated by Lyn upon low and high intensity stimulations, respectively. In contrast, the negative regulators, SHIP and Src homology 2 domain-containing protein tyrosine phosphatase-1, interacted with FcepsilonRI beta, and their phosphorylation was controlled by Lyn. Therefore, we conclude that Lyn-mediated positive vs negative regulation depends on the intensity of the stimuli. Studies of mutant FcepsilonRI beta showed that FcepsilonRI beta subunit-ITAM (ITAM motif) regulates degranulation and cytokine production positively and negatively depending on the intensity of FcepsilonRI stimulation. Furthermore, Lyn-mediated negative regulation was shown to be exerted via the FcepsilonRI beta-ITAM.

Animals↗
PubMed2001

Effects of P2Y(1) and P2Y(12) receptor antagonists on platelet aggregation induced by different agonists in human whole blood.

ADP plays a major role in the amplification of platelet aggregation induced by other platelet agonists. ADP initiates platelet activation via the P2Y(1) receptor and amplifies platelet activation via the P2Y(12) receptor. Using the selective P2Y(1) receptor antagonist A2P5P and the selective P2Y(12) receptor antagonist AR-C69931MX, we assessed the relative contributions of P2Y(1) receptor and P2Y(12) receptor activation to platelet aggregation in hirudin-anticoagulated whole blood induced by PAF, 5HT, epinephrine, TRAP, streptokinase, U46619 and collagen. The effects of aspirin were assessed concurrently. A2P5P and AR-C69931MX variably inhibited aggregation induced by most of the agonists studied, whereas aspirin only inhibited aggregation induced by streptokinase and collagen. In some experiments, A2P5P and AR-C69931MX yielded additive inhibition of aggregation. All three antagonists interacted synergistically to inhibit collagen-induced aggregation. These studies demonstrate that P2Y(1) receptor activation plays a significant role in amplifying aggregation induced by agonists other than ADP, in addition to the established roles of P2Y(12) receptor activation and thromboxane A(2) synthesis.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1994

Transphosphorylation as the mechanism by which the high-affinity receptor for IgE is phosphorylated upon aggregation.

When aggregated, the high-affinity receptors for IgE on mast cells (Fc epsilon RI) launch a series of phosphorylations, particularly of protein tyrosines. We have analyzed how aggregation initiates this cascade. We examined Fc epsilon RI from unstimulated cells and from cells exposed to a polyvalent hapten conjugate that aggregates the Fc epsilon RI via the receptor-bound anti-hapten IgE. We also examined the latter receptors after they had been disaggregated in vitro with monovalent hapten. By an in vitro kinase assay: (i) Unaggregated and disaggregated receptors are associated with a kinase that phosphorylates an exogenous (peptide) substrate but minimally, or not at all, the subunits of Fc epsilon RI or associated proteins (endogenous substrates). After aggregation, phosphorylation of the exogenous substrate is linear with time, but the modification of the endogenous substrates reaches a plateau, presumably because only those endogenous substrates that are adjacent to the kinase are phosphorylated. (ii) Aggregated receptors and disaggregated receptors have enhanced kinase activity toward exogenous substrate. The state of phosphorylation of the receptor correlates strongly with the yield of enhanced kinase activity. We propose that upon aggregation of Fc epsilon RI, a constitutively associated kinase phosphorylates endogenous substrates by transphosphorylation. As a result, additional kinase activity becomes manifest and this promotes further transphosphorylation. In view of the homology between Fc epsilon RI and other receptors central to the immune response, the latter receptors likely utilize a similar transphosphorylation mechanism.

Animals↗
PubMed1991

The putative agrin receptor binds ligand in a calcium-dependent manner and aggregates during agrin-induced acetylcholine receptor clustering.

