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PubMed2000

Thrombopoietin potentiates collagen receptor signaling in platelets through a phosphatidylinositol 3-kinase-dependent pathway.

Collagen activates platelets through a tyrosine kinase-dependent pathway, involving phospholipase Cgamma2. Functional responses such as aggregation and secretion induced by collagen are potentiated by preincubation with thrombopoietin (TPO). In this study, we show that collagen and thrombopoietin activate the phosphatidylinositol 3-kinase (PI 3-kinase) pathway and that this contributes to their respective actions. The structurally distinct inhibitors of PI 3-kinase, wortmannin, and LY294002, completely inhibit formation of phosphatidylinositol 3,4,5-trisphosphate by collagen. This leads to a substantial reduction in the formation of inositol phosphates and phosphatidic acid, 2 indices of PLC activity, and the consequent inhibition of intracellular Ca(++) [Ca(++)](i), aggregation and secretion. Potentiation of the collagen response by TPO is prevented in the presence of wortmannin and LY294002. However, when the 2 PI 3-kinase inhibitors are given after the addition of TPO but before the collagen, recovery of potentiation is observed. This suggests that potentiation is mediated through activation of PI 3-kinase. TPO stimulates aggregation of platelets from a low percentage of donors and this is also blocked by wortmannin. These results suggest that the PI 3-kinase pathway plays an important role in signaling by collagen and in the priming action of TPO.

Androstadienes↗
PubMed1993

Cell adherence to fibronectin and the aggregation of the high affinity immunoglobulin E receptor synergistically regulate tyrosine phosphorylation of 105-115-kDa proteins.

Adherence of cells to extracellular matrix components modulates cellular responses. Here we compared the array of tyrosine phosphorylated proteins induced by the aggregation of the high affinity receptor for IgE (Fc epsilon RI) in fibronectin-adherent and in nonadherent rat basophilic leukemia (RBL-2H3) cells. Adherence to fibronectin in the absence of Fc epsilon RI aggregation induced tyrosine phosphorylation of 105-115-kDa proteins. This phosphorylation was reversed by EDTA and by a synthetic peptide containing the sequence Arg-Gly-Asp, demonstrating a requirement for fibronectin-integrin interaction. Aggregation of Fc epsilon RI in fibronectin-adherent cells markedly enhanced the tyrosine phosphorylation of the same 105-115-kDa proteins. There were minimal differences in tyrosine phosphorylation of other proteins induced by the aggregation of Fc epsilon RI in nonadherent and in fibronectin-adherent cells. Direct activation of protein kinase C and/or increase in calcium influx induced the phosphorylation of the 105-115-kDa proteins only in fibronectin-adherent cells. The magnitude of the phosphorylation of the 105-115-kDa proteins induced by the aggregation of Fc epsilon RI in fibronectin-adherent cells was substantially greater than the sum of that due to adherence to fibronectin and the aggregation of Fc epsilon RI in nonadherent cells. Therefore, cell adherence and the aggregation of Fc epsilon RI synergistically regulate tyrosine phosphorylation of the 105-115 kDa proteins.

Amino Acid Sequence↗
PubMed1991

Immobilization and internalization of mutated IgE receptors in transfected cells.

Earlier studies have shown that the mast cell receptor IgE (Fc epsilon RI) for is expressed on COS-7 cells transfected with the cDNA for each of the three types of subunits that form the tetrameric, alpha beta gamma 2, receptor. Although such transfected COS cells fail to exhibit some of the early biochemical perturbations initiated by aggregation of the receptor on normal mast cells and related tumor lines, we show here that other characteristics of the endogenous Fc epsilon RI are retained. Thus, the unaggregated transfected wild-type receptors were found to have a restricted translational diffusion similar to that observed for endogenous receptors on mast cells as assessed by fluorescence photobleaching and recovery. Similarly, as with endogenous receptors the mobility of transfected receptors was sharply reduced when the receptors were aggregated by reaction with small oligomers of IgE. In addition, aggregation of the transfected Fc epsilon RI caused them to be internalized by the COS cells by a cytochalasin-sensitive mechanism, albeit at a considerably slower rate than was seen with endogenous receptors on mast cells or with transfected receptors in a line of receptor-deficient mast cells. We also examined the mobility and internalization before and after aggregation, of some 13 different combinations of receptor subunit mutants in which one or more of the five cytoplasmic domains of the receptor had been truncated. Our results show that whatever interactions between the receptor and cellular components may account for the phenomena we studied, such interactions do not critically depend upon the bulk of the cytoplasmic domains of the receptor.

