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PubMed1992

Effects of adenosine derivatives on human and rabbit platelet aggregation. Correlation of adenosine receptor affinities and antiaggregatory activity.

The inhibitory effects of several adenosine analogues, including the new A2-selective agonists 2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamido-adenosi ne (CGS 21680) and 2-hexynyl-5'-N-ethylcarbox-amidoadenosine (2-hexynyl-NECA), were investigated in vitro on human and rabbit platelet aggregation. The compounds examined inhibited ADP-induced platelet aggregation over a wide range of potency. The rank order of activity was similar between the two species thus showing that the rabbit is a useful animal model for studying the effects of adenosine derivatives on platelet aggregation. 2-Hexynyl-NECA was found to be the most potent adenosine compound of those currently available, having IC50 values of 0.10 and 0.07 microM in human and rabbit platelets, respectively. Conversely, the A1 agonists R(-)-N6-(2-phenylisopropyl) adenosine (R-PIA), S(+)-N6-(2-phenylisopropyl) adenosine (S-PIA) and 2-chloro-N6-cyclopentyladenosine (CCPA) were the least potent compounds with IC50 values in the micromolar range. The potency of the compounds in inhibiting platelet aggregation was found to be highly correlated with their affinity for A2 receptors as measured using 3H-CGS 21680 binding in rat brain striatum.

Adenosine↗
PubMed1984

Initial characterization of the calcium channel activated by the cross-linking of the receptors for immunoglobulin E.

It is currently thought that aggregation of the receptor for immunoglobulin E on mast cells, basophils, and a tumor analog, rat basophilic leukemia (RBL) cells, induces an enhanced permeability of the plasma membrane to calcium, thereby initiating degranulation of the cells. Even in the absence of calcium ions, aggregation of the receptor causes depolarization of the plasma membrane (Kanner, B. I., and Metzger, H. (1983) Proc. Natl. Acad. Sci. U. S. A. 80, 5744-5748), suggesting that other ions can traverse the putative channel. Direct evidence for this now has been obtained with measurements of increased 22Na+ fluxes in the absence of calcium ions, induced by aggregation of receptors. This reaction was optimally studied in the presence of ouabain. When aggregation of the receptor was induced by reacting the cell-bound IgE with a multivalent antigen, the sodium flux was completely inhibited by univalent hapten. The sodium flux was also completely inhibited by 2 mM calcium. Aggregation-induced 45Ca2+ fluxes were observed in the presence of millimolar concentrations of external Ca2+, but not in its absence. Depolarization of the plasma membrane potential by the addition of potassium to the medium in the presence of calcium did not itself induce degranulation. In fact, aggregation of the receptors for IgE in the presence of high external potassium resulted in a greatly diminished degranulation. These data indicate that the ion channel modulated by aggregation of receptor differs from the voltage-dependent type of calcium channels. We suggest that in the absence of calcium this channel is rather unspecific, but that calcium can modify it to become calcium selective.

Animals↗
PubMed1987

The platelet fibrinogen receptor: an immunogold-surface replica study of agonist-induced ligand binding and receptor clustering.

Platelet aggregation requires the binding of fibrinogen to its receptor, a heterodimer consisting of the plasma-membrane glycoproteins (GP) IIb and IIIa. Although the GPIIb-IIIa complex is present on the surface of unstimulated platelets, it binds fibrinogen only after platelet activation. We have used an immunogold-surface replica technique to study the distribution of GPIIb-IIIa and bound fibrinogen over broad areas of surface membranes in unstimulated, as well as thrombin-activated and ADP-activated human platelets. We found that the immunogold-labeled GPIIb-IIIa was monodispersed over the surface of unstimulated platelets, although the cell surface lacked immunoreactive fibrinogen. On thrombin-stimulated platelets, approximately 65% of the GPIIb-IIIa molecules were in clusters within the plane of the membrane. Fibrinogen, which had been released from the alpha-granules of these cells, bound to GPIIb-IIIa on the cell surface and was similarly clustered. To determine whether the receptors clustered before ligand binding, or as a consequence thereof, we studied the surface distribution of GPIIb-IIIa after stimulation with ADP, which causes activation of the fibrinogen receptor function of GPIIb-IIIa without inducing the release of fibrinogen. In the absence of added fibrinogen, the unoccupied, yet binding-competent receptors on ADP-stimulated platelets were monodispersed. The addition of fibrinogen caused the GPIIb-IIIa molecules to cluster on the cell surface. Clustering was also induced by the addition of the GPIIb-IIIa-binding domains of fibrinogen, namely the tetrapeptide Arg-Gly-Asp-Ser on the alpha-chain or the gamma-chain decapeptide gamma 402-411. These results show that receptor occupancy causes clustering of GPIIb-IIIa in activated platelets.