Agrin derived from Torpedo electric organ induces the clustering of acetylcholine receptors (AChRs) on cultured myotubes. As a first step toward characterizing the plasma membrane receptor for agrin, we have examined agrin binding to cultured myotubes. Agrin binding is saturable as measured by radioimmunoassay and, like agrin-induced AChR clustering, requires extracellular calcium. Immunofluorescence shows that on myotubes incubated with agrin at 4 degrees C, agrin binds in a uniform, finely punctate pattern that correlates poorly with the distribution of AChRs. Myotubes stimulated with agrin at 37 degrees C for greater than or equal to 2 hr show a coclustering of agrin binding sites and AChRs. By contrast, if anti-AChR antibodies are used either to cluster or to internalize AChRs, the distribution and number of agrin binding sites remain unchanged. The aggregation and calcium dependence of the putative agrin receptor may represent important control points in postsynaptic differentiation.

Agrin↗
PubMed1998

A molecular switch changes the signalling pathway used by the Fc gamma RI antibody receptor to mobilise calcium.

BACKGROUND: Leukocytes express Fc gamma receptors, which are specific for the constant region of immunoglobulin G. Aggregation of these receptors activates a repertoire of responses that can lead to targeted cell killing by antibody-directed cellular cytotoxicity. The nature of the myeloid response to Fc gamma receptor aggregation is highly variable and depends on the maturation state of the cell, but little is known about the signalling mechanisms underlying this variability. RESULTS: We show here that differentiation of a monocytic cell line, U937, to a more macrophage phenotype resulted in an absolute and fundamental switch in the nature of the phospholipid signalling pathway recruited following Fc gamma receptor aggregation. In cytokine-primed monocytes, aggregation of the high-affinity receptor Fc gamma RI resulted in the activation of phospholipase D and sphingosine kinase, which in turn led to the transient release of stored calcium; these effects were mediated by the gamma chain, an Fc gamma RI accessory protein. In contrast, in cells differentiated to a more macrophage type, aggregation of Fc gamma RI resulted in the Fc gamma RIIa-mediated activation of phospholipase C, and the resulting calcium response was prolonged as calcium entry was stimulated. CONCLUSIONS: The switch in Fc gamma RI signalling pathways upon monocyte differentiation is mediated by a switch in the accessory molecule recruited by Fc gamma RI, which lacks its own intrinsic signal transduction motif. As many immune receptors have separate polypeptide chains for ligand binding and signal transduction (allowing a similar switch in signalling pathways), the mechanism described here is likely to be widely used.

Bucladesine↗
PubMed2001

Kinetic proofreading models for cell signaling predict ways to escape kinetic proofreading.

In the context of cell signaling, kinetic proofreading was introduced to explain how cells can discriminate among ligands based on a kinetic parameter, the ligand-receptor dissociation rate constant. In the kinetic proofreading model of cell signaling, responses occur only when a bound receptor undergoes a complete series of modifications. If the ligand dissociates prematurely, the receptor returns to its basal state and signaling is frustrated. We extend the model to deal with systems where aggregation of receptors is essential to signal transduction, and present a version of the model for systems where signaling depends on an extrinsic kinase. We also investigate the kinetics of signaling molecules, "messengers," that are generated by aggregated receptors but do not remain associated with the receptor complex. We show that the extended model predicts modes of signaling that exhibit kinetic discrimination for some range of parameters but for other parameter values show little or no discrimination and thus escape kinetic proofreading. We compare model predictions with experimental data.

Animals↗
PubMed1992

Granulocyte Fc gamma receptor recognition of cell bound and aggregated IgG: effect of gamma-interferon.