Amino Acid Sequence↗
PubMed1984

Retention of the glycoprotein IIb-IIIa complex in the isolated platelet cytoskeleton. Effects of separable assembly of platelet pseudopodal and contractile cytoskeletons.

To investigate the association of the putative platelet fibrinogen receptor (glycoprotein IIb-III(a) with the cytoskeleton, 125I-surface labeled human platelets washed by gel-filtration were activated under conditions which allow selective assembly of the platelet cytoskeleton. The four conditions were activation with arachidonate or phorbol 12-myristate 13-acetate (PMA) with and without pretreatment with cytochalasin E. Activation with arachidonate generates a complete cytoskeletal core (pseudopodal and contractile elements) while PMA activation forms only an actin plus actin-binding protein pseudopodal core. Pretreatment with cytochalasin E leads to actomyosin contractile core formation if arachidonate activated, and essentially blocks cytoskeletal development if PMA activated. Cytoskeletal cores from arachidonate or PMA-activated platelets retained 26 (+/- 3%) of the total 125I-IIIa. Pretreatment with cytochalasin E followed by arachidonate or PMA activation reduced the 125I-IIIa retention to near control levels (unactivated platelets: 4 +/- 2%). The role of aggregation vs. receptor occupancy in the retention of IIb-IIIa was assessed by activation of platelets with arachidonate in the presence of fibrinogen fragment D (0.6-12 mg/ml). Aggregation was blocked by increasing concentrations of fragment D reagent while cytoskeletal assembly was not altered. The IIIa retention correlated with extent of aggregation with maximal retention corresponding to full aggregation. To determine if cytoskeletal development is necessary for the expression of the fibrinogen binding site, binding studies were performed with unlabeled platelets and 125I-fibrinogen. The mean number of binding sites and the mean dissociation constant were not significantly different among the four activation conditions. Although the development of a platelet cytoskeletal core is not required for the expression of the fibrinogen binding site, the retention of the glycoprotein IIb-IIIa complex is dependent on fibrinogen-supported aggregation as well as the formation of the pseudopodal cytoskeleton.

Arachidonic Acid↗
PubMed1998

Hemoglobin A0 and alpha-crosslinked hemoglobin (alpha-DBBF) potentiate agonist-induced platelet aggregation through the platelet thromboxane receptor.

Chemically modified hemoglobins are potential oxygen-carrying blood substitutes, but their in vivo administration has been associated with a variety of unexpected side events, including increased platelet reactivity. We studied the effects of hemoglobin A0 (HbA0) and alpha-crosslinked hemoglobin (alpha-DBBF) on platelets in vitro. Neither hemoglobin A0 nor alpha-DBBF activated platelets when added alone, but both proteins potentiated submaximal agonist-induced platelet aggregation without increasing other markers of platelet activation such as serotonin secretion. Only agonists that are known to cause release of platelet arachidonic acid (AA) were potentiated while aggregation induced by ADP, which does not release AA, was not potentiated. Blockade of the thromboxane receptor with SQ-29,548 prevented the HbA0-induced and the alpha-DBBF-induced potentiation suggesting that the AA/thromboxane signaling pathway mediates the interaction of platelets with hemoglobin.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2001

Uniform platelet activation exists before coronary stent implantation despite aspirin therapy.