Adenosine Diphosphate↗
PubMed2001

C-terminal peptide of thrombospondin-1 induces platelet aggregation through the Fc receptor gamma-chain-associated signaling pathway and by agglutination.

A peptide from the C-terminal domain of thrombospondin-1 (Arg-Phe-Tyr-Val-Val-Met-Trp-Lys; known as 4N1-1) has been reported to induce platelet aggregation and to bind to the integrin-associated protein (IAP), which is also known as CD47. In this study, it was discovered that 4N1-1 or its derivative peptide, 4N1K, induces rapid phosphorylation of the Fc receptor (FcR) gamma chain, Syk, SLP-76, and phospholipase C gamma2 in human platelets. A specific inhibitor of Src family kinases, 4-amino-4-(4-methylphenyl)-7-(t-butyl) pyrazola[3,4-d]pyrimidine, prevented phosphorylation of these proteins, abolished platelet secretion, and reduced aggregation by approximately 50%. A similar inhibition of aggregation to 4N1-1 was obtained in the presence of Arg-Gly-Asp-Ser in mouse platelets deficient in FcR gamma chain or SLP-76 and in patients with type I Glanzmann thrombasthenia. These results show that 4N1-1 signals through a pathway similar to that used by the collagen receptor glycoprotein (GP) VI. The alphaIIbbeta3-independent aggregation induced by 4N1-1 was also observed in fixed platelets and platelets from patients with Bernard-Soulier syndrome, which are deficient in GPIbalpha. Surprisingly, the ability of 4N1-1 to stimulate aggregation and tyrosine phosphorylation was not altered in platelets pretreated with anti-IAP antibodies and in IAP-deficient mice. These results show that the C-terminal peptide of thrombospondin induces platelet aggregation through the FcR gamma-chain signaling pathway and through agglutination. The latter pathway is independent of signaling events and does not use GPIbalpha or alphaIIbbeta3. Neither of these pathways is mediated by IAP.

Amino Acid Sequence↗
PubMed1995

Simultaneous cross-linking by two nontriggering bivalent ligands causes synergistic signaling of IgE Fc epsilon RI complexes.

We have used two bivalent ligands that bind IgE to study the relationship between the aggregation of receptors with high affinity for IgE (Fc epsilon RI) and the responses (receptor immobilization, Ca2+ influx, and degranulation) of rat basophilic leukemia (RBL-2H3) cells. One of these is a symmetric bivalent ligand, N,N'-bis[[epsilon-[(2,4-dinitrophenyl)amino]caproyl]-L-tyrosyl]-L- cystine ((DCT)2-cys), which binds specifically to the combining sites of a mAb anti-DNP IgE and efficiently cross-links cell surface IgE, but does not trigger significant degranulation or increases in intracellular Ca2+. Several lines of evidence, including lateral mobility measurements, indicate that this ligand preferentially forms stable cyclic complexes containing two (DCT)2-cys and two IgE. The second ligand is a mAb anti-IgE, B1E3, which causes lateral mobility changes consistent with dimerized IgE-Fc epsilon RI and also does not trigger increases in intracellular Ca2+ or degranulation. The two ligands together trigger robust responses. In the presence of B1E3, (DCT)2-cys causes immobilization of IgE-Fc epsilon RI in a broad concentration range; in a more narrow concentration range, it is a potent stimulant of changes in both degranulation and Ca2+. We have compared the dose-response curves for cellular activation to simulated IgE aggregation curves, i.e., curves that predict the equilibrium IgE aggregate size distribution as a function of the (DCT)2-cys concentration. Our results indicate that maximal cellular activation occurs at a much higher (DCT)2-cys concentration than maximal IgE aggregation. When IgE aggregation is maximal, almost all aggregated IgE is in cyclic dimers. Thus, cyclic dimers appear to be functionally ineffective, even after they have been cross-linked by B1E3. Aggregated IgE-Fc epsilon RI that is effective in stimulating a cellular response may have particular structural or dynamic properties that allow critical interactions for initiating the signaling cascade.

