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PubMed1977

A comparative study of the effect of modification of the surface of human platelets on the receptors for aggregated immunoglobulins and for ristocentin-von Willebrand factor.

The receptors for aggregated immunoglobulin G (IgG) (an Fc receptor) and for ristocetin-von Willebrand factor on human platelets were studied by means of various modifications of the platelet surface. The expression of these receptors was measured by the agglutination of platelets to ristocetin in the presence of von Willebrand factor, which is part of the factor VIII complex, and by the binding of aggregated IgG coupled to 3H-labelled diazobenzene. Treatment of platelets with chymotrypsin, trypsin, papain and pronase which removed protein and glycoprotein from the platelet under conditions where the release reaction was inhibited caused loss of the expression of the receptor for ristocetin-von Willebrand factor and an enhancement of that for aggregated IgG. Induction of membrane changes with ADP and of the release reaction with the ionophore A23187 abolished agglutination to ristocentin-von Willebrand factor but did not alter the receptor for aggregated IgC. Possible contributions of unspecific membrane changes, produced by protease treatment of platelets, to the modification of receptor expression were eliminated by the use of formaldehyde-treated platelets. Trypsin, papain and pronase destroyed the ability of these platelets to agglutinate to ristocetin-von Willebrand factor but produced no change in the binding of aggregated IgC. Therefore, the receptor for ristocetin-von Willebrand factor is truly sensitive to proteolysis while the Fc receptor is not, but is partially masked by protease-sensitive material.

Adenosine Diphosphate↗
PubMed2002

Ligand-dependent aggregation of polyglutamine-expanded androgen receptor in neuronal cells.

Spinal and bulbar muscular atrophy (SBMA) is a motor neuronopathy caused by a polyglutamine expansion in the androgen receptor that forms characteristic inclusions in affected neurons. In order to assess the role of ligand binding in androgen receptor aggregation, we examined the distribution of an androgen receptor with 51 glutamine residues in transfected mouse neuroblastoma cells treated with androgens and antiandrogens. Stimulation with testosterone of cells grown in depleted medium or exposed to tamoxifen, resulted in the aggregation of the expanded androgen receptor into characteristic cytoplasmic inclusions. By contrast, very few aggregates were obtained after treatment with cyproterone acetate and none after treatment with flutamide. Furthermore, aggregation was not correlated with an overt change in accumulation of smaller androgen receptor species. Differential modulation of polyglutamine-expanded androgen receptor aggregation by ligands in neuronal cells may partly explain the absence of an overt disease phenotype in female carriers of the SBMA mutation and define conditions to explore further the role of androgen receptor aggregation in the pathogenesis of SBMA.

Androgen Antagonists↗
PubMed1994

Src homology 2 domains of Syk and Lyn bind to tyrosine-phosphorylated subunits of the high affinity IgE receptor.

Aggregation of the high affinity IgE receptor (Fc epsilon RI) on rat basophilic leukemia RBL-2H3 cells results in activation of the protein tyrosine kinases Syk and Lyn. Here, we report that fusion proteins containing the Src homology 2 (SH2) domains of Syk and Lyn precipitated tyrosine-phosphorylated proteins from RBL-2H3 cell lysates. There was no detectable precipitation with the N-terminal Syk SH2 domain, minimal with the C-terminal Syk SH2, and strong when the two SH2 domains were expressed in tandem. The Syk SH2 domains showed pronounced selectivity in the binding of tyrosine-phosphorylated proteins. Thus, Syk SH2 precipitated only three phosphoproteins, two of which were the beta and gamma subunits of Fc epsilon RI. In contrast, the fusion protein with Lyn SH2, in addition to precipitating the same Fc epsilon RI components, bound to many other phosphoproteins. Tyrosine phosphorylation of the beta and gamma subunits of Fc epsilon RI was essential for their precipitation with the SH2 fusion proteins. By direct binding studies, there was more binding of Syk SH2 to Fc epsilon RI gamma than to Fc epsilon RI beta, whereas Lyn SH2 bound only to Fc epsilon RI beta. The Syk SH2 fusion protein competitively inhibited the association of gamma and beta with Syk in lysates of activated cells. The SH2-mediated association of these two protein tyrosine kinases with Fc epsilon RI could play an important role in receptor signaling.

