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PubMed1997

Proteolytic activation of a putative receptor leading to vasoconstriction and platelet aggregation.

Submandibular enzymatic vasoconstrictor (SEV), a member of the kallikrein family of enzymes, elicits biological effects by a proteolytically mediated mechanism. We studied 1) whether SEV is able to aggregate platelets and 2) whether SEV may activate a receptor other than the cloned thrombin receptor. SEV (10(-8)M) aggregated platelets, released ATP and increased intracellular Ca2+. Elastase treatment rendered human platelets unresponsive to SEV and thrombin (TH), but not to cathepsin G. In desensitization experiments performed with gamma-TH, after two successive additions of approximately 50 nM gamma-TH, a third dose elicited 15.8 +/- 3.4% of the initial response (n = 4), but platelets responded to approximately 20 nM SEV by 33.8 +/- 7.2% of control (p < 0.03 vs last response to gamma-TH). After desensitization to SEV (n = 4), the response to a third dose was 4 +/- 1.3% of control, but gamma-TH still induced 37.7 +/- 12.4% aggregation (p < 0.02 vs last response to SEV). Incubation of washed rabbit platelets with alpha-TH digested with elastase (10(-10) M TH added to 7 micrograms/ml elastase for 1 min) rendered them unresponsive to additional challenges with TH, but they still responded to an equipotent dose of SEV (2.7 x 10(-9) M) by 86 +/- 48% of control. In isolated rabbit aortic rings contracted with 10(-6) M norepinephrine (NE) to 42 +/- 3% of maximum. SEV (2.8 x 10(-8) M) caused further contraction to 87 +/- 4%. In contrast, alpha-TH (1.6 x 10(-7) M) tended to relax both NE- and SEV-contracted rings by 14 +/- 2 and 16.2 +/- 2%, respectively (n = 3 each). We concluded that part of the platelet-aggregating effect of SEV may be mediated by activation of a receptor(s) different from that of TH.

Animals↗
PubMed2003

A role for the juxtamembrane domain of beta-dystroglycan in agrin-induced acetylcholine receptor clustering.

Synaptic differentiation results from an exchange of informational molecules between synaptic partners during development. At the vertebrate neuromuscular junction, agrin is one molecule presented by the presynaptic motor neuron that plays an instructive role in postsynaptic differentiation of the muscle cell, most notably in aggregation of acetylcholine receptors (AChRs). Although agrin is the best-characterized synaptogenic molecule, its mechanism of action remains uncertain, but clearly, it requires the receptor tyrosine kinase MuSK (muscle-specific kinase), the intracellular protein rapsyn, an Src-like kinase, and cytoskeletal components. In addition, the transmembrane protein dystroglycan interacts with the cytoskeleton and is implicated in agrin responsiveness. This alpha-beta heterodimer can bind agrin via its extracellular alpha subunit and associates with the membrane cytoskeleton via its beta subunit. In this study, we demonstrate that overexpression of the beta subunit of dystroglycan in cultured muscle cells inhibits agrin-induced AChR clustering. Deletion analysis and point mutagenesis demonstrate that the inhibition is mediated by an intracellular, juxtamembrane region composed of basic amino acids. Finally, the inhibition mediated by beta-dystroglycan extends to the minimal agrin fragment required for AChR clustering, suggesting that dystroglycan plays an important role in postsynaptic differentiation in response to agrin.

Agrin↗
PubMed1985

Effect of antibody-mediated crosslinking of insulin on its bioactivity and receptor binding.

Precipitating anti-insulin antibodies or anti-insulin IgG/anti-IgG complexes bind insulin in a highly aggregated form and thus should preferably be capable of inducing receptor aggregation, which has recently been suggested to be a precondition for insulin bioactivity. We, therefore, studied the influence of antibody-mediated crosslinking of insulin on the glucose conversion into CO2 in rat fat cells and glycogen synthesis in rat liver cells. As far as possible receptor-bound insulin was measured in parallel. Insulin bound to antibodies with low insulin precipitating capacity had no or little bioactivity and receptor reactivity on fat cells. The bioactivity, however, could be restored in part by addition of a second antibody. On liver cells, second antibody-mediated crosslinking of insulin-antibody complexes resulted in an enhancement of receptor reactivity, and insulin bioactivity of such crosslinked immune complexes was demonstrable. An insulin-precipitating antiserum was shown to form insulin-antibody complexes with significant bioactivity in fat cells which correlated with their receptor binding. In each case antibodies had no or little effect in the absence of insulin. Our data suggest that insulin neutralization by antibodies can be compensated by crosslinking the insulin-antibody complexes or by formation of big complexes precipitating by themselves. This is probably due to the induction of receptor aggregation.

