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PubMed1990

Stimulation of prostaglandin E1 binding to human blood platelet membrane by insulin and the activation of adenylate cyclase.

Incubation of human platelet-rich plasma with physiological amounts of insulin resulted in the increase of the binding of prostaglandin E1 by more than 2-fold when compared to the control platelets. Scatchard analysis of the binding of the prostaglandin to the hormone-treated platelets showed that the increased binding was due to the increase of receptor numbers rather than the increase of affinity of the binding sites. The membranes prepared from the insulin-treated platelets also showed similar enhanced binding of the prostaglandin. However, addition of insulin directly to the membranes isolated from the platelets which had not been previously incubated with the hormone failed to show any effect. This increased binding of the prostanoid to the membranes prepared from the insulin-treated platelets resulted in the stimulation of adenylate cyclase by more than 2-fold when compared with the control of membrane preparation by the prostaglandin alone. In contrast, treatment of platelets with the hormone which increased the prostanoid binding to these cells did not influence the cyclic AMP phosphodiesterase activity of either the membrane or cytosolic fraction. The increase in the cellular level of cyclic AMP by prostaglandin E1 was 2-fold greater in the hormone-treated cells than in the case of untreated platelets stimulated by the agonist alone. The incubation of platelet-rich plasma with insulin, as expected, decreased the amount of prostaglandin E1 needed to inhibit platelet aggregation by more than 50% when compared to the control platelets.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1991

Restoration by insulin of impaired prostaglandin E1/I2 receptor activity of platelets in acute ischemic heart disease.

Treatment of normal platelet-rich plasma with a physiological amount of insulin (100 microunits/ml, optimum concentration) for 3 hours at 23 degrees C stimulated the binding of prostaglandin E1 by more than twofold (3,940 +/- 250 sites/10(8) platelets) compared with the nontreated, control platelet-rich plasma (1,590 +/- 265 sites/10(8) platelets). After platelet-rich plasma from patients with acute ischemic heart disease (n = 43), whose platelets showed impaired prostaglandin E1/I2 receptor activity (850 +/- 100 sites/10(8) platelets), was incubated with insulin (optimum amounts varied from 100 to 200 microunits/ml), the binding of the prostanoid was restored to normal levels (1,790 +/- 140 sites/10(8) platelets) in 75% of the cases. Twenty-five percent of the patients did not respond to the stimulatory effect of insulin. The increased binding of the prostanoid to the insulin-treated platelets also resulted in increased cyclic AMP levels both in normal subjects (44.14 +/- 3.1 pmol/10(8) [insulin-treated] platelets versus 16.35 +/- 2.91 pmol/10(8) [control] platelets) and in patients with acute ischemic heart disease (23.87 +/- 4.1 pmol/10(8) [insulin-treated] platelets versus 7.70 +/- 2.0 pmol/10(8) [control] platelets) by the prostanoid (1.0 microM). The treatment of platelet-rich plasma with the hormone decreased the minimum inhibitory concentration of the prostanoid from 34 +/- 14 to 15 +/- 9 nM (p less than 0.001) in the case of normal volunteers and from 49 +/- 15 to 32 +/- 11 nM (p = 0.002) in the case of "responder" patients. Insulin did not produce any effect on the inhibition of platelet aggregation by the prostaglandin in "nonresponder" patients. In the follow-up study, although the stimulatory effects of insulin on platelets from responder patients were improved to normal levels, the platelets from the nonresponder patients remained persistently unresponsive to the effect of the hormone.

Acute Disease↗
PubMed1997

Binding of copolymer 1 and myelin basic protein leads to clustering of class II MHC molecules on antigen-presenting cells.

