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PubMed1991

Two of the three actin-binding domains of gelsolin bind to the same subdomain of actin. Implications of capping and severing mechanisms.

Gelsolin binds two monomers in the nucleating complex with G-actin in calcium and caps actin filaments. However, 3 actin-binding domains have been identified within its 6 repeating sequence segments corresponding to S1 S2-3 and S4-6. S1 and S4-6 bind only G-actin whereas S2-3 binds specifically to F-actin. Two of the three domains (S2-3 and S4-6) are required for nucleation and a different pair (S1 and S2-3) for severing. Here we show for the first time that the domains unique to nucleation (S4-6) or severing (S1) compete for the same region on subdomain 1 of G-actin. We further show that S2-3 binds actin monomers weakly in G-buffer conditions and that this interaction persists when S1 or S4-6 are also bound. Thus gelsolin associates with two distinct regions on actin. Since S2-3 does not bind monomeric actin in F-buffer, we suggest that its high affinity 1:1 stoichiometry for filament subunits reflects interaction with two adjacent subunits.

Actins↗
PubMed1991

Demonstration of a transcription element in vitro between the capping site and translation initiation site of the mouse myelin basic protein gene.

A transcription element was identified, by in vitro analyses, just downstream from the capping site of the mouse myelin basic protein (MBP) gene. Deletion of this element caused a dramatic drop of transcription efficiency in mouse brain, rat liver and HeLa cell nuclear extracts, regardless of the form of DNA being closed circular or linear form. DNase I footprint analysis demonstrated the presence of a ubiquitous trans-acting factor for this region. This element functioned even when it is located in the normal direction downstream from the adenovirus major late promoter. Mutation analysis suggested that an essential part of the downstream element was located between +25 and +45.

Animals↗
PubMed1985

Effect on human platelets of catecholamines at levels achieved in the circulation.

Epinephrine at concentrations varying between 3.3 and 12.5 nM had no effect on blood platelets when added alone, but augmented the in vitro platelet response to collagen and thrombin. Both aggregation and secretion responses were enhanced. Norepinephrine produced similar effects but was 50-60% less active than epinephrine. The minimum concentration of epinephrine or norepinephrine to achieve potentiation of platelet responses was even lower in the presence of 5-hydroxy- tryptamine. In contrast to the effects observed with higher concentrations of catecholamines, the synergistic interaction of these low concentrations of catecholamines with other agonists was not transient. The augmented response to catecholamines was mediated by platelet alpha 2-adrenoceptors. The response was inhibited by aspirin indicating that metabolism of arachidonic acid contributes to the synergy between low concentrations of catecholamines and other agonists. These studies show that the levels of the hormones epinephrine and norepinephrine obtained in circulating blood in humans, can be sufficient to enhance platelet responses. The action of catecholamines on platelets may be important in hemostasis and could provide an explanation for the association between certain risk factors and cardiovascular disease.

Adenosine Diphosphate↗
PubMed1979

C3b binding immune complexes and immunoconglutinins in human sera. Detection by enzyme-linked immunosorbent assay (ELISA).

An enzyme-linked immunosorbent assay (ELISA) designed to measure autoantibodies against C3b (immunoconglutinins: IK) also detects immune complexes (IC). Solid phase C3b, in addition to binding IK of IgG, IgM and IgA classes, bound aggregated human IgG, IgA and aggregated immunologically purified anti-tetanus toxid antibodies as well as model complexes of tetanus toxoid-human anti-toxoid. Significant C3b binding IgG, IgM and IgA activities were seen in the sera of 20 SLE patients but not in sera from healthy blood donors. Ultracentrifugation analysis of two SLE sera revealed C3b binding IgG and IgA activities in both light (7S) and heavy (greater than or equal to 11S) fractions. This indicates simultaneous presence of IK and IC in these sera. On the basis of the known relationship between IK and IC formation we suggest that the solid phase C3b ELISA may be of value in evaluating immune reactions in patients.

Antigen-Antibody Complex↗
PubMed1982

Pyridoxal phosphate blocks aggregation of molybdate treated glucocorticoid receptors in HeLa S3 cells.