Amino Acid Sequence↗
PubMed1984

The mechanism of intercellular aggregation. I. The kinetics of the Fc gamma receptor-mediated aggregation of P388D1 cells with antibody-coated lymphocytes at 4 degrees C.

The formation of specific, heterophilic conjugates between cells from the P388D1 mouse macrophage line and antibody-coated mouse spleen cells was followed in cell suspensions at 4 degrees C by dual parameter flow cytometry. Intercellular aggregation in this system is mediated by the binding of the Fc portions of IgG antibodies on the spleen cells with Fc receptors (Fc gamma R) on P388D1. We show that the rate of aggregation reaches a plateau with increasing cell concentrations, suggesting that the initial collision between cells is not the rate limiting step of conjugate formation. The rates of aggregation are strongly dependent upon the cell surface densities of both Fc gamma R and antibody. In conjugates, however, only small fractions of available receptors or antibodies are utilized in bond formation. The rate-limiting step of aggregation, therefore, involves the formation of ligand-receptor bonds, and may be the diffusion of antibodies and receptors toward one another in small areas of intercellular contact. Inhibitor studies implicate microfilaments, but not microtubules, divalent cations, or energy-dependent processes as being important in aggregation. Finally, conjugates are stable when diluted into medium alone, but dissociate in media containing protein A, soluble immune complexes, or anti-Fc gamma R antibodies. This suggests that conjugates are stabilized by multiple intercellular ligand-receptor bonds, which constantly break and reform at the cell:cell interface, and that protein A, immune complexes, and anti-Fc gamma R disaggregate the conjugates by preventing the reformation of broken bonds.

Animals↗
PubMed1983

Some properties of the human platelet vasopressin receptor.

Aggregation of human platelets by vasopressin is potently inhibited by 1-[beta mercapto-(beta, beta'-cyclopentamethylene propionic acid)]-L-arginine vasopressin, a selective vasopressor (V1) antagonist. 1-Desamino-8-D-arginine-vasopressin, a selective anti-diuretic (V2) agonist failed to induce aggregation and acted as a weak antagonist. Vasopressin analogues which lacked the N-terminal amino group or which contained an uncharged amino acid residue at position 8 acted as partial agonists for the human platelet. The response to such partial agonists could be enhanced by increasing the cytosolic Ca2+ concentration but not by altering the level of cyclic-3', 5'-AMP. These observations provide further evidence indicating that the platelet vasopressin receptor is of the V1 sub-type.

Adenosine Diphosphate↗
PubMed1987

Properties of a second epitope of the murine Fc receptor for aggregated IgG.

The murine macrophage and lymphocyte Fc receptor for aggregated IgG (Fc gamma R) has previously been characterized by using the anti-Fc gamma R monoclonal antibody (mAb), 2.4G2. In the studies presented here, we describe a new mAb, 6B7C, that defines a second epitope of the Fc gamma R. The tissue distribution of the 6B7C epitope is coincident with the 2.4G2 epitope. However, only the 2.4G2 epitope is accessible to mAb binding on intact primary macrophages or lymphocytes. The 6B7C epitope is not detectable on primary macrophages or lymphocytes but is exposed on a portion of B lymphocyte Fc gamma R after activation by lipopolysaccharide and on some tumor cell lines. The expression of the 6B7C epitope on the surface of B lymphoblasts and tumor cell lines seems to correlate with their ability to release soluble Fc gamma R. The 6B7C mAb has the advantage that it reacts with native as well as denatured receptor and therefore can be used for techniques such as immunoblotting.

Animals↗
PubMed2006

Selective inhibition of the Fc epsilon RI-induced de novo synthesis of mediators by an inhibitory receptor.