Adipose Tissue↗
PubMedDate not supplied

[Reculatory fragments of collagen in gastric mucosa homeostasis].

The new glyproline family was distinguished from the regulatory peptides recently. It includes the simplest proline- and glycine-containing peptides: PG, GP, PGP, and respective peptides with hydroxylated proline residues. Glyproline's bioactivity covers many important systems of the body including suppression of some reaction in the blood coagulation and platelet aggregation and gastric mucosal maintenance. It was shown that PGP, PG and GP have a wide spectrum of antiulcer activity with respect to gastric mucosal damages of various aetiology. GHyp and HypGP show also antiulcer action. In vivo glyprolines being fragments of collagen may be generated during synthesis and catabolism of collagen. It is well known that approximately 10-60% of newly synthesized collagen degrade intracellularly with succeeding secretion of small peptides composed of less than 5 aminoacid residues out of cells. Different simplest proline and hydroxyproline fragments of glyprolines are revealed in various type of collagen: GP, GHyp, PG, PPG, PGP, PHypG., GPHyp, GPP, GPG, GHypP, HypGP. It is possible that these fragments may be also secreted out of cells during the stage of degradation of newly synthesized collagen. We showed that the intragastric (per oral) introduction of hydrolyzed gelatin, having 20 small peptide fragments, including PGP and HypGP, also increase gastric stability showing protective and therapeutic antiulcer effect. The corresponding receptors for glyprolines are not completely identified yet but it may be supposed that PGP, GP and other glyprolines interact with the same receptors with which the III type collagen is binding with platelet's receptors. It is supposed that octapeptide sequence KPGGluPGPK of collagen is rather important for binding with receptor. When this sequence in the structure of collagen's molecule binds with the receptor, platelet aggregation is induced. Free octapeptide blocks the receptor and inhibits platelet aggregations. Qualitatve characteristics of parameters of inhibition with intact octapeptide and glyproline, as well as the receptor's structure--that's our concern for the nearest future.

Animals↗
PubMed1984

Spontaneous redistribution of cell-surface glycoproteins in lymphoid cells during cytokinesis.

The 'unperturbed' distribution of plasma membrane glycoproteins during cytokinesis has been examined by immunofluorescence and electron microscopy on dividing mouse and rat lymphoid cells fixed before being labelled with the appropriate reagents. Two groups of molecules which cap 'spontaneously' to the uropod of non-dividing cells, i.e., the common receptors for Helix pomatia (HPA) and peanut agglutinin (PNA) (and in particular the thymocyte glycophorin-like glycoprotein) and membrane immunoglobulins, redistribute spontaneously to the cleavage furrow during cytokinesis. By electron microscopy, the redistributed molecules (HPA receptors) appear to be aggregated in clusters. Other glycoproteins, such as Concanavalin A receptors and Thy.1 antigens, which do not cap spontaneously on interphase cells, remain uniformly distributed or are somewhat depleted over the cleavage furrow. The results suggest that a spontaneous 'transport' of certain membrane molecules from the nuclear pole to the cleavage furrow occurs normally during cytokinesis by a mechanism analogous to that of uropod formation and spontaneous capping in interphase cells. The existence of redistribution phenomena in dividing cells imposes some restrictions on the possible mechanisms of redistribution and on certain aspects of the cleavage process.

Animals↗
PubMed1992

Thrombin receptor activating peptides: importance of the N-terminal serine and its ionization state as judged by pH dependence, nuclear magnetic resonance spectroscopy, and cleavage by aminopeptidase M.

Peptides derived from the recently identified thrombin receptor were tested for their ability to induce platelet aggregation in platelet-rich plasma. The 14 amino acid peptide identified as the new N-terminus after thrombin cleavage (T-14) and an 11 amino acid peptide (T-11) lacking the 3 C-terminal amino acids of T-14 were studied. Both induced platelet aggregation at micromolar concentrations, with T-11 about twice as potent as T-14. Induction of platelet aggregation by these two peptides showed an unusual pH dependence, being more potent at pH 7.2 than at pH 8.1; thrombin-induced aggregation showed a reverse pH dependence. Proton NMR studies of T-11 demonstrated that the chemical shift of the C-alpha proton of the N-terminal serine had a pH dependence that mirrored the aggregation potency. Acetylating the N-terminus of T-11 resulted in loss of aggregating activity, and this peptide did not show the pH-dependence change in chemical shift. The T-14 and T-11 peptides lost aggregating activity when incubated in plasma due to cleavage of the N-terminal serine by an enzyme identified as aminopeptidase M based on its pattern of inhibition and the ability of purified aminopeptidase M (EC3.4.11.2) to cleave the T-11 peptide. Endothelial cell aminopeptidase M was also able to cleave T-11. Inhibiting aminopeptidase M with amastatin enhanced aggregation induced by T-11 but not thrombin. These studies suggest that ionization of the N-terminus of the T-11 and T-14 peptides may be important in initiating platelet aggregation.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed2001

Subversion of integrins by enteropathogenic Yersinia.