Animals↗
PubMed2003

Synthesis and secretion of monocyte chemotactic protein-1 stimulated by the high affinity receptor for IgE.

In prior studies aggregation of the high affinity receptors for IgE, Fc epsilon RI, on a rat mast cell line, RBL-2H3, stimulated transcription of the gene for monocyte chemotactic protein-1 (MCP-1) and secretion of the protein. Unexpectedly, those delayed events appeared much less constrained by kinetic proofreading than had been documented for other receptor-initiated responses. The results of the present experiments are consistent with the proposal that the biosynthesis and secretion of MCP-1 result from a soluble messenger formed in the reaction cascades initiated by the receptor, and that Ca(2+) could serve as that messenger. Interestingly, whereas receptor-mediated signals were required for transcription of the gene for MCP-1 and secretion of the chemokine, such signals were not required for the intervening step of translation of its mRNA.

Animals↗
PubMed2004

Camptothecin- and etoposide-induced apoptosis in human leukemia cells is independent of cell death receptor-3 and -4 aggregation but accelerates tumor necrosis factor-related apoptosis-inducing ligand-mediated cell death.

During camptothecin- and etoposide (VP-16)-induced apoptosis in HL-60 cells, the expression level of cell death receptor-3 (DR3), cell death receptor-4 (DR4), and FAS remained mostly unchanged, whereas the expression of silencers of death domain (SODD) and FLICE inhibitory proteins, inhibitors of the cell death receptor signaling pathways, decreased substantially. By indirect immunofluorescence and immunoperoxidase imaging and with gel filtration column chromatography, we observed rapid aggregation at the cell surface and the appearance of high molecular weight protein complexes primarily involving DR3, and DR3 and DR4 after camptothecin and VP-16 treatment, respectively. Both drugs failed to rapidly promote FAS aggregation in these cells. The high expression level of SODD or of dominant negative forms of FADD (FADD-DN) and DAP3 (DAP3-DN), or of NH2-terminal deletion mutant of TRADD (TRADD-ND) achieved by transient transfection experiments, did not impair the kinetics of apoptosis after camptothecin and VP-16 treatment in HL-60 and U937 cells. Taken together, these observations suggested that camptothecin and VP-16 induced rapid aggregation of DR4 and DR3, but paradoxically, the importance of these events in signaling apoptosis is uncertain, because the kinetics of apoptosis were unaffected, even in the presence of a high expression level of SODD, FADD-DN, TRADD-ND, and DAP3-DN. However, camptothecin or VP-16 treatment in combination with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) substantially accelerated kinetics of apoptosis than treatment with camptothecin, VP-16, or TRAIL alone. In contrast, cotreatment of camptothecin or VP-16 with TWEAK or TL1A did not facilitate apoptosis in HL60 cells. These findings suggest that DR4 aggregation mediated by camptothecin or VP-16 could represent a mean that accelerates TRAIL-induced apoptosis.

Adaptor Proteins, Signal Transducing↗
PubMed1998

The P2Y1 receptor is necessary for adenosine 5'-diphosphate-induced platelet aggregation.