Copolymer 1 (Cop 1), a synthetic copolymer of amino acids, effective in suppression of experimental allergic encephalomyelitis (EAE) and myelin basic protein (MBP), was shown to bind extensively and promiscuously to the class II MHC molecules on antigen-presenting cells (APC) without prior processing. In the case of human APC, binding has earlier been demonstrated to DR but not DQ or class I molecules. In the present study, we examined whether binding of Cop 1 and MBP affects MHC class II expression on the cell membrane. Biotinylated derivatives of these antigens were used to monitor their direct binding to MHC molecules on living APC by flow cytometry using phycoerythrin-streptavidin, while the levels of MHC surface expression were monitored by staining with FITC-conjugated anti-class I- and class II-specific antibodies. When Cop 1 or MBP were incubated with the APC, intensity of cell staining with anti-DR, but not with anti-DQ or anti-class I antibodies, was significantly increased, compared to the staining of control APC not reacted with these antigens. In contrast, staining intensity was unaffected when p84-102, a human immunodominant epitope of MBP, or ovalbumin (OVA), a protein which undergoes proteolytic degradation prior to binding, were incubated with the APC. Cycloheximide, a protein synthesis inhibitor, had no effect on the enhanced staining intensity with anti-DR antibody of cells treated with Cop 1 or MBP, whereas it inhibited the enhanced staining of both DR and DQ molecules caused by the respective antibodies, in the absence of these antigens. Brefeldin A, a protein transport inhibitor, lowered the levels of staining intensity with anti-DR and anti-DQ antibodies in both cases, with and without antigen added to the APC. Fluorescence microscopic analysis revealed that cells incubated with Cop 1 or MBP, but not with p84-102 or OVA, exhibit both bright staining of the cell membrane and clusters produced by the aggregation of DR molecules with these antigens. Taken together, these observations indicate that Cop 1 and MBP, due to their polyvalent character, lead to increased fluorescence intensity of their complexes with HLA-DR, possibly due to recruitment and clustering of previously synthesized DR molecules. This can explain the efficient binding of these antigens to the MHC class II molecules.

Adjuvants, Immunologic↗
PubMed1998

Agrin can mediate acetylcholine receptor gene expression in muscle by aggregation of muscle-derived neuregulins.

The neural isoforms of agrin can stimulate transcription of the acetylcholine receptor (AChR) epsilon subunit gene in electrically active muscle fibers, as does the motor neuron upon the formation of a neuromuscular junction. It is not clear, however, whether this induction involves neuregulins (NRGs), which stimulate AChR subunit gene transcription in vitro by activating ErbB receptors. In this study, we show that agrin- induced induction of AChR epsilon subunit gene transcription is inhibited in cultured myotubes overexpressing an inactive mutant of the ErbB2 receptor, demonstrating involvement of the NRG/ErbB pathway in agrin- induced AChR expression. Furthermore, salt extracts from the surface of cultured myotubes induce tyrosine phosphorylation of ErbB2 receptors, indicating that muscle cells express biological NRG-like activity on their surface. We further demonstrate by RT-PCR analysis that muscle NRGs have Ig-like domains required for their immobilization at heparan sulfate proteoglycans (HSPGs) of the extracellular matrix. In extrasynaptic regions of innervated muscle fibers in vivo, ectopically expressed neural agrin induces the colocalized accumulation of AChRs, muscle-derived NRGs, and HSPGs. By using overlay and radioligand-binding assays we show that the Ig domain of NRGs bind to the HSPGs agrin and perlecan. These findings show that neural agrin can induce AChR subunit gene transcription by aggregating muscle HSPGs on the muscle fiber surface that then serve as a local sink for focal binding of muscle-derived NRGs to regulate AChR gene expression at the neuromuscular junction.

Agrin↗
PubMed1985

Characterization of human IgG Fc receptors.

