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Results for “Receptor Aggregation”

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PubMed1994

Intrinsic ligand binding properties of the human and bovine alpha-interferon receptors.

The Type I interferon receptor (IFN-alpha R) interacts with all IFN-alpha s, IFN-beta and IFN-omega, and seems to be a multisubunit receptor. To investigate the role of a cloned receptor subunit (IFN-alpha R1), we have examined the intrinsic ligand binding properties of the bovine and human IFN-alpha R1 polypeptides expressed in Xenopus laevis oocytes. Albeit with different efficiencies, Xenopus oocytes expressing either the human or bovine IFN-alpha R1 polypeptide exhibit significant binding and formation of crosslinked complexes with human IFN-alpha A and IFN-alpha B. Thus, the IFN-alpha R1 polypeptide most likely plays a direct role in ligand binding.

Animals↗
PubMed1993

Detection of distinct sets of newly synthesized polypeptides in supernatants of TCR-triggered T cell clones. Implication for the search for new lymphokines.

Using metabolic radiolabelling of proteins, which are newly synthesized during TCR-triggered T cell activation we were able to visualize distinct patterns of secreted polypeptides (with molecular weights ranging from 6 to 44 kDa) in supernatants of different T helper-1, T helper-2 and cytotoxic T cell clones. Most of these detected proteins are secreted in response to TCR-crosslinking (or to combined action of PMA and A231287), in an extracellular Ca(2+)-dependent manner and their appearance in supernatants was completely blocked by the addition of RNA synthesis or protein synthesis inhibitors or EGTA. Cyclosporin A (CsA) blocks secretion of several detected polypeptides, but does not affect TCR-triggered synthesis and secretion of others reflecting the existence of TCR-triggered, CsA-insensitive protein synthesis and secretion pathway. The insensitivity of secretion of several easily detectable polypeptides to inhibition by CsA offers a promising approach to further define the CsA-resistant and calcineurin-independent molecular pathways of TCR-triggered T cell activation. Several lymphokines (e.g., interferon-gamma, tumor necrosis factor, interleukin-4 and interleukin-10) are identified among the visualized set of secreted polypeptides. Since other, yet unidentified, secreted polypeptides in the same set of secreted proteins share important properties with known lymphokines it seems promising to use described approach in search for new lymphokines.

Animals↗
PubMed1990

Age-related changes in the cholinergic components within the central nervous system. II. Working memory impairment and its relation to hippocampal muscarinic receptors.

Cognitive performance in aging Wistar rats was monitored using the radial arm maze and the latter was correlated with the density of muscarinic receptors in the CNS, using quantitative in vitro receptor autoradiography. Significant working memory deficits were observed in 12, 17 and 24-month-old rats as compared to 3-month-old animals. In addition, the number of the muscarinic receptors declined significantly with age (from 27 to 42% depending on the brain region sampled) utilising [3H]QNB and [3H]PZ receptor binding assays. The above trend became evident already at the age of 12 months. The present findings support the association of central cholinergic activity with memory processes.

Age Factors↗
PubMed1984

Molecular motion and association on the cell surface.

The size, shape, flexibility and topological relationships of proteins and lipids on cell surfaces and in artificial membranes have been studied by: (1) rotational and translation diffusion using time-resolved spectroscopy of singlet and triplet probes, and (2) fluorescence energy transfer in a flow system.

Animals↗
PubMed1995

The rabbit B cell antigen receptor is non-covalently associated with unique heteromeric protein complexes: possible insights into the membrane IgM/IgD coexpression paradox.