The human P2Y1 receptor heterologously expressed in Jurkat cells behaves as a specific adenosine 5'-diphosphate (ADP) receptor at which purified adenosine triphosphate (ATP) is an ineffective agonist, but competitively antagonizes the action of ADP. This receptor is thus a good candidate to be the elusive platelet P2T receptor for ADP. In the present work, we examined the effects on ADP-induced platelet responses of two selective and competitive P2Y1 antagonists, adenosine-2'-phosphate-5'-phosphate (A2P5P) and adenosine-3'-phosphate-5'-phosphate (A3P5P). Results were compared with those for the native P2Y1 receptor expressed on the B10 clone of rat brain capillary endothelial cells (BCEC) and for the cloned human P2Y1 receptor expressed on Jurkat cells. A2P5P and A3P5P inhibited ADP-induced platelet shape change and aggregation (pA2 = 5) and competitively antagonized calcium movements in response to ADP in fura-2-loaded platelets, B10 cells, and P2Y1-Jurkat cells. In contrast, these compounds had no effect on ADP-induced inhibition of adenylyl cyclase in platelets or B10 cells, whereas known antagonists of platelet activation by ADP such as Sp-ATPalphaS were effective. These identical signaling responses and pharmacologic properties suggest that platelets and BCEC share a common P2Y1 receptor involved in ADP-induced aggregation and vasodilation, respectively. This P2Y1 receptor coupled to the mobilization of intracellular calcium stores was found to be necessary to trigger ADP-induced platelet aggregation. The present results, together with data from the literature, also point to the existence of another as yet unidentified ADP receptor, coupled to adenylyl cyclase and responsible for completion of the aggregation response. Thus, the term, P2T, should no longer be used to designate a specific molecular entity.

Adenosine Diphosphate↗
PubMed1997

Involvement of the ras-like GTPase rab3d in RBL-2H3 mast cell exocytosis following stimulation via high affinity IgE receptors (Fc epsilonRI).

Aggregation of high affinity IgE receptors (Fc epsilonRI) expressed on mast cells and basophils is a potent stimulus for the release of inflammatory mediators from cytoplasmic granules. Fc epsilonRI-dependent exocytosis requires activation of protein kinase C and mobilization of calcium from intra- and extracellular stores. However, how these events ultimately regulate the membrane fusion step between cytoplasmic granules and the plasma membrane still remains unclear. In this study, we investigated the role of the small GTPases of the rab3 subfamily in the regulated exocytosis following stimulation of rat basophilic leukemia cells (RBL-2H3). Analysis using reverse-transcriptase-based PCR showed that RBL-2H3 cells expressed rab3a and rab3d isoforms, with a predominance of rab3d at the mRNA level. Investigation of the subcellular distribution using isoform-specific Abs demonstrated that the majority of rab3a was expressed in the cytosol, whereas rab3d was found predominantly in the membrane fraction. To determine whether these proteins play a role in Fc epsilonRI-triggered exocytosis, we established RBL-2H3 transfectants that overexpressed wild-type and expressed GTP-binding mutant forms (N135I) of rab3a and rab3d. Whereas expression of rab3a proteins did not significantly affect degranulation as tested by beta-hexosaminidase release, those of both wild-type and mutant rab3d proteins inhibited degranulation. Calculations of the initial fast and of the second slow release rates showed that they are both inhibited about twofold, suggesting that rab3d interferes with a rate-limiting step in Fc epsilonRI-stimulated exocytosis.