We have compared the effects of sodium molybdate and pyridoxal phosphate on the sedimentation properties of cytoplasmic glucocorticoid receptors. Whole HeLa S3 cells were incubated with [3H]-Dexamethasone (Dex) at 0-4 degrees C to produce unactivated cytoplasmic steroid receptors. When these cells are lysed in 10 mM Tris, 1 mM EDTA, 12 mM alpha-thioglycerol pH 7.4 (buffer A), [3H]-Dex receptor sediment as 7-8S species in sucrose gradients prepared in the same buffer. Sedimentation of receptors on gradients containing buffer A plus 20 mM sodium molybdate (buffer B) results in an approximately 9S species. Treatment of these receptors with pyridoxal phosphate (10 mM) followed by reduction with NaBH4 and sedimentation on sucrose gradients prepared in either buffer A or B results in the production of 3-4S species. Although [3H]-Dex labeled cells lysed in buffer B yield approximately 9S species when analyzed in gradients prepared in buffer B, centrifugation of these receptors in buffer A yield 7-8S species. Similarly when cells are lysed in buffer A labeled receptors sediment in sucrose gradients prepared in buffer B as approximately 9S species. Receptors prepared in buffer B and treated with pyridoxal phosphate and NaBH4 sediment in buffer B gradients as two discrete approximately 7S and approximately 3.5S species. Pyridoxal phosphate and NaBH4 treated receptors prepared in buffer B sediment as disperse 3-6S species when analyzed in buffer A gradients. Based on these observations we conclude that pyridoxal phosphate, NaBH4 reduced receptors are not particularly susceptible to subsequent molybdate action, but molybdate pre-treated receptors can be influenced by pyridoxal phosphate.

Centrifugation, Density Gradient↗
PubMed1982

Normal platelet aggregation in myotonic dystrophy.

In 18 patients with myotonic dystrophy, spontaneous aggregation and platelet aggregation induced by thrombin, adenosine diphosphate and epinephrine were compared with normal aggregation patterns. In 17 of the 18 patients the results were not significantly different from normal. In 1 patient spontaneous aggregation and hypersensitive platelets were found. These results are in disagreement with earlier reports on a specific hypersensitivity to epinephrine in myotonic dystrophy. Neither the clinical data (myotonia, paresis) nor the laboratory data (creatine kinase, myoglobin, immunoglobulin G) were correlated with the platelet aggregations.

Adenosine Diphosphate↗
PubMed1995

Ganglioside characterization of a cell line displaying motor neuron-like phenotype: GM2 as a possible major ganglioside in motor neurons.

We have examined ganglioside compositions and the presence of sulfated glucuronyl glycolipids of immortalized motor neuron-like cell lines, neuroblastoma-spinal cord (NSC) hybrid cell lines established by fusing mouse neuroblastoma N18TG2 with motor neuron-enriched embryonic spinal cord cells. Among NSC cell lines, only NSC-34 aggregates acetylcholine receptors on co-cultured myotube and expresses a receptor for S-laminin, a neuromuscular junction specific basal lamina protein. GM2, which is only a minor ganglioside component of CNS, was the major component in NSC-34 occupying almost 75% of total gangliosides, whereas GD1a and GM3 were major species in the parental N18TG2, which had only 8.5% GM2. These results indicated that NSC lines have unique ganglioside pattern that is distinctive from other nervous tissues, and this pattern, especially that of NSC-34 cells, might reflect the characteristics of mouse spinal motor neuron gangliosides. Sulfated glucuronyl paragloboside was demonstrated to be present in N18TG2, however, it could not be detected in either of NSC cell lines. Even though the pathogenesis of amyotrophic lateral sclerosis remains unknown, autoimmunological participation has been suggested. Because high-titered antibody against GM2 has been observed in a patient with amyotrophic lateral sclerosis-like disease, GM2 which is possibly expressed on the surface of motor neurons might serve as a potential target antigen in this disorder.

Animals↗
PubMed1984

Functional significance of the platelet alpha2-adrenoceptor: studies in patients with myeloproliferative disorders.

Platelet alpha-adrenoceptor status was examined in 35 patients with myeloproliferative disorders (MPD) and 35 normal controls by means of radioligand binding studies with 3H-yohimbine (3H-YOH) and in vitro platelet function tests. A group of 'adrenaline insensitive' MPD patients identified in the functional studies were found to be identical to normal controls and other MPD patients with respect to their alpha 2-adrenoceptor status as assessed by the binding studies. Possible explanations for the dissociation between radioligand binding studies and functional responses in the platelet are discussed.

Adenine Nucleotides↗
PubMed1985

Differential labeling of platelet alpha 2 adrenoceptors by 3H dihydroergocryptine and 3H yohimbine in patients with myeloproliferative disorders.