BACKGROUND: Platelets play an important role in the natural history of coronary artery disease. Enhanced platelet aggregation and receptor expression unquestionably occur after coronary stent implantation; however, the functional characteristics of platelets before stenting have not been fully elucidated. METHODS: Platelets were assessed before intervention by platelet-rich plasma aggregation (PA) with 5 mmol adenosine diphosphate (ADP) and 1 mg/mL collagen; whole blood aggregation (WBA) by 1 mg/mL collagen; shear-induced closure time (CT); contractile force (CF); and expression of 9 surface receptors by flow cytometry in 126 patients undergoing elective coronary artery stent placement. All patients received aspirin for at least 7 days. The data were compared with those from 64 healthy volunteers. RESULTS: Each test revealed sustained platelet activation in patients undergoing coronary stenting compared with control values. These differences were significant for collagen-induced PA (P =.031); CF (P =.0001); expression of glycoprotein (GP) IIb/IIIa (P =.0001); P-selectin (P =.0008); platelet/endothelial cell adhesion molecule (PECAM)-1 (P =.0001); CD107a (P =.0001); CD107b (P =.0004); and CD63 (P =.009). CONCLUSION: Platelets are indeed activated before coronary stenting despite antecedent therapy with aspirin.

Adult↗
PubMed1999

Formation of the neuromuscular junction. Agrin and its unusual receptors.

Synapses are essential relay stations for the transmission of information between neurones and other cells. An ordered and tightly regulated formation of these structures is crucial for the functioning of the nervous system. The induction of the intensively studied synapse between nerve and muscle is initiated by the binding of neurone-specific isoforms of the basal membrane protein agrin to receptors on the surface of myotubes. Agrin activates a receptor complex that includes the muscle-specific kinase and most likely additional, yet to be identified, components. Receptor activation leads to the aggregation of acetylcholine receptors (AChR) and other proteins of the postsynaptic apparatus. This activation process has unique features which distinguish it from other receptor tyrosine kinases. In particular, the autophosphorylation of the kinase domain, which usually induces the recruitment of adaptor and signalling molecules, is not sufficient for AChR aggregation. Apparently, interactions of the extracellular domain with unknown components are also required for this process. Agrin binds to a second protein complex on the muscle surface known as the dystrophin-associated glycoprotein complex. This binding forms one end of a molecular link between the extracellular matrix and the cytoskeleton. While many components of the machinery triggering postsynaptic differentiation have now been identified, our picture of the molecular pathway causing the redistribution of synaptic proteins is still incomplete.

Agrin↗
PubMed1993

Heterogeneous receptors mediate endothelin-1-induced changes in blood pressure, hematocrit, and platelet aggregation.

Using selective endothelin (ET) receptor antagonists, we investigated which ET receptor subtypes mediate the changes in blood pressure and hematocrit produced by intraarterial injection of ET-1 in the anesthetized rabbit. In addition, the receptor through which ET-1 stimulates the release of prostacyclin (PGI2) and, hence, inhibits ex vivo platelet aggregation, was identified. FR 139317 (ETA antagonist, 0.6 mg kg-1 min-1 preceded by a loading dose of 3 mg kg-1 i.v.) and PD 145065 (nonselective ETA/ETB antagonist, 0.6 mg kg-1 min-1 preceded by a loading dose of 3 mg kg-1 i.v.) attenuated the ET-1 (1 nmol kg-1 i.a.)-induced rise in mean arterial pressure (MAP) by 89% and 75%, respectively. In contrast to FR 139317, PD 145065 also abolished the initial, transient depressor response brought about by ET-1. ET-1 caused a significant increase in hematocrit 15 min after its injection. PD 145065 caused a significantly greater inhibition of this hemoconcentration than FR 139317. ET-1 inhibited ex vivo platelet aggregation by 96%, measured 5 min after injection of the peptide. PD 145065, but not FR 139317, abolished the antiaggregatory effects of ET-1. Thus, the ET-1-induced vasoconstriction in the anesthetized rabbit is predominantly mediated via the ETA receptor, whereas the depressor and antiaggregatory actions of ET-1 are caused by activation of the ETB receptor. Moreover, activation of both receptor subtypes by ET-1 accounts for the increase in hematocrit produced by ET-1 in vivo.

Animals↗
PubMed2006

Cell surface dynamics: the balance between diffusion, aggregation and endocytosis.