We describe several proteins that are components of the rabbit B cell receptor complex. Two proteins (37 kDa and 42 kDa) were found in non-covalent association with IgM expressed on B cells from peripheral blood. These proteins were also immunoprecipitated by anti-B29 (Ig-beta) and anti-mb1 (Ig-alpha) monoclonal antibodies. As in the mouse and human, the IgM associated molecules were found as heteromeric structures with non-reduced apparent molecular weights of approximately 70-75 kDa. On rabbit B cells we also found these proteins in a 100-135 kDa complex which may represent trimeric or tetrameric structures. By Western blot, the 37 kDa protein was identified as rabbit Ig-beta (B29), suggesting that the 42 kDa protein is rabbit Ig-alpha. These data suggest that rabbit IgM is associated with both Ig-alpha/beta and Ig-(alpha beta)2 or alpha beta gamma complexes. When similar immunoprecipitation studies were performed on lysates made from B cells isolated from appendix follicles, we found two additional IgM associated protein complexes containing 34 kDa and 36 kDa proteins.

Animals↗
PubMed1995

Evidence for multivalent structure of T-cell antigen receptor complex.

The T-cell antigen receptor (alpha beta or gamma delta TCR) is known to associate with four polypeptides (CD3 gamma, delta, epsilon and zeta) to form the TCR-CD3 complex. Although the six chains are well characterized, the molecular mass of the TCR-CD3 complex and stoichiometry of the components are currently uncertain. We analysed the TCR of a T-T hybridoma which expresses two distinct heterodimers. When the hybridoma was incubated with a mAb (MR9.2) specific for the V alpha 10V beta 5.1 heterodimer, both of the heterodimers were lost from the cell surface, as measured with mAb MR9.2 and MR9.7 (V alpha 1V beta 1-specific). The ability to co-modulate V alpha 1V beta 1 and V alpha 10V beta 5.1 suggested that TCR complexes could contain two alpha beta-heterodimers. Density gradient sedimentation analysis provided further evidence for higher order TCR. The sedimentation patterns of the TCR were compared to that of the B-cell antigen receptor and the well-characterized VSV membrane G-protein as well as to soluble marker proteins. Maximal cell surface murine and human TCR sedimentation coefficients were substantially greater than the 9-10S predicted for a 210 kDa monovalent alpha beta gamma delta epsilon 2 zeta 2 structure. The TCR sedimented in mild non-ionic detergents as large 18 +/- 3S complexes co-migrating with a 443 kDa marker protein. In contrast, the IgM B-cell antigen receptor had a maximal sedimentation coefficient of 10 +/- 3S, consistent with a predicted size of approximately 300 kDa. Taken together, the results suggested that T-cell antigen receptors can contain more than one alpha beta-heterodimer which could be incorporated into a minimal divalent 10-chain TCR-CD3 complex (e.g. alpha beta gamma epsilon epsilon delta zeta zeta alpha beta).

Animals↗
PubMed1990

A rapid method for quantitating lymphocyte receptor capping: capping defect in AIDS patients.

Capping of concanavalin A (Con A) and anti-Leu-8 (L8) receptors on human peripheral blood mononuclear (PBM) membranes was studied utilizing fluorochrome-conjugated ligands and flow cytometric analysis. Histogram profiles of fluorescent intensities consistently revealed a time-dependent decrease in numbers of brightly fluorescing events concurrent with an increase in numbers of dimly fluorescing events when capping occurs. Differences in fluorescence profiles were detectable by flow cytometric analysis as early as 5 min after capping conditions were initiated. A pronounced defect in receptor capping of PBM cells from AIDS patients was observed. This technique represents a rapid and reproducible means for detecting early changes in cell membrane receptor mobility.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Agrin and the molecular choreography of synapse formation.

High concentrations of neurotransmitter receptors characterize neuromuscular junctions as well as neuron-neuron synapses in the brain and periphery. Synaptic function is critically dependent upon this marshalling of neurotransmitter receptors to the post-synaptic membrane. This review discusses agrin's role in orchestrating the molecular topography of the post-synaptic apparatus at nerve-muscle synapses and the emerging evidence suggesting a role for agrin in synaptogenesis in the brain.

Agrin↗
PubMed1994

Angiotensin II stabilizes a multimeric type 2 (AT2) receptor complex in murine neuroblastoma N1E-115 cells.