Platelet alpha adrenoceptor status was examined using the radioligands 3H-yohimbine (3H-YOH) and 3H-dihydroergocryptine (3H-DHE) in 14 patients with myeloproliferative disorder (MPD) and 10 normal controls. Platelets from normal controls and MPD patients sensitive to adrenaline induced aggregation exhibited approximately 50% more binding sites identified by 3H-DHE than 3H-YOH, whereas MPD platelets insensitive to adrenaline showed selective loss of these 'extra' 3H-DHE sites. In functional studies after 30 minutes preincubation with the unlabelled antagonists, DHE was more potent than YOH at inhibiting adrenaline induced aggregation in normal platelets. In addition, the affinity constant for DHE was virtually identical in binding and functional experiments, whereas for YOH the affinity constant for binding was approximately 10 fold more potent than that for aggregation. These results suggest that the alpha adrenoceptor binding site on human platelets labelled by 3H-DHE may be of more functional relevance than that labelled by 3H-YOH alone.

Blood Platelets↗
PubMed1988

"A" subunit of factor XIII is present on bovine platelet membrane and mediates collagen-induced platelet activation.

The Fab fragment of a polyclonal antibody against platelet factor XIII inhibited the collagen-induced platelet aggregation in a dose-dependent manner. This inhibitory effect was specific for collagen, and it had no effect on arachidonic acid-, ADP-, and serotonin-induced aggregations. This finding strengthens our notion that platelet factor XIII is involved in collagen-induced platelet aggregation. (Saito, Y., Imada, T., Takagi, J., Kikuchi, T. and Inada, Y. J. Biol. Chem. 261, 1355-1358, 1986). We have investigated membrane localization of bovine platelet factor XIII using immunological techniques. Immunofluorescent visualization revealed that the factor XIII was expressed on the surface of non-permeabilized bovine platelets, where we detected neither lactate dehydrogenase, a cytoplasmic enzyme marker, nor B subunit of factor XIII, which is present in plasma. Cell surface iodination and immunoprecipitation also confirmed that it existed on the surface of platelets.

Animals↗
PubMed1988

Inhibition by endothelial cells of platelet aggregating activity of thrombin--role of thrombomodulin.

Cultured human umbilical vein endothelial cells inhibited the platelet aggregating activity of thrombin in the absence of plasma. Using a new method in which thrombin-induced platelet aggregation was measured in the presence of endothelial cells, we showed that aspirin-treated endothelial cells inhibited platelet aggregating activity of thrombin in an incubation time- and cell number-dependent manner. This inhibitory effect of endothelial cells was partially blocked by the pretreatment of endothelial cells with monoclonal anti-thrombomodulin IgG (anti-TMIgG). It is suggested that (1) endothelial cells play a role in the clearance of thrombin by binding and inactivating this enzyme and that (2) thrombomodulin on endothelial cells, apart from its role for protein C activation, may be involved in this endothelial function.

Aspirin↗
PubMed1989

Alpha 2-adrenoceptors and platelet function in patients with variant angina.

We have previously reported that platelets of patients with variant angina exhibited pronounced hyperactivity to epinephrine, as assessed by aggregation study. To determine whether this is associated with a change in surface alpha-adrenoceptor status, we investigated the capacity and affinity of binding sites for [3H]dihydroergocryptine, a potent alpha-antagonist, of platelet lysates prepared from 22 patients with ischemic heart disease and 13 control subjects of similar age. [3H]DHE binding capacity to platelets from control subjects, 6 patients with acute myocardial infarction, 9 with effort angina and 7 with variant angina were 233 +/- 44 (SD), 226 +/- 53, 252 +/- 58 and 348 +/- 48 fmol/mg protein and its affinity were 2.05 +/- 1.40, 0.98 +/- 0.46, 1.59 +/- 0.37 and 1.49 +/- 0.66 nM, respectively. The patients with variant angina had significantly higher capacity of platelet alpha-adrenoceptor than controls (49% increase) or patients with other types of ischemic heart disease. In contrast, the affinity for [3H]DHE was not significantly different as compared with other three groups. Similar increments in the binding capacity for [3H]-rauwolscine, alpha 2 antagonist, were found in platelet lysates prepared from 6 patients with variant angina. These results suggest that increased capacity of platelet alpha-adrenoceptor may explain enhanced reactivity to epinephrine in patients with variant angina.

Adrenergic alpha-Agonists↗
PubMed1994

Patterns of cell movement within the Dictyostelium slug revealed by cell type-specific, surface labeling of living cells.