The cell membrane lies at the interface between an extracellular set of signals and the appropriate intracellular response. Specifically, lymphocyte activity is determined by the spatial and structural response to antigens, as mediated by cell surface receptors. In order to correlate experimentally observed cellular activities, such as secretion, anergy, death, survival and division to external stimuli, it is necessary to monitor cell surface dynamics. B-lymphocyte activation results from the stimulation by large immune complexes comprising antigens, B-cell receptors (BcRs) and co-receptors. Compartmentalisation of the interacting molecular components is required in order to assure the rapid initiation of specialised and sustained signalling cascades. In this study, a Monte Carlo simulation of the cell membrane dynamics was developed to clarify the receptor dynamics, aggregation mechanisms and their combined effect on cellular functions. This simulation is based on experimentally measured parameters and represents a feasible, advanced and reliable framework to investigate the cell surface. The current study focussed on B-cell surface dynamics. A model demonstrating the basic properties of BcR dynamics and how BcR kinetics is affected by lipid rafts is developed. The authors studied BcR interactions with multivalent ligands and the influence of lipid rafts on this interaction. Finally, the dynamics of the initial steps of BcR-mediated cell activation is estimated and the effect of the association of signalling molecules with lipid rafts is demonstrated. These results are used to suggest some novel hypotheses on BcR-mediated B-cell activation.

Animals↗
PubMed1986

Differential effects of molybdate on the hydrodynamic and DNA-binding properties of the non-activated and activated forms of the androgen receptor in calf uterus.

Calf uterine cytosol contains an androgen receptor with a relative molecular mass of approx. 90,000. In this study we have analysed the structure and aggregation properties of the androgen receptor, using sucrose density gradient centrifugation on a vertical rotor (VTi65). In the presence of 10 mM NaCl the androgen receptor in whole cytosol sedimented at 8 S irrespective of the presence of molybdate. In 400 mM NaCl the receptor dissociated to a 4.3 S entity. In whole cytosol molybdate promoted a partial shift of the 4.3 S receptor into the aggregated 8 S state. The time of exposure of the receptor to molybdate and NaCl determined the proportion of receptor sedimentating at 8 S and 4.3 S. The DNA-binding form of the uterine androgen receptor when analysed under the conditions of the DNA-cellulose binding assay, sedimented at 6.5 S. Increasing concentrations of molybdate shifted its sedimentation coefficient gradually from 6.5 S to 4.5 S and in parallel reduced the DNA-binding capacity. Molybdate added to a partially purified, DNA-binding form of the androgen receptor did not promote receptor aggregation to faster sedimentating forms. This suggests that such preparations are devoid of an androgen receptor-aggregation factor. Indirect evidence for such a factor was obtained from reconstitution experiments with whole cytosol. Our results indicate that the DNA-binding form of the androgen receptor interacts with a cytosol factor to form the 8 S receptor complex. Molybdate has diverse effects: in the presence of the cytosol factor it stabilizes the 8S complex; in its absence molybdate prevents in a concentration-dependent way DNA-binding as well as reaggregation of the monomeric 4.3 S form.

Animals↗
PubMed1986

Formation of the vertebrate neuromuscular junction.