Enteropathogenic Yersinia are gram-negative bacterial species that translocate from the lumen of the intestine and are able to grow within deep tissue sites. During the earliest stages of disease, the organism is able to bind integrin receptors that are presented on the apical surface of M cells in the intestine, which allows its internalization and subsequent translocation into regional lymph nodes. The primary integrin substrate is the outer-membrane protein invasin, which binds with extraordinarily high affinity to at least five different integrins that have the (beta)(1) chain. Bacterial uptake into host cells is modulated by the affinity of receptor-substrate interaction, receptor concentration and the ability of the substrate to aggregate target receptors.

Adhesins, Bacterial↗
PubMed2001

[Nitric oxide and endothelins in pulmonary hypertension].

For recent decades, the medical treatment of primary pulmonary hypertension(PH) have shown an improved outcome as a bridge to lung transplantation. Both nitric oxide (NO) and endothelin(ET) have reported as a major vasoactive mediators in initiating PH. NO is a potent vasodilator released from endothelial cells to adjacent smooth muscle cells in vascular wall. Inhalation of NO has exerted dramatic effects with minimum complication for PH patients. ET-1, after binding to ETA receptor, promotes a strong vasoconstriction, cell growth and platelet aggregation. ETB receptor promotes the clearance of circulating ET-1 in the lung, and stimulates the release of NO and PGI2. Therapeutic trials of ETA receptor antagonist and NO donors for PH may be promising because of their direct action against vasoconstriction.

Endothelin Receptor Antagonists↗
PubMed1979

Human platelet membrane receptor for bovine von Willebrand factor (platelet aggregating factor): an integral membrane glycoprotein.

The platelet membrane receptor for bovine von Willebrand factor, platelet aggregating factor, has been reported to be a property of a soluble glycoprotein, glycocalicin, that is loosely attached to the platelet surface and represents one of the major glycoproteins of the platelet glycocalyx. The studies reported here, however, demonstrate that fractions from human platelets containing glycocalicin have no bovine von Willebrand factor receptor activity. Instead, only fractions containing platelet membranes have receptor activity. By using a nonionic detergent, Brij 99, active receptor can be solubilized from the membrane. Some quantitation of the intact or solubilized receptor activity is possible because the aggregation curves produced by mixtures of various dilutions of membranes and a constant concentration of standard normal bovine plasma are linear when plotted against the logarithm of the concentration of receptor. The dose-response curve obtained with Brij 99-solubilized membranes is not parallel to that obtained with intact membranes. Lectin-specificity studies of the bovine von Willebrand factor receptor, soluble in Brij 99, demonstrate binding to a wheat germ agglutinin-Sepharose 4B affinity gel but little or no binding to similar affinity gels of concanavalin A or Lens culinaris lectin. By using wheat germ agglutinin-Sepharose 4B as a lectin affinity column, partial purification of the receptor is possible. Stability studies of the receptor in intact membranes show essentially no loss of activity for at least 6 days when membranes are stored at 4 degrees C in buffers containing 1 mM EDTA. One freezing and thawing cycle results in minimal loss of initial activity but the receptor activity of the thawed material is less stable over time than is fresh material. Repeated freezing and thawing destroys the activity and, once lost, it can not be recovered, even with detergents.

Blood Coagulation Factors↗
PubMed1994

Time-dependent inhibition by glyceryl trinitrate of platelet aggregation caused by U46619 (a thromboxane/endoperoxide receptor agonist).

Glyceryl trinitrate is a weak inhibitor of platelet aggregation in vitro. Its effect on platelet aggregation in response to U46619 (a thromboxane/endoperoxide receptor agonist) was studied turbidometrically in platelet-rich plasma from healthy volunteers. The object was to determine whether inhibition was influenced by a period of preincubation between preparation of platelet-rich plasma and addition of glyceryl trinitrate. Incubation was performed at 37 degrees C and 22 degrees C. Samples were removed at intervals and transferred to an aggregometer cuvette at 37 degrees C. Glyceryl trinitrate (100 microM) or an equal volume of distilled water was added 5 min before U46619 (2 microM), and aggregation recorded as change in light transmission. Inhibition by glyceryl trinitrate was markedly time and temperature dependent, with a progressive increase in inhibitory potency between 120 and 300 min preincubation at 37 degrees C but not at 22 degrees C. The explanation of this is unknown but the effect was not influenced by lipopolysaccharide or by cycloheximide, so it does not appear to be due to exposure to endotoxin or to enzyme induction in vitro.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2004

Deglycosylation of Fas receptor and chronic morphine treatment up-regulate high molecular mass Fas aggregates in the rat brain.