Aggregation of the type 1 Fc-epsilon receptors (Fc-epsilon-RI) on mast cells initiates a network of biochemical processes culminating in secretion of both granule-stored and de novo-synthesized inflammatory mediators. A strict control of this response is obviously a necessity; nevertheless, this regulation is hardly characterized. Here we report that a prototype inhibitory receptor, the mast cell function-associated antigen (MAFA), selectively regulates the Fc-epsilon-RI stimulus-response coupling network and the subsequent de novo production and secretion of inflammatory mediators. Specifically, MAFA suppresses the PLC-gamma2-[Ca2+]i, Raf-1-Erk1/2, and PKC-p38 coupling pathways, while the Fyn-Gab2-mediated activation of PKB and Jnk is essentially unaffected. Hence, the activities of several transcription/nuclear factors for inflammatory mediators (NF-kappaB, NFAT) are markedly reduced, while those of others (Jun, Fos, Fra, p90rsk) are unaltered. This results in a selective inhibition of gene transcription of cytokines including IL-1beta, IL-4, IL-8, and IL-10, while that of TNF-alpha, MCP-1, IL-3, IL-5, or IL-13 remains unaffected. Taken together, these results illustrate the capacity of an immunoreceptor tyrosine-based inhibitory motif-containing receptor to cause tight and specific control of the production and secretion of inflammatory mediators by mast cells.

Animals↗
PubMed1985

Specificity of neuronal factors which aggregate acetylcholine receptors on cultured myotubes.

Neuronal factors from conditioned medium of neuroblastoma X glioma hybrid cells or isolated from embryonic pig brain aggregate acetylcholine receptors (AChR) on cultured chicken and rat myotubes. A membrane surface protein labelled with a fluorescent monospecific antibody was not aggregated with the same treatment. Antibodies against AChR block the action of the aggregating factors but do not produce large aggregates themselves. These findings indicate that the factors specifically react with the AChR on developing myotubes.

Animals↗
PubMed1995

Early clinical experience with integrelin, an inhibitor of the platelet glycoprotein IIb/IIIa integrin receptor.

Aggregation of platelets leading to thrombosis is one of the hallmarks of unstable angina, acute myocardial infarction, and ischaemic complications following coronary angioplasty. Activated platelets bind to fibrinogen through the glycoprotein IIb/IIIa integrin receptor. New agents have been developed to bind this receptor and thus prevent aggregation of platelets. One such compound (integrelin) is a cyclical peptide that has been shown to be a potent inhibitor of the glycoprotein IIb/IIIa receptor in man. A number of phase I and phase II clinical trials have been completed to evaluate this agent for the indications of unstable angina, acute myocardial infarction, as well as an adjunct to coronary angioplasty. This article will focus on the clinical investigation of integrelin with particular emphasis on its use during angioplasty. It has been consistently shown across different trials that integrelin can inhibit between 70% and 95% of platelet aggregation responses to 20 mumols of ADP at a variety of dosages used in the phase II trials. Preliminaray data also suggest that a more clinically unstable patient may require a higher dose of integrelin to cause a near complete inhibition of the platelet aggregation response to ADP. Future studies will need to explore more definitely the relationship between dose of glycoprotein IIb/IIIa receptor blockers and clinical instability.

Angioplasty, Balloon, Coronary↗
PubMed1993

Mumps virus alters aggregation of acetylcholine receptors in cultured rat skeletal muscle cells.

Cultured myoblasts, but not myotubes, from rat skeletal muscles were infected with the RW strain of mumps virus. Such myoblasts then fused to form myotubes containing viral antigen. The infected myotubes showed a significant decrease in the number of dorsal, linear acetylcholine receptor (AChR) aggregates as determined by FITC-conjugated alfa-bungarotoxin. Infected myotubes co-cultivated with spinal cord cells showed no increase in the number of dorsal, linear AChR aggregates, compared to normal, uninfected myotubes. In addition, an increased proliferation of the myoblasts, which remained uninfected in the infected cultures, was noted. This may indicate a release of a growth stimulating factor from the virus containing cells. This study shows that mumps virus infection can lead to an altered receptor organization in a morphologically preserved cell.