The sequence of events leading to the formation of the NMJ based on the data presented in this chapter from rat, chick, and Xenopus muscle can be divided into three developmental stages, as shown in Table I. The essential components of the NMJ are acquired early. Acetylcholine is present and can be released from the growing nerve. Acetylcholine receptors are present in the muscle membrane and are functional even at the earliest times. These components of the junction--ACh release and functional ACh receptors--can develop independently of each other; i.e., cell culture studies have shown that nerve cells are capable of releasing ACh before their growing tips have come into contact with the postsynaptic muscle membrane. Conversely, muscle cells grown without nerve synthesize and incorporate in their membranes functional ACh receptors. This situation ensures that functional (table; see text) contacts can occur even at the earliest times. Local accumulation of ACh receptors is also detected at the earliest times of junction formation. Although cell culture studies have demonstrated that receptors can aggregate in the absence of nerve, it would appear that the nerve plays an important role in directing where the highest density of receptors will be localized. Acetylcholinesterase, identified both histochemically and electrophysiologically, occurs at the presumptive NMJ shortly after synaptic transmission and receptor clustering have begun, suggesting that these events may play a role in localizing cholinesterase. Although the studies on rat and chick muscle support this view, development of AChE on Xenopus muscle does not require prior exposure to nerve or muscle activity. The ultrastructural features characteristic of the adult NMJ also do not become apparent until after synaptic transmission and receptor clustering have been seen. However, detection of small regions of specialization could be easily overlooked at the ultrastructural level, particularly if the tissue has not been serially sectioned. The young tissue is more fragile (Gordon et al., 1974) and may be more susceptible to mechanical damage or alterations from the fixation procedures (Kullberg et al., 1977). For these reasons, results pertaining to when the ultrastructural specializations occur are difficult to interpret and must await identification of these structures by other means. A number of other changes occur at the NMJ late in development: (1) ACh receptors become metabolically more stable, (2) there is a conversion in the kinetics of the ACh receptor channel, and (3) junctional folds become apparent. The extent to which these changes occur varies among the different organisms discussed.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetylcholinesterase↗
PubMed2006

Synthesis and evaluation of benzothiophene derivatives as ligands for imaging beta-amyloid plaques in Alzheimer's disease.

The imaging of the distribution of beta-amyloid (Abeta) plaques in the brain is becoming an important diagnostic modality in Alzheimer's disease (AD). Here, we synthesized novel benzothiophene derivatives and labeled them with (18)F for the potential diagnostic imaging of AD patients using positron emission tomography. The K(i) values of benzothiophene derivatives were evaluated by competitive binding assay using 2-(3'-[(125)I]iodo-4'-N-methylaminophenyl)benzothiazole as a radioligand and Abeta(1-40) or Abeta(1-42) aggregates as receptors. All synthesized benzothiophene derivatives showed high binding affinities (K(i)=0.28-6.50 nM) to both Abeta(1-40) and Abeta(1-42) aggregates. Binding affinities were increased by O-alkylation or N-alkylation of 2-(4'-hydroxyphenyl)benzothiophene or 2-(4'-aminophenyl)benzothiophene. Biodistribution studies of 2-(4'-O-(2''-[(18)F]fluoroethyl)hydroxyphenyl)benzothiophene ([(18)F]) and 2-(4'-O-(3''-[(18)F]fluoropropyl)hydroxyphenyl)benzothiophene ([(18)F]) in normal mice were performed after intravenous injection through the tail vein. In biodistribution data, [(18)F] and [(18)F] showed high initial brain uptakes at 2 min (5.2+/-0.4% and 3.3+/-0.2% ID/g, respectively), and brain activities washed out to 2.0+/-0.2% and 0.5+/-0.1% ID/g at 4 h, respectively. In conclusion, benzothiophene derivatives showed excellent binding affinities for Abeta aggregates and high initial brain uptakes in normal mice.

Alzheimer Disease↗
PubMed1985

Alpha- and beta-adrenoceptors in circulating blood cells of essential hypertensive patients: increased receptor density and responsiveness.

In 40 male patients with established essential hypertension (P diast greater than 95 mmHg) platelet alpha 2-adrenoceptor density (by 3H-yohimbine binding) and -responsiveness (by adrenaline-induced aggregation) as well as lymphocyte beta 2-adrenoceptor density (by (+/-)-125 iodocyanopindolol binding) and -responsiveness (by cyclic AMP responses to isoprenaline) were determined and compared with those in 40 male age-matched normotensives (P diast less than 90 mmHg). In essential hypertensive patients mean platelet alpha 2- and lymphocyte beta 2-adrenoceptor densities were significantly increased. When data from all 80 subjects were combined, significant positive correlations between mean arterial blood pressure and alpha 2- and beta 2-adrenoceptor densities, respectively, were found. The increases in alpha 2- and beta 2-adrenoceptor densities were accompanied by enhanced responsiveness to adrenergic stimulation: in platelets adrenaline-induced aggregation--via alpha 2-adrenoceptor stimulation--was exaggerated, and in lymphocytes isoprenaline produced significantly greater increases in the intracellular level of cyclic AMP. It is concluded that the increased density and responsiveness of alpha 2-and beta 2-adrenoceptors in circulating blood cells of essential hypertensive patients may reflect increased sympathetic activity, which might contribute to the elevation of blood pressure.