Previous work has demonstrated that crosslinking of [125I]AngII to CHAPS solubilized angiotensin Type 2 receptors (AT2) in N1E-115 neuroblastoma cells identifies two radiolabeled proteins of 110 and 66 kDa. Similarly, affinity purification of AT2 receptors using AngII yields two proteins of 110 and 66 kDa. In the present study, anti-AT2 receptor antisera were used to examine the relationship between these two proteins. Agonist treatment (AngII) of intact cells increased the 110 kDa band while decreasing the 66 kDa protein. In intact or solubilized membranes, the ratio of 110 kDa/66 kDa proteins was significantly higher in the presence of an agonist and substantially lower with the antagonist Sar1,Ile8-AngII, suggesting that AngII stabilizes a large 110 kDa multimeric complex that may include the 66 kDa protein. To directly examine this hypothesis, anti-AT2 antisera were further purified against either the 110 or 66 kDa proteins. Both purified antibodies displayed crossreactivity with the two proteins. Moreover, when harshly reduced and denatured, the 110 kDa protein released a prominent immunoreactive 66 kDa protein, as well as other smaller proteins. Collectively, these results suggest that the 110 kDa protein consists, in part, of the 66 kDa protein and, as such, that an AT2 receptor subtype may exist as a multimeric complex that is stabilized by agonist occupancy.

Angiotensin II↗
PubMed1986

Binding of polycation DEAE-dextran to Chinese hamster ovary cells induces reversible Ca2+ influx and inhibits capping of concanavalin A acceptor proteins.

Binding of the polycation DEAE-dextran to the cell surface of HA-1 CHO cells caused a marked increase in 45Ca2+ exchange influx. The effect was fairly selective for Ca2+, undirectional (efflux was not increased) and was rapidly reversed by treatment with polyanion dextran sulfate. 45Ca2+ influx could not be stimulated by treatment with multivalent lectins or fibronectin. In addition to stimulating 45Ca2+ flux, DEAE-dextran inhibited the capping of concanavalin-A acceptor proteins. Inhibition of capping occurred over the same DEAE-dextran concentration range (20-200 micrograms/ml) which stimulated 45Ca2+ uptake, possibly implicating increased cellular [Ca2+] in the inhibition of concanavalin A acceptor protein capping in this cell type. The profound effect of DEAE-dextran on cellular Ca2+ uptake and the rapid reversal of the effect by dextran sulfate might make the polycation a useful agent for the induction of transient increases in cellular [Ca2+].

3-O-Methylglucose↗
PubMed1992

The role of CD45 in T-cell activation--resolving the paradoxes?

CD45 is one of the most abundant transmembrane glycoproteins expressed on the surface of haematopoietic cells. Despite the striking advances of the past few years in the understanding of the actions of CD45 at a molecular level, several paradoxes remain. This article argues that these paradoxes are more apparent than real, and suggests that CD45 plays a key role on the T-cell surface in regulating coupling of the antigen-receptor complex to intracellular signalling pathways.

CD3 Complex↗
PubMed1992

Two TNF receptors.

In the past few years, considerable progress has been made on the identification and characterization of tumor necrosis factor (TNF) receptors. The relative roles played by the two receptor types in signaling the diverse functions of TNF are less clear. Here, Louis Tartaglia and David Goeddel summarize progress to date and propose a model of TNF receptor triggering that reconciles the seemingly conflicting data.

Animals↗
PubMed1993

Distinct roles for CD4 and CD8 as co-receptors in antigen receptor signalling.

The co-ordinated interactions of multiple membrane molecules with the T-cell receptor for antigen (the TCR-CD3) are prerequisite for T-cell activation. In this review we consider the involvement of CD4, CD8, and CD45 on the two lymphocyte lineages. Experiments from many laboratories have provided concordant results leading to the consensus that CD4 and CD8 are functional analogues, providing similar supplementary signals to those generated through the TCR-CD3 complex on MHC class-II- and MHC class-I-restricted T cells, respectively. However, recent results demonstrate striking differences in the coreceptor functions of CD4 and CD8. These differences reflect the distinct properties of the molecules themselves, which in turn are associated with CD45 involvement in the activation of CD4+ and CD8+ T cells.