This study was designed to immunodetect and characterize Fas receptor aggregates (oligomerization) in the brain and to assess its possible modulation in opiate addiction. High molecular mass, sodium dodecyl sulfate (SDS)- and beta-mercaptoethanol-resistant Fas aggregates (approximately 110/120 and approximately 203 kDa specific peptides) were immunodetected with a cytoplasmic domain-specific antibody in brain tissue (rat, mouse and human) and SH-SY5Y cells by Western blot analysis. Preincubation of rat cortical membranes with N-ethylmaleimide (NEM; 1 mM for 1 h at 37 degrees C) reduced the immunodensity of approximately 203 kDa Fas aggregates (51%) and increased that of 35 kDa native Fas (172%) and 51/48 kDa glycosylated Fas (47%), indicating that disulfide bonds are involved in Fas dimerization. Enzymatic N-deglycosylation of Fas receptor increased the content of Fas aggregates (approximately 110/120 kDa: five- to sixfold, and approximately 203 kDa: two- to threefold), suggesting that Fas glycosylation is involved in regulating receptor dimerization. Chronic (10-100 mg/kg for 5 days), but not acute (30 mg/kg for 2 h), treatment with morphine (a micro-opioid peptide receptor agonist) induced up-regulation of Fas aggregates in the brain (approximately 110/120 kDa: 39%, and approximately 203 kDa: 89%). The acute and/or chronic treatments with delta- and kappa-opioid peptide receptor agonists and with a sigma1-receptor agonist did not readily alter the content of Fas aggregates in the rat brain. The results indicate that Fas aggregates are natively expressed in the brain and that its density is regulated by the state of Fas glycosylation. These forms of Fas (receptor homodimerization) are functionally relevant because they were up-regulated in the brain of morphine-dependent rats.

Animals↗
PubMed1996

Rapid dephosphorylation of the GTPase dynamin after FcepsilonRI aggregation in a rat mast cell line.

As part of our studies aimed at exploring the potential role(s) of protein phosphatases in mast cell signaling, we analyzed the phosphorylation status of tyrosine-containing proteins in a rat mast (RBL) cell line that expresses both native rat high affinity IgE receptors (FcepsilonRI) and functional human FcepsilonRIalpha. After FcepsilonRI aggregation, there was a rapid increase in the tyrosine phosphorylation of a number of proteins, including those of m.w. 72 and 110 kDa. Concurrent with these events, however, there was a rapid dephosphorylation of a 100-kDa protein that was constitutively phosphorylated in the unstimulated cells. Using a specific mAb, this 100-kDa protein was identified as the GTPase dynamin. Dynamin was shown to associate with the SH3 domain of the src-related tyrosine kinase p56lyn in RBL 2H3 cells both in vitro and in vivo. FcepsilonRI aggregation causes rapid internalization of the aggregated receptors via clathrin-coated pits and dynamin is known to play a role in clathrin-mediated endocytosis, so the dephosphorylation of dynamin may provide the signal for targeting the aggregated receptors to the endocytic pathway.

Animals↗
PubMed2001

Ceramide enables fas to cap and kill.

Recent studies suggest that trimerization of Fas is insufficient for apoptosis induction and indicate that super-aggregation of trimerized Fas might be prerequisite. For many cell surface receptors, cross-linking by multivalent ligands or antibodies induces their lateral segregation within the plasma membrane and co-localization into "caps" on one pole of the cell. In this study, we show that capping of Fas is essential for optimal function and that capping is ceramide-dependent. In Jurkat T lymphocytes and in primary cultures of hepatocytes, ceramide elevation was detected as early as 15-30 s and peaked at 1 min after CH-11 and Jo2 anti-Fas antibody treatment, respectively. Capping was detected 30 s after Fas ligation, peaked at 2 min, and was maintained at a lower level for as long as 30 min in both cell types. Ceramide generation appeared essential for capping. Acid sphingomyelinase -/- hepatocytes were defective in Jo2-induced ceramide generation, capping, and apoptosis, and nanomolar concentrations of C(16)-ceramide restored these events. To further explore the role of ceramide in capping of Fas, we employed FLAG-tagged soluble Fas ligand (sFasL), which binds trimerized Fas but is unable to induce capping or apoptosis in Jurkat cells. Cross-linking of sFasL with M2 anti-FLAG antibody induced both events. Pretreatment of cells with natural C(16)-ceramide bypassed the necessity for forced antibody cross-linking and enabled sFasL to cap and kill. The presence of intact sphingolipid-enriched membrane domains may be essential for Fas capping since their disruption with cholesterol-depleting agents abrogated capping and prevented apoptosis. These data suggest that capping is a ceramide-dependent event required for optimal Fas signaling in some cells.