Granulocyte Fc gamma receptors are important components in the recognition of IgG-coated cells and immune complexes. Two proteins have been identified on resting human granulocytes which function as Fc gamma receptors, Fc gamma RII (CD32) and Fc gamma RIII (CD16). A third protein, Fc gamma RI (CD64), is not constitutively expressed on resting granulocytes, but can be induced by activation with gamma-interferon. We examined the role of these three Fc gamma receptors on human granulocytes in the binding of both IgG-sensitized erythrocytes and soluble oligomeric IgG. In these studies we employed anti-Fc gamma receptor antibodies which complete for the Fc gamma RII and Fc gamma RIII ligand binding sites. Preincubation of granulocytes with saturating concentrations of high-affinity anti-Fc gamma RII monoclonal antibody did not alter the recognition of IgG sensitized human cells by granulocytes. Furthermore, ligand binding studies demonstrated that anti-Fc gamma RII antibody altered neither the number nor the affinity of granulocyte binding sites for human trimeric IgG. In contrast, Fab anti-Fc gamma RIII inhibited the binding of both IgG (anti-D) sensitized human RBCs and IgG sensitized sheep RBCs. Similarly, a reduction in the expression of Fc gamma RIII by treatment with phosphatidyl-inositol specific phospholipase C reduced PMN recognition of IgG-sensitized cells. Also, anti-Fc gamma RIII decreased the number of granulocyte binding sites for human IgG trimer without a change in receptor affinity. Fc gamma RI, which was induced by gamma-IFN, increased granulocyte recognition of both IgG sensitized RBCs and IgG trimer. These data suggest that Fc gamma RIII is the primary Fc gamma receptor on granulocytes which recognizes IgG sensitized RBCs and low molecular weight complexes of IgG. With gamma-interferon activated granulocytes, Fc gamma RI appears to enhance this recognition process.

Antibodies, Monoclonal↗
PubMed1998

Phagocytosis of the malarial pigment, hemozoin, impairs expression of major histocompatibility complex class II antigen, CD54, and CD11c in human monocytes.

In Plasmodium falciparum malaria, large proportions of resident macrophages and circulating monocytes and leukocytes contain massive amounts of the malarial pigment, hemozoin. Previous studies have shown that important functions (e.g., the generation of the oxidative burst, the ability to repeat phagocytosis, and protein kinase C activity) were severely impaired in hemozoin-loaded monocytes. Expression of membrane antigens directly involved in the immune response and in the phagocytic process, and/or under protein kinase C control, in hemozoin-loaded human monocytes was studied. Expression of major histocompatibility complex (MHC) class II after gamma interferon stimulation was blocked in hemozoin-loaded monocytes at the protein expression and gene transcription levels but was preserved in control monocytes loaded with opsonized latex beads or anti-D(Rho)-immunoglobulin G (IgG)-opsonized human erythrocytes. Expression of CD54 (intracellular adhesion molecule 1) and CD11c (p150,95 integrin) was also decreased in hemozoin-loaded monocytes. Expression of MHC class I, CD16 (low-affinity Fc receptor for aggregated IgG), CD32 (low-affinity Fc receptor for aggregated IgG), CD64 (high-affinity receptor for IgG), CD11b (receptor for complement component iC3b [CR3]), CD35 (receptor for complement components C3b and C4b [CR1]), and CD36 (non-class-A scavenger receptor) was not specifically affected by hemozoin loading. These results suggest that hemozoin loading may contribute to the impairment of the immune response and the derangement of antigen presentation reported in previous studies of P. falciparum malaria.

Adult↗
PubMed1997

The negative signaling molecule SH2 domain-containing inositol-polyphosphate 5-phosphatase (SHIP) binds to the tyrosine-phosphorylated beta subunit of the high affinity IgE receptor.

The SH2 domain-containing inositol-polyphosphate 5-phosphatase, SHIP, associates with FcgammaRIIB and negatively regulates both B-cell and mast cell function. We report here that SHIP was tyrosine-phosphorylated after high affinity IgE receptor (FcepsilonRI) aggregation in rat basophilic leukemia RBL-2H3 cells. The tyrosine phosphorylation of SHIP was an early event after receptor aggregation and was present in cells deficient in the protein-tyrosine kinase Syk. Furthermore it was not secondary to the increase of intracellular calcium or the activation of protein kinase C. SHIP was precipitated by immobilized phosphorylated synthetic peptides based on the immunoreceptor tyrosine-based activation motif (ITAM) of the beta but not the gamma subunit of the high affinity IgE receptor. Tyrosine phosphorylation of SHIP and its association with the tyrosine-phosphorylated beta subunit of FcepsilonRI could play an important role in down-regulating receptor-mediated signal transduction in mast cells. Thus, whereas the activation molecule Syk associates with the gamma subunit ITAM, the beta subunit ITAM binds the negative signaling molecule SHIP. Therefore, unlike B cells where the antigen receptor and coreceptors such as FcgammaRIIB or CD22 each recruits molecules with opposite effects, the FcepsilonRI contains subunits which recruit molecules that activate and inhibit signal transduction.