Amino Acid Sequence↗
PubMed1988

Localization of chemoattractant receptors on Dictyostelium discoideum cells during aggregation and down-regulation.

cAMP chemoattractant receptors on the surface of Dictyostelium discoideum cells are visualized by means of immunocytochemistry. Receptor antigen is virtually absent from growing cells and begins to accumulate after about 6 hr of starvation, concomitant with the increase in surface cAMP binding activity. In aggregating cells, the antigen is uniformly distributed over the cell surface. Persistent cAMP stimulation, which leads to down-regulation of cAMP binding activity, induces a striking rearrangement of receptor antigen into patches or internal vesicles. A similar patching of receptor antigen is observed during tight aggregate formation, when surface cAMP binding activity decreases. These observations indicate that receptor down-regulation involves receptor agglomeration and suggest that receptor down-regulation takes place in vivo, when tight aggregates are being formed.

Cell Aggregation↗
PubMed1998

Strychnine-sensitive stabilization of postsynaptic glycine receptor clusters.

The cellular and molecular mechanisms underlying the postsynaptic aggregation of ionotropic receptors in the central nervous system are not understood. The glycine receptor (GlyR) and its cytoplasmic domain-associated protein, gephyrin, are clustered at the postsynaptic membrane and constitute a good model for addressing these questions. The glycine receptor is inhibited by strychnine. The effects of chronic strychnine treatment on the expression and cellular distribution of gephyrin and glycine receptor were therefore tested using primary cultures of spinal cord neurons. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis revealed that the glycine receptor alpha1, alpha2, beta subunits and gephyrin mRNAs were expressed at comparable levels in strychnine-treated and untreated cultures. The number of immunoreactive cells and the subcellular distribution of gephyrin and GlyR subunits was determined with standard and confocal immunofluorescence. The proportion of gephyrin and glycine receptor-immunoreactive (IR) cells was unaffected by strychnine treatment. Confocal microscopy revealed that the glycine receptor was mainly localized intracellularly near the nucleus. This cytoplasmic glycine receptor was not associated with the Golgi apparatus nor with the rough endoplasmic reticulum and therefore is not likely to correspond to neosynthesized proteins. The number of GlyR clusters on the somato-dendritic membrane was dramatically reduced on neurons displaying intracellular staining. In contrast, the subcellular distribution and the number of gephyrin clusters was not modified by the treatment. The fact that gephyrin postsynaptic localization was not modified by strychnine suggests that the aggregation of glycine receptor and gephyrin is governed by different mechanisms. The distribution of other cell surface molecules such as NCAM or GABAA receptor beta2/3 subunits was not modified by strychnine treatment. Chronic exposure of the cultures to tetrodotoxin did not affect gephyrin or glycine receptor cluster formation. Taken together, these results indicate that functional glycine receptor, but not electrical synaptic activity, is required for the formation of glycine receptor clusters.

Animals↗
PubMed1986

Aggregated C-reactive protein binds to human polymorphonuclear leukocytes and potentiates Fc receptor-mediated chemiluminescence.

Aggregated C-reactive protein (CRP), an acute phase reactant, binds to and influences the functional activities of human mononuclear leukocytes. Our purpose was to examine the potential interactions between CRP and human polymorphonuclear leukocytes (PMNL). Binding of CRP to PMNL was examined by flow cytometry after cell incubation with fluorescein-labeled heat-aggregated CRP (Agg-CRP) or Agg-CRP and fluorescein-conjugated F(ab')2 anti-CRP antibodies. It was determined that, at an optimal dose of Agg-CRP (100 micrograms), approximately 36% of PMNL were fluorescence positive. This was in contrast to the 70% of monocytes and 8% of lymphocytes that expressed Agg-CRP binding sites. Although less than half of resting PMNL bound Agg-CRP, up to 93% of PMNL activated with 1.0 micrograms/ml of phorbol myristate acetate (PMA) expressed binding sites for Agg-CRP. Exposure to PMA similarly enhanced the amount of Agg-CRP bound per PMNL as determined by mean channel fluorescence. To evaluate whether Agg-CRP binding to PMNL could induce or modify a biologic response, respiratory burst activity was assessed by measuring luminol-enhanced chemiluminescence. Whereas Agg-CRP alone did not elicit a chemiluminescence response, Agg-CRP synergistically enhanced the chemiluminescence response induced by heat-aggregated IgG (Agg-IgG). Although this enhancing effect of Agg-CRP could be observed at both optimal and suboptimal concentrations of Agg-IgG, no enhancement of PMA or serum-opsonized zymosan-induced CL was detected. These data demonstrate that aggregated CRP binds to and selectively modulates the response of PMNL to Fc receptor-mediated activation.