Adenylyl Cyclases↗
PubMed1980

Serotonin receptor site in human platelets from control and chlorpromazine treated subjects.

Human platelets are activated by epinephrine (E), norepinephrine (NE), ADP, and serotonin (5-HT) by a process that can be measured as cellular aggregation and at the completion of which 5-HT is released from storage vesicles. Among the three neurotransmitters, only the 5-HT response at its maximum concentration is transient (reversible), and in a given platelet preparation can be produced only once. This effect is highly specific. Structural analogues of 5-HT, such as tryptolines (TLNs) or 5-methoxy-N,N dimethyltryptamine (5-MNDTA), with agonist properties in animal behavioral models, cannot induce a 5-HT-like response in the platelet system; however, they competitively inhibit the platelet aggregation response (PAR) to 5-HT if preincubated with the platelets. Inhibition constants of TLNs for 5-HT and E are of an order of magnitude higher than the KM values for aggregation. A transient '5-HT-like' PAR can be produced by compounds structurally unrelated to 5-HT, such as the following: a preparation of adenylylimidodiphosphate (AIP) can cause a transient PAR similar to the 5-HT response with a KM of 0.2-0.5 mM. Experimental evidence suggests that this ATP analogue is also an inhibitor of the second phase of aggregation (17) and release of dense vesicle content, thereby exhibiting only a monophasic and transient PAR. A '5-HT-like' PAR can also be produced by a combination of E and ATP at concentrations at which neither by itself causes aggregation. These transient PARs may serve as tools to investigate the underlying mechanism of the self-restricted yet exhaustible ability of platelets to respond to the aggregation inducer. Drug-free schizophrenic patients having their first psychotic episode have a transient 5-HT PAR indistinguishable from that of control subjects. However, after 2-3 weeks on chlorpromazine (CPZ) as the sole neuroleptic, the patients defined as schizophrenic could be divided into 2 sub-groups: a) those who developed an enhanced and irreversible PAR to 5-HT and were reported as good clinical responders; and b) those whose transient 5-HT PAR remained unchanged for 10-12 weeks and were reported as slow, poor or non-responders. The study of the mechanism of the enhanced 5-HT PAR in CPZ-treated patients may contribute to the understanding of certain aspects of the mode of action of CPZ.

Adenosine Triphosphate↗
PubMed1994

Similarities between beta amyloid peptides 1-40 and 40-1: effects on aggregation, toxicity in vitro, and injection in young and aged rats.

Peptides corresponding to the first 40 amino acids of beta amyloid peptide (beta 1-40) and the reverse sequence (beta 40-1) were synthesized, purified, and compared for their ability to aggregate and cause toxicity in vitro to human neuroblastoma cells (SH-SY5Y), as well as for effects following injection into young or aged rats. Aggregation of both peptides produced similar sedimentation velocity profiles and resulted in significant toxicity in vitro with no observable differences between beta 1-40 and beta 40-1. In addition, when injected into the cortex of young rats, beta 1-40 was more toxic than beta 40-1 although both resulted in significant lesions. However, in aged rats the two peptides resulted in lesions of similar size. Alz 50 staining and abnormal neurites were associated with both beta 1-40 and beta 40-1 lesions; however, no evidence of plaques or tangles was found in either age group. While both peptides were toxic in vitro, only beta 1-40 elicited Alz 50 staining of SH-SY5Y cells. Electron microscopic examination of beta 1-40 and beta 40-1 aggregates showed that beta 1-40 formed fibrillar structures whereas beta 40-1 resulted in amorphous particles. Thus, although both peptides were toxic to cultured cells and aged rats, the toxicities may have resulted from different mechanisms.

Amyloid beta-Peptides↗