Amino Acid Sequence↗
PubMed2004

The influence of actin microfilaments on signaling by the receptor with high-affinity for IgE.

Aggregation of the receptors with high-affinity for IgE (FcRI) stimulates a variety of cellular responses, but excessive aggregation inhibits such responses. Actin filaments have been implicated in the inhibitory phenomenon because disrupting the filaments enhances the cellular reactions stimulated by the aggregated receptors. To clarify further the molecular mechanism and physiological importance of the actin-mediated inhibition, we assessed the effect of inhibitors of actin polymerization on the initial signaling events of mast cells alternatively stimulated by nitrophenyl ligands that dissociate slowly (high-affinity) or rapidly (low-affinity) from receptor-bound anti-dinitrophenyl IgE. The inhibitors amplified the phosphorylation of FcRI and of Syk induced by addition of either ligand but at physiological temperatures, the augmentation of the response to the low-affinity ligand was especially exaggerated. The effect of actin is on the earliest events, and although the molecular mechanism(s) by which the filaments regulate the intensity of proximal signaling remains unclear, several possibilities have been excluded. That the inhibitors only minimally augment the responses stimulated by preformed dimers of IgE, and in general show smaller effects with more limited aggregation, suggests that the actin-mediated "down-regulation" may be more prominent in laboratory experiments than under physiological circumstances.

Actin Cytoskeleton↗
PubMed2001

ADP receptor antagonists inhibit platelet aggregation induced by the chemokines SDF-1, MDC and TARC.

The ability of the chemokines SDF-1, MDC and TARC to induce platelet aggregation depends strongly on low levels of ADP. The ADP receptors involved have now been characterized using the P2Y(1) and P2T(AC) receptor antagonists, A2P5P and AR-C69931MX. Stimulation of aggregation by the chemokines at 10 s was not blocked by AR-C69931MX, but was strongly inhibited by A2P5P. Pertussis toxin abolished the chemokine-stimulated aggregation. We conclude that the P2Y(1) ADP receptor plays a critical role in the initial phases of SDF-1-, MDC- and TARC-induced platelet aggregation, which involve a pertussis toxin-sensitive G protein.

Adenosine Diphosphate↗
PubMed1989

Evidence that aggregation of mouse sperm receptors by ZP3 triggers the acrosome reaction.

In the mouse, considerable evidence indicates that initial sperm binding to the zona pellucida (ZP) is mediated by ZP3. In addition, this same glycoprotein is also responsible for inducing the acrosome reaction (AR). Whereas the O-linked oligosaccharides of ZP3 appear to mediate sperm-ZP binding, the portion of ZP3 bearing AR activity has not been defined. To try to understand the bifunctional role of ZP3 (binding and AR inducing activities), we have examined the hypothesis that ZP3 aggregates sperm receptor molecules. By analogy with findings in a variety of other extracellular signal transducing systems, including receptors for growth factors and insulin, this aggregation event could initiate the cascade resulting in the AR. To test this hypothesis, we have generated monospecific polyclonal antibodies against ZP2 and against ZP3, and examined the effects of these probes on capacitated sperm incubated in the absence or presence of various ZP protein preparations. For some experiments, we have used proteolytic fragments of ZP3, a preparation known to retain specific binding, but not AR-inducing, activity. We show here that capacitated mouse sperm, incubated with ZP glycopeptides, displayed ARs when incubated subsequently with anti-ZP3 IgG; ARs did not occur when parallel sperm samples were incubated with anti-ZP2 IgG or with anti-ZP3 Fab fragments. When capacitated sperm were treated successively, with (a) ZP3 glycopeptides, (b) anti-ZP3 Fab fragments, and (c) goat anti-rabbit IgG, ARs occurred in the majority of sperm. An alternative approach to examine this hypothesis used ZP proteins obtained from tubal eggs treated previously with bioactive phorbol diester (12-O-tetradecanoyl phorbol-13-acetate [TPA]). This preparation arrests capacitated sperm in an intermediate state of the AR. We demonstrate here that these sperm can be induced to undergo a complete AR by subsequent treatment with anti-ZP3 IgG. Together, these findings are consistent with the hypothesis under examination, and suggest that the aggregation of sperm molecules recognized by ZP3 glycopeptides or by TPA-treated ZP is sufficient to trigger the events that occur during acrosomal exocytosis.