Animals↗
PubMed1997

Lymphotactin gene expression in mast cells following Fc(epsilon) receptor I aggregation: modulation by TGF-beta, IL-4, dexamethasone, and cyclosporin A.

Recruitment of lymphocytes is a prominent feature of allergic inflammation. However, the mechanisms by which lymphocytes are attracted to such sites are not understood. Recently, cDNAs encoding a lymphocyte-specific chemokine, lymphotactin (Ltn), were isolated from mouse pro-T cell and human CD8+ T cell libraries, leading us to hypothesize that mast cells might also produce Ltn. Using the reverse transcriptase-PCR and Northern blot analysis, we found that the Ltn gene is inducible in C1.MC/C57.1 and murine bone marrow-cultured mast cells (BMCMC) by Fc(epsilon)RI aggregation. Activation of a human mast cell (HMC-1) or basophil cell line (KU812) similarly led to transcription of Ltn. Fc(epsilon)RI aggregation-dependent Ltn mRNA expression was detected by 1 to 2 h, maximal at 6 h, independent of de novo protein synthesis, and was inhibited by cyclosporin A and dexamethasone. Compared with macrophage inflammatory protein alpha (MIP-1alpha), Fc(epsilon)RI-dependent Ltn and MIP-1alpha mRNA levels were up-regulated by IL-4, but not IFN-gamma, although higher levels of IL-4 (100 and 1000 U/ml) inhibited Ltn expression only; and TGF-beta preferentially enhanced Fc(epsilon)RI-dependent Ltn mRNA levels, suggesting that Ltn and MIP-1alpha have shared and unique regulatory mechanisms. A rabbit polyclonal Ab against a synthetic peptide was developed for use in immunoblot analysis and detected a 15-kDa Ltn protein within mast cell pellets and in the supernatants of mast cells following Fc(epsilon)RI aggregation. Ltn is thus expressed in mast cells and may contribute to the recruitment of lymphocytes to areas of allergic inflammation.

Animals↗
PubMed2005

IgE regulation of mast cell survival and function.

Traditionally, it is thought that IgE binding to mast cells via the high-affinity receptor (FcepsilonRI) is simply a passive 'sensitization' step prior to activation by receptor aggregation or cross-linking with multivalent antigen or other cross-linking agents. However, in addition to receptor up-regulation, recent studies have shown that monomeric IgE can induce survival and other activation events including increased histamine content, degranulation, leukotriene release, receptor internalization, adhesion, migration and DNA synthesis. Various IgE molecules exhibit a vast spectrum of heterogeneity: the highly cytokinergic (HC) group of IgEs at an extreme end of the spectrum can induce survival and other activation events very efficiently, whereas poorly cytokinergic (PC) IgEs at the other end can do so less efficiently. All the IgEs tested appear to be capable of inducing receptor aggregation with HC IgEs having a higher capacity to do so than PC IgEs. HC IgEs can promote the production and secretion of various cytokines including the one(s) that can sustain survival in an autocrine and paracrine mechanism. Consistent with receptor aggregation induced by monomeric IgE, other means of receptor aggregation, e.g. IgE+antigen and IgE+anti-IgE, can also induce survival and other events in unique ranges of stimulation intensity.

Animals↗
PubMed2003

Possible role of intramembrane receptor-receptor interactions in memory and learning via formation of long-lived heteromeric complexes: focus on motor learning in the basal ganglia.