C-Reactive Protein↗
PubMed1995

Contrasting effects of thrombin and the thrombin receptor peptide, SFLLRN, on aggregation and release of 14C-serotonin by human platelets pretreated with chymotrypsin or serratia marcescens protease.

Chymotrypsin cleaves glycoprotein Ib (GPIb) on platelets and reduces their responsiveness to thrombin; platelets from patients with the Bernard-Soulier syndrome, which lack GPIb, are also less responsive to thrombin than platelets from normal donors. However, Bernard-Soulier platelets respond normally to the thrombin receptor peptide SFLLRN (13). We compared responses of 14C-serotonin-labeled, chymotrypsin-treated platelets (and control platelets) to thrombin (0.25-2 U/ml) and SFLLRN (5-40 microM). Chymotrypsin treatment strongly inhibited thrombin-induced aggregation and release of 14C-serotonin when concentrations of thrombin of 0.5 U/ml or lower were used, even though these responses of control platelets remained near the maximum. In contrast, there was little difference between the responses of control and chymotrypsin-treated platelets to SFLLRN, even when the responses of control platelets were less than maximal. Thus, chymotrypsin treatment greatly inhibits the response to thrombin of the seven transmembrane domain thrombin receptor cloned by Coughlin's group (1, 2). Since Serratia marcescens protease also hydrolyses GPIb, but has less effect than chymotrypsin on other glycoproteins, we pretreated platelets with several concentrations of S. marcescens protease. Concentrations that abolished aggregation and release of 14C-serotonin in response to thrombin had little effect on these responses to SFLLRN. One interpretation of these findings would be that by cleaving GPIb, both proteases are affecting an interaction that may be important for activation of the cloned receptor by thrombin, but irrelevant to activation of this receptor by SFLLRN.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1995

The receptor tyrosine kinase ARK mediates cell aggregation by homophilic binding.

The ARK (AXL, UFO) receptor is a member of a new family of receptor tyrosine kinases whose extracellular domain contains a combination of fibronectin type III and immunoglobulin motifs similar to those found in many cell adhesion molecules. ARK mRNA is expressed at high levels in the mouse brain, prevalently in the hippocampus and cerebellum, and this pattern of expression resembles that of adhesion molecules that are capable of promoting cell aggregation through homophilic or heterophilic binding. We report here the ability of the murine ARK receptor to mediate homophilic binding. Expression of the ARK protein in Drosophila S2 cells induces formation of cell aggregates consisting of ARK-expressing cells, and aggregation leads to receptor activation, with an increase in receptor phosphorylation. Homophilic binding does not require ARK tyrosine kinase activity, since S2 cells expressing a receptor in which the intracellular domain was deleted were able to undergo aggregation as well as cells expressing the wild-type ARK receptor. Similar results were obtained with NIH 3T3 and CHO cells expressing high levels of ARK, although in this case ARK expression appeared to be accompanied by constitutive activation. The purified recombinant extracellular domain of ARK can induce homotypic aggregation of coated fluorescent beads (Covaspheres), and this protein can also function as a substrate for adhesion by S2 and NIH 3T3 cells expressing ARK. These results suggest that ARK represents a new cell adhesion molecule that through its homophilic interaction may regulate cellular functions during cell recognition.

3T3 Cells↗
PubMed1995

Chemical cross-linking of IgE-receptor complexes in RBL-2H3 cells.