Acrosome↗
PubMed2005

How receptor mosaics decode transmitter signals. Possible relevance of cooperativity.

It has been demonstrated that receptor-receptor interactions between G-protein-coupled receptors (GPCRs) occur at the plasma-membrane level. It has also been shown that clustering of GPCRs in aggregates or receptor mosaics (RMs) results in the reciprocal modulation of their binding and decoding characteristics. It is hypothesized that cooperativity plays an important part in the decoding of signals processed by RMs of GPCRs. Thus, the binding of the ligand at one receptor alters the likelihood of the same ligand binding at the next site, in the case of RMs, formed by identical receptors and/or by iso-receptors (receptors that bind the same ligand).

Allosteric Regulation↗
PubMed1984

Direct visualization of binding, aggregation and internalization of human growth hormone in cultured human lymphocytes.

The distribution of human growth hormone (hGH) receptor complexes on IM-9 cultured lymphocytes was studied using fluorescein and 125I-labelled hGH (F-hGH and [125I]hGH). The cells labelled with F-hGH were visualized with a sensitive video intensification microscopic system which permitted direct observation of the location of the fluorescent hormone on the surface of the living lymphocytes. At 4 degrees C F-hGH bound diffusely to the cell surface and remained dispersed but following incubation for 30 min at 37 degrees C the hormone receptor complexes aggregated into patches on the cell surface and formed a single cap on one pole of the cell. Progressive internalization into the cell was demonstrated at 37 degrees C with [125I]hGH. It is hypothesized that the aggregation and internalization of the hGH receptor complexes are associated with the action and degradation of the hormone and probably also with the mechanism of down-regulation of the receptors.

Cells, Cultured↗
PubMed1992

Aggregation of IgE-receptor complexes on rat basophilic leukemia cells does not change the intrinsic affinity but can alter the kinetics of the ligand-IgE interaction.

The aggregation of IgE anchored to high-affinity Fc epsilon receptors on rat basophilic leukemia (RBL) cells by multivalent antigens initiates transmembrane signaling and ultimately cellular degranulation. Previous studies have shown that the rate of dissociation of bivalent and multivalent DNP ligands from RBL cells sensitized with anti-DNP IgE decreases with increasing ligand incubation times. One mechanism proposed for this effect is that when IgE molecules are aggregated, a conformational change occurs that results in an increase in the intrinsic affinity of IgE for antigen. This possibility was tested by measuring the equilibrium constant for the binding of monovalent DNP-lysine to anti-DNP IgE under two conditions, where the cell-bound IgE is dispersed and where it has been aggregated into visible patches on the cell surface using anti-IgE and a secondary antibody. No difference in the equilibrium constant in these two cases was observed. We also measured the rate of dissociation of a monovalent ligand from cell surface IgE under these two conditions. Whereas the affinity for monovalent ligand is not altered by IgE aggregation, we observe that the rate of ligand dissociation from IgE in clusters is slower than the rate of ligand dissociation from unaggregated IgE. These results are discussed in terms of recent theoretical developments concerning effects of receptor density on ligand binding to cell surfaces.

Animals↗