There are cells scattered in the rear, prespore region of the Dictyostelium slug that share many of the properties of the prestalk cells and that are therefore called anterior-like cells (ALCs). By placing the gene encoding a cell surface protein under the control of an ALC-specific promoter and immunologically labeling the living cells, we analyze the movement of ALCs within the slug. There is a posterior to anterior cellular flow, and the ALCs change their movement pattern as they enter the prestalk zone. Prestalk cells are periodically shed from the migrating slug. They must be replaced if the correct ratio of prestalk to prespore cells is to be maintained, and we present evidence for the transdifferentiation of prespore into prestalk cells, with ALCs functioning as intermediates in the transition. The slug has, therefore, a surprisingly dynamic structure, both with respect to cellular differentiation and cell movement.

Amino Acid Sequence↗
PubMed1996

Induction of costimulatory molecules B7-1 and B7-2 in murine B cells. the CBA/N mouse reveals a role for Bruton's tyrosine kinase in CD40-mediated B7 induction.

The binding of CD40 ligand on activated T cells to CD40 on resting B cells induces the expression of costimulatory molecules B7-1 (CD80) and B7-2 (CD86). The induction of B7 molecules by CD40 ligand-CD40 interaction represents a critical step in rendering B cells competent for antigen presentation. The CBA/N mouse has a defect in CD40 signalling which has been attributed to a mutation in Bruton's tyrosine kinase. We have compared the ability of murine CD40 ligand to induce B7-1 and B7-2 expression on B cells isolated from CBA/N and wild-type CBA/J mice. We find that the CBA/N defect partially impairs both B7-1 and B7-2 induction via CD40. Subsequent experiments investigated the roles of different second messenger systems in B7-1 and B7-2 induction in normal B cells. In M12 B lymphomas either CD40 cross-linking or cAMP treatment can induce B7 molecules. Here we report that treatment with dibutyryl-cAMP also induces B7 molecules in normal B cells provided that they have been preactivated by CD40 cross-linking. We also find that PMA and ionomycin treatment of B cells induces B7-2 but not B7-1 expression. Our data therefore show roles for BTK, cAMP and PMA/ionomycin in B7 induction, as well as providing further evidence for differential regulation of B7-1 and B7-2 induction in B cells.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed1981

Effect of levamisole on pokeweed mitogen stimulation of immunoglobulin production in vitro.

The effects of levamisole (LMS) on immunoglobulin (Ig) production were studied in vitro using peripheral blood lymphocytes from normal subjects stimulated with pokeweed mitogen (PWM). Cells were cultured for 9 days with varying concentrations of LMS and PWM, and immunoglobulin secretion in the supernatants was quantified by solid phase radioimmunoassay. The results showed that 1) the effect of LMS in vitro depends upon the degree of lymphocyte stimulation by PWM. When PWM stimulation is optimal, typical pharmacologic concentrations of LMS (0.5 micro/ml) decrease both IgM and IgG production by 50%. However, at lower suboptimal doses of PWM, LMS, at similar concentrations, enhances immunoglobulin production by 24% (p less than 0.01). Unstimulated lymphocytes are not affected by LMS. 2) The target cell upon which LMS acts is present among a T subpopulation that lacks the Fc receptor for aggregated rabbit IgG (T gamma -negative). We suggest that the diverse effects of LMS on autoimmune disease in vivo may depend upon both the size and degree of activation of the T gamma -negative lymphocyte pool.

B-Lymphocytes↗
PubMed1989

The role of adenosine triphosphate in migraine.

Classical migraine is associated with two distinct phases; an initial vasoconstriction followed by vasodilatation. The "purinergic" hypothesis for migraine was originally put forward in 1981 as a basis for the reactive hyperaemia and pain during the headache phase. It was suggested that adenosine 5'-triphosphate (ATP) and its breakdown products adenosine 5'-monophosphate and adenosine were strong contenders for mediating the vasodilatation following the initial vasospasm and subsequent hypoxia. ATP was also implicated in the pathogenesis of pain during migraine via stimulation of primary afferent nerve terminals located in the cerebral vasculature. Recent studies have shown that the ATP-induced cerebral vasodilation is endothelium-dependent via activation of P2Y-purinoceptors on the endothelial cell surface and subsequent release of endothelium-derived relaxing factor (EDRF); and that the endothelial cells are the main local source of the ATP involved, although adenosine 5'-diphosphate and ATP released from aggregating platelets may also contribute to this vasodilatation. These findings have extended the "purinergic" hypothesis for migraine in two ways. Firstly, they have clarified the mechanism of purinergic vasodilatation during the headache phase of migraine. Secondly, they suggest that a purinergic mechanism may also be involved in the initial local vasospasm, via P2X-purinoceptors on smooth muscle cells occupied by ATP released either as a cotransmitter with noradrenaline from perivascular sympathetic nerves or from damaged endothelial cells.

Adenosine Triphosphate↗