Learning in neuronal networks occurs by instructions to the neurons to change their synaptic weights (i.e., efficacies). According to the present model a molecular mechanism that can contribute to change synaptic weights may be represented by multiple interactions between membrane receptors forming aggregates (receptor mosaics) via oligomerization at both pre- and post-synaptic level. These assemblies of receptors together with inter alia single receptors, adapter proteins, G-proteins and ion channels form the membrane bound part of a complex three-dimensional (3D) molecular circuit, the cytoplasmic part of which consists especially of protein kinases, protein phosphatases and phosphoproteins. It is suggested that this molecular circuit has the capability to learn and store information. Thus, engram formation will depend on the resetting of 3D molecular circuits via the formation of new receptor mosaics capable of addressing the transduction of the chemical messages impinging on the cell membrane to certain sets of G-proteins. Short-term memory occurs by a transient stabilization of the receptor mosaics producing the appropriate change in the synaptic weight. Engram consolidation (long-term memory) may involve intracellular signals that translocate to the nucleus to cause the activation of immediate early genes and subsequent formation of postulated adapter proteins which stabilize the receptor mosaics with the formation of long-lived heteromeric receptor complexes. The receptor mosaic hypothesis of the engram formation has been formulated in agreement with the Hebbian rule and gives a novel molecular basis for it by postulating that the pre-synaptic activity change in transmitter and modulator release reorganizes the receptor mosaics at post-synaptic level and subsequently at pre-synaptic level with the formation of novel 3D molecular circuits leading to a different integration of chemical signals impinging on pre- and post-synaptic membranes hence leading to a new value of the synaptic weight. Engram retrieval is brought about by the scanning of the target networks by the highly divergent arousal systems. Hence, a continuous reverberating process occurs both at the level of the neural networks as well as at the level of the 3D molecular circuits within each neuron of the network until the appropriate tuning of the synaptic weights is obtained and, subsequently, the reappearance of the engram occurs. Learning and memory in the basal ganglia is discussed in the frame of the present hypothesis. It is proposed that formation of long-term memories (consolidated receptor mosaics) in the plasma membranes of the striosomal GABA neurons may play a major role in the motivational learning of motor skills of relevance for survival. In conclusion, long-lived heteromeric receptor complexes of high order may be crucial for learning, memory and retrieval processes, where extensive reciprocal feedback loops give rise to coherent synchronized neural activity (binding) essential for a sophisticated information handling by the central nervous system.

Animals↗
PubMed2001

Paralytic zebrafish lacking acetylcholine receptors fail to localize rapsyn clusters to the synapse.

Physiological analysis of two lines of paralytic mutant zebrafish, relaxed and sofa potato, reveals defects in distinct types of receptors in skeletal muscle. In sofa potato the paralysis results from failed synaptic transmission because of the absence of acetylcholine receptors, whereas relaxed mutants lack dihydropyridine receptor-mediated release of internal calcium in response to the muscle action potential. Synaptic structure and function appear normal in relaxed, showing that muscle paralysis per se does not impede proper synapse development. However, sofa potato mutants show incomplete development of the postsynaptic complex. Specifically, in the absence of ACh receptors, clusters of the receptor-aggregating protein rapsyn form in the extrasynaptic membrane but generally fail to localize to the subsynaptic region. Our results indicate that, although rapsyn molecules are capable of self-aggregation, interaction with ACh receptors is required for proper subsynaptic localization.

Acetylcholine↗
PubMed1987

IgE receptor-mediated depolarization of rat basophilic leukemia cells measured with the fluorescent probe bis-oxonol.

Receptor-mediated changes in plasma membrane potential were recorded in rat basophilic leukemia (RBL) cells with the potential-sensitive fluorescent indicator bis-oxonol. Depolarization of the mitochondria with metabolic inhibitors was not detected by bis-oxonol, suggesting that only potential changes across the plasma membrane were being measured. The resting membrane potential of RBL cells was largely generated by the equilibrium distribution of K+ and not through electrogenic activity of the sodium pump. Depolarization was maintained as long as IgE receptors remained aggregated. We believe that at physiologic calcium concentrations a large portion of the measured potential change may be due to calcium influx across the plasma membrane. Prevention of calcium influx by lanthanum, disruption of aggregated receptors, or prior depolarization in a high K+ saline solution completely inhibited the antigen-induced depolarization. The time course of the antigen-stimulated increase in bis-oxonol fluorescence was similar, but not identical, to the antigen-stimulated rise in cytoplasmic free ionized calcium measured with fura-2. Antigen-stimulated depolarization was inhibited by removing both calcium and sodium and could be restored by the addition of either ion. Reduction of total cellular adenosine triphosphate inhibited depolarization in response to antigen stimulation.