Aggregation of the high-affinity receptors for IgE (Fc epsilon RI) on mast cells activates nonreceptor kinases and other enzymes, thereby initiating a complex biochemical cascade. We have employed a chemical cross-linker in order to stabilize the association of Fc epsilon RI with other cellular proteins that are involved in the early events. We reacted the water-soluble, membrane-impermeant chemical cross-linker 3,3'-dithiobis(sulfosuccinimidyl propionate) (DTSSP) with permeabilized rat mucosal mast cells of the RBL line and analyzed immunoprecipitates of the receptor in detergent lysates of cells that had biosynthetically incorporated [35S]cysteine. Gel electrophoresis revealed substantial amounts of nonreceptor components only when the cells had been reacted with DTSSP. Receptors isolated from cells whose receptor-bound IgE had been aggregated with antigen prior to cross-linking yielded a similar pattern of 35S-labeled proteins. However, when the cells had also been exposed to [gamma-32P]ATP, the proteins associated with the cross-linked, aggregated receptors revealed enhanced incorporation of 32P compared to those associated with cross-linked, unaggregated receptors. A variety of antibodies were used to try to identify the associated proteins. Of those tested for, two, the src-like kinase p53/56lyn and the delta isoform of protein kinase C, were associated with the cross-linked Fc epsilon RI in amounts much greater than could be accounted for by nonspecific cross-linking.

Animals↗
PubMed2005

Platelet aggregation and adenosine diphosphate/adenosine triphosphate receptors: a historical perspective.

The work of many investigators since adenosine diphosphate (ADP) was recognized as a platelet aggregating agent in 1961 has led to an appreciation of the important part that ADP plays in hemostasis and thrombosis. Recently, interest has focused on the platelet receptors for ADP and adenosine triphosphate (ATP). Platelets are unique because they have two P2Y receptors that must act in concert to achieve a normal aggregation response. The P2Y (1) receptor is responsible for mobilizing internal calcium, platelet shape change, and weak aggregation. The P2Y (12) receptor inhibits adenylyl cyclase, but the concentration of cyclic AMP is reduced only if it has been raised from its low basal levels by stimulation of adenylyl cyclase by an aggregation inhibitor such as adenosine or prostaglandin I (2). The abnormal bleeding of the rare patients whose platelets lack P2Y (12) and the beneficial clinical effects of ticlopidine and clopidogrel that block this receptor indicate that P2Y (12), in addition to inhibiting adenylyl cyclase, may have an as yet unidentified role that is needed for its cooperative aggregation effect with P2Y (1). ATP stimulates a rapid influx of calcium into platelets through the P2X (1) receptor, and it may synergize with ADP when these two nucleotides are released from platelets at a site of vessel injury.

Adenosine Diphosphate↗
PubMed2003

Fc gamma RIIB activation leads to inhibition of signalling by independently ligated receptors.

The inhibitory IgG receptor, Fc gamma RIIB, blocks signalling by co-aggregated antigen receptors on mature and activated B-cells. Fc gamma RIIB is also expressed by immature B-cells; however, its function on these cells has not been defined. In the present paper, we demonstrate that immature B-cells are highly sensitive to inhibitory signalling mediated by Fc gamma RIIB. Co-aggregation of Fc gamma RIIB with the B-cell antigen receptor (BCR) on immature B-cells leads to near ablation of late phase calcium mobilization. Concomitant with enhanced inhibitory signalling, we found that Src-homology-2-domain-containing inositol 5'-phosphatase (SHIP) is expressed at much higher levels in immature B-cells than in mature B-cells. Perhaps most importantly, we report that SHIP activated by BCR-Fc gamma RIIB co-aggregation inhibits independently ligated receptors whose signalling requires PtdIns(3,4,5) P (3). We found that stromal-derived factor 1 (SDF-1)-induced cell migration is impaired by prior activation of Fc gamma RIIB. This inhibition is reduced in SHIP-deficient B-cells. Therefore receptor-mediated signalling responses that are dependent on PtdIns(3,4,5) P (3) are subject to both direct and indirect inhibition by Fc gamma RIIB-activated SHIP.

Animals↗