Animals↗
PubMed1994

Monte Carlo simulation of ligand-receptor interactions on a cell surface.

In this paper we develop a compartmentalized, discrete simulation model for investigating the spatial distribution and dynamic properties of receptor crosslinking on the surface of a cell. Results generated by the model are compared with some of the major results of existing analytical models, and differences are discussed in relation to differences in the model assumptions. Finally, the model is used to evaluate the dynamic effects of a time-varying non-homogeneous ligand concentration.

Diffusion↗
PubMed1996

Cross-linking of concanavalin A receptors on cortical neurons induces programmed cell death.

The loss of neurons by programmed cell death is a normal feature of the nervous system during development and has recently been implicated as a major mechanism of cell death in neurodegenerative diseases. In some cases, programmed cell death is induced by the activation of membrane receptors and is referred to as activation-induced programmed cell death. Activation-induced programmed cell death has been previously described in cells from the immune system, in which the activation of receptors by receptor clustering leads to programmed cell death. To determine whether activation-induced programmed cell death occurs in neurons, Concanavalin A was used to cross-link membrane receptors on cortical neurons. Concanavalin A-induced neuronal death was dose dependent and effective at concentrations previously shown to induce activation-induced programmed cell death in lymphocytes. Programmed cell death was attenuated when Concanavalin A-specific binding to neurons was blocked with methyl alpha-D-mannopyranoside. Succinyl Concanavalin A, which bound to Concanavalin A receptors but was ineffective at cross-linking them, did not induce programmed cell death. Concanavalin A-induced neuronal death exhibited many of the hallmarks associated with programmed cell death, such as membrane blebbing, nuclear condensation and margination, and internucleosomal DNA cleavage. In addition, neurons exposed to Concanavalin A displayed a rapid, robust, and persistent increase in the immediate early gene protein c-Jun. A similar increase in c-Jun precedes programmed cell death induced by beta-amyloid in neurons, and under some conditions an increase in c-Jun has been shown to be required for programmed cell death to occur in neurons. Increased expression of c-jun and other immediate early genes has also been correlated with activation-induced programmed cell death in lymphocytes. These observations suggest that Concanavalin A induces activation-induced programmed cell death in neurons via signals produced from the cross-linking of receptors on neuronal membranes. These results also raise the possibility that beta-amyloid induces programmed cell death in a similar manner, by causing the cross-linking of receptors on neuronal membranes. This mechanism may be relevant to neuronal programmed cell death that occurs during development and neurodegeneration.

Animals↗
PubMed1987

Correlation of clustering peak density and total amount of acetylcholine receptor on cultured mouse myotubes.

The development of acetylcholine receptor (AChR) and its clustering were studied quantitatively on mouse myotubes in nerve-muscle co-cultures. AChR was visualized by fluorescence-labeled antibodies (F-Ab) against crude AChR or fluorescence-labeled alpha-bungarotoxin (F-alpha-BuTX). The F-Ab stain was observed throughout the entire surface of the myotube at day 8 and appeared clustered at day 13. Both peak density and total amount of fluorescence in F-Ab stained myotubes were plotted against days in culture. Both fluorescence indices markedly increased from days 8 to 13 of culture were greater in extent in myotubes incubated in the presence of spinal cord explant, as compared with its absence. Similar results were observed in myotubes stained with F-alpha-BuTX. D-Tubocurarine (D-TC, 0.1 mg/ml) and native alpha-BuTX (1 microgram/ml) clearly inhibited both the total amount of fluorescence and the development of peak fluorescence density in the F-Ab stained myotubes. But the inhibition by D-TC appeared at the later day in culture than alpha-BuTX did. Low temperature (28 degrees C) and cholesterol (1 microgram/ml) treatment inhibited peak fluorescence density without affecting total amount of fluorescence. These results show that the development of ACh can be characterized both by clustering peak density (indicating the lateral mobility of AChR) and by total amount of fluorescence.

Animals↗