Animals↗
PubMed2001

Phosphatidylinositol 3'-kinase blocks CD95 aggregation and caspase-8 cleavage at the death-inducing signaling complex by modulating lateral diffusion of CD95.

Activation of phosphatidylinositol 3'-kinase (PI 3'-K) after ligation of CD3 protects Th2 cells from CD95-mediated apoptosis. Here we show that protection is achieved by inhibition of the formation of CD95 aggregates and consequent activation of caspase-8. Inhibition of aggregate formation is mediated by changes in the actin cytoskeleton, which in turn inhibit lateral diffusion of CD95, reducing its diffusion coefficient, D, 10-fold. After cytochalasin D treatment of stimulated cells, the lateral diffusion of CD95 increases to the value measured on unstimulated cells, and CD95 molecules aggregate to process caspase-8 and mediate apoptosis. Regulation of functional receptor formation by modulating lateral diffusion is a novel mechanism for controlling receptor activity.

Actins↗
PubMed1992

Hypothesis for the receptors of human blood platelet aggregation and its inhibition by structure-activity relationship.

We tried to clarify the size and the common charge distribution of the inhibition or stimulation of human platelet aggregation by structure-activity relationship. Numerous inhibiting and stimulating agents were able to enter the receptors. Inhibitory receptor had recess of 14 x 12.5 A in diameter. Stimulatory receptor had recess of 11 x 12 A in diameter. In the recess, there were three charges, two negative and one positive in the inhibitory receptor, and one negative and two positive in the stimulatory receptor, respectively. Charge distributions and conformation of inhibiting or stimulating agents were similar for the inhibitory agents, prostaglandin I2 (PGI2), PGD2, PGE1 adenosine and isoproterenol and conformation of the stimulating agents, thromboxane A2 (TXA2), platelet activating factor (PAF), adenosine diphosphate (ADP) and adrenaline. Each molecule had 3-10 inhibiting and stimulating conformations. The ratio of the number of conformations for inhibition and stimulating of platelet aggregation was highest for PGI2 which showed the strongest inhibitory activity. TXA2 was opposite in both respects.

Humans↗
PubMed1992

Recombinant neuromuscular synapses.

The developing neuromuscular junction has provided an important paradigm for studying synapse formation. An outstanding feature of neuromuscular differentiation is the aggregation of acetylcholine receptors (AChRs) at high density in the postsynaptic membrane. While AChR aggregation is generally believed to be induced by the nerve, the mechanisms underlying aggregation remain to be clarified. A 43-kD protein (43k) normally associated with the cytoplasmic aspect of AChR clusters has long been suspected of immobilizing AChRs by linking them to the cytoskeleton. In recent studies, the AChR clustering activity of 43k has, at last, been demonstrated by expressing recombinant AChR and 43k in non-muscle cells. Mutagenesis of 43k has revealed distinct domains within the primary structure which may be responsible for plasma membrane targeting and AChR binding. Other lines of study have provided clues as to how nerve-derived (extracellular) AChR-cluster inducing factors such as agrin might activate 43k-driven postsynaptic membrane specialization.

Actins↗
PubMed2006

Signalling platforms that modulate the inflammatory response: new targets for drug development.

Therapeutically controlling inflammation is essential for the clinical management of many high-prevalence human diseases. Drugs that block the pro-inflammatory cytokines tumour-necrosis factor-alpha and interleukin-1 (IL-1) can improve outcomes for rheumatoid arthritis and other inflammatory diseases but many patients remain refractory to treatment. Here we explore the need for developing new types of anti-inflammatory drugs and the emergence of novel drug targets based on the clustering of IL-1 receptors into multi-protein aggregates associated with cell adhesions. Interference with receptor aggregation into multi-protein complexes effectively abrogates IL-1 signalling. The exploration of the crucial molecules required for receptor clustering, and therefore signal transduction, offers new targets and scope for anti-inflammatory drug development.

Anti-Inflammatory Agents↗