Adenosine Triphosphate↗
PubMed1996

Functional contributions of the FcepsilonRIalpha and FepsilonRIgamma subunit domains in FcepsilonRI-mediated signaling in mast cells.

The functional contributions of the alpha and gamma subunit domains of the high affinity receptor for IgE (Fcepsilon-RI) were determined following chimeric receptor aggregation. Chimeric receptors of the extracellular (EC) and cytoplasmic tail (CT) domains of FcepsilonRI and the IL-2R p55 subunit (I) were constructed and stably expressed in RBL-2H3 cells. Signaling (inositol phosphate production, tyrosine phosphorylation, Ca2+ mobilization, and secretion of histamine and arachidonic acid metabolites) via alpha/gamma/gamma or I/gamma/gamma was similar to the native rat receptor, and both were shown to associate with endogenous FcepsilonRIbeta and FcepsilonRIgamma subunits. Therefore, the contributions of the EC domains could not be evaluated. The chimeras alpha/I/gamma and I/I/gamma were found to be single polypeptide chains, as they did not associate with beta and gamma. Signaling via alpha/I/gamma resulted in the appearance of biochemical events common to the native receptor. Cross-linking I/I/gamma elicited histamine release, [14C]arachidonic acid metabolites, tyrosine phosphorylation, Ca2+ mobilization, and only inositol trisphosphate production, which were not of a similar magnitude to the native FcepsilonRI. No biochemical events were elicited by cross-linking alpha/I/I or I/I/I. These results demonstrate that both the FcepsilonRIalpha EC domain and the FcepsilonRIgamma CT domain are essential for the FcepsilonRI signaling process, and that while FcepsilonRIIgamma CT plays a critical role in FepsilonRI signaling, the EC domain of FcepsilonRIalpha has a major contribution in signaling, as well as a role in modulating the magnitude of the biochemical events.

Animals↗
PubMedDate not supplied

[Signalling during radiation-induced apoptosis of thymocytes].

The mechanisms of signal triggering, enhancement and transduction during radiation-induced apoptosis of the thymocytes are discussed. Apoptosis is triggered by aggregation of receptors accompanied by activation of protein tyrosine kinases. The receptor aggregation is caused by radiation-induced cross-links. The signal is transduced to the gene from protein tyrosine kinase through Ras-proteins, protein kinase C, and transcription factors. The necessity of the lipoxygenase gene expression and synthesis of this enzyme for support and enhancement of the apoptotic signal is postulated.

Animals↗
PubMed1986

Establishment of a differentiated mesodermal line from P19 EC cells expressing functional PDGF and EGF receptors.

Aggregation of pluripotent P19 embryonal carcinoma (EC) cells in the presence of DMSO induces differentiation to various mesodermal cell types, including spontaneously contracting muscle. We have established clonal cell lines from these cultures and characterized one (MES-1) in particular for its response to growth factors. In contrast to the undifferentiated stem cells, but as a number of myoblast and muscle cell lines, MES-1 cells respond to both carbachol and bradykinin by the rapid release of Ca2+ from intracellular stores. In addition, MES-1 express receptors for and respond mitogenically to epidermal growth factor (EGF) and platelet-derived growth factor (PDGF). Isolated membranes from these cells retain the capacity to bind both ligands; addition of EGF to membranes induces endogenous phosphorylation of several proteins, including the EGF receptor itself and a 38 kD protein, while addition of PDGF specifically induces phosphorylation of the PDGF receptor. By contrast, other derivatives of P19, isolated from retinoic acid (RA)-treated aggregates and resembling neuroectodermal or endodermal cell types respond only to EGF; PDGF neither binds nor induces phosphorylation and a mitogenic response in these cells. During differentiation from EC cells therefore MES-1 cells developed a combination of growth factor receptor characteristics typical of somatic mesodermal cells and indicate that such receptors on EC-derived mesodermal cells are also functional.

Animals↗