A murine monoclonal antibody, KuFc79, has been developed that reacts with human IgG Fc receptors on monocytes, B lymphocytes, and granulocytes. The specificity of KuFc79 for Fc receptors was demonstrated by the ability of Fab fragments to block Fc-mediated phagocytosis by monocytes. This finding was further substantiated by the decrease of KuFc79 binding to monocytes and granulocytes (58 and 70%, respectively) after modulation of surface IgG receptors with aggregated IgG. In addition, Fab KuFc79-conjugated Sepharose was used to isolate functional IgG Fc-binding molecules from soluble extracts of the human monocyte-like cell line U937. By immunoprecipitation, it was further shown that KuFc79 immunoprecipitated molecules of 42,000 and 70,000 daltons from U937 and a human lymphoblastoid cell line, SB. A lower m.w. species of approximately 33,000 was also precipitable from granulocytes. Extensive microheterogeneity of these molecules was noted by isoelectric focusing, which appears to be due to differential sialation.

Animals↗
PubMed1985

The heart as a sensory organ.

Three groups of receptors in the heart are activated by changes in pressure in the cardiac chambers. Those at the venous-atrial junctions with myelinated vagal afferent nerves indicate changes in heart rate and degree of atrial filling. A second group, present in all the cardiac chambers, served by unmyelinated vagal afferent nerves, signals changes in ventricular preload, afterload and cardiac contractility. A third group, also present in all the cardiac chambers, has both myelinated and unmyelinated afferent nerves that pass to the spinal cord. Their normal function is unknown. Abnormal activation of the cardiac mechanoreceptors during myocardial ischemia may be important in the genesis of life-threatening arrhythmias.

Arrhythmias, Cardiac↗
PubMedDate not supplied

What controls the position, number, size, and distribution of neuromuscular junctions on rat muscle fibers?

This review focuses on mechanisms that determine the position, number, size, and distribution of neuromuscular junctions (NMJs) on skeletal muscle fibers. Most of the data reviewed derive from studies of ectopic NMJ formation on soleus (SOL) muscle fibers in adult rats, which recapitulates essential aspects of NMJ formation in normal development. Transplanted axons induce acetylcholine receptor (AChR) aggregates, which are multiple and irregularly distributed initially but subsequently undergo massive reorganization such that one or a few winners survive and reach a certain size while the rest are eliminated (the losers). Results obtained by blocking nerve activity early and stimulating the SOL electrically show that evoked muscle impulse activity is responsible for the growth of winners to a given size and the creation of refractory zones, about 0.75 long, on each side of the winners, in which the elimination of losers occurs. Consequently, when two or more aggregates or NMJs survive on one fiber, they are, on average, at least 1.5 mm apart. Locally applied neural agrin induces comparable aggregation of AChRs and other postsynaptic proteins on denervated SOL fibers and such aggregates undergo similar activity-dependent selection for survival or elimination in refractory zones. In a dose-dependent way, neural agrin alone also induces expression of epsilon-AChR subunits and stabilizes AChRs to a half-life of 10 days, as found at normal NMJs. It is argued that signs of prepatterning of innervation sites by intrinsic muscle mechanisms may refer to epiphenomena that play no important role in NMJ formation. The conclusion is that neural agrin initiates and then maintains NMJs where motor axons happen to contact receptive muscle fibers and that evoked muscle impulse activity then ensures that the NMJs reach their appropriate size, efficiency and spatial distribution along each fiber.

Animals↗
PubMed1987

The 5-hydroxytryptamine system of blood platelets: physiology and pathophysiology.

The 5-hydroxytryptamine (5HT)-system of human blood platelets consists of a relatively specific uptake mechanism for 5HT at the plasma membrane, intracellular storage organelles (dense bodies), a metabolizing enzyme (monoaminoxidase B) and a 5HT2-receptor whose stimulation leads to activation of the phosphatidylinositide turnover, a rise in free cytoplasmic Ca2+, phosphorylation of proteins and a shape change reaction. There is neither a relevant 5HT-biosynthesis nor a marked physiological 5HT-turnover in platelets. Under physiological conditions the platelet 5HT-system may have a role as a scavenger for free extracellular 5HT and in hemostasis. Disturbances which have been described in pathophysiological states include impairment of 5HT-uptake (hypertension, migraine), impairment of 5HT-storage (storage pool deficiencies, thromboembolic disorders, hypertension) and increased sensitivity to activating agents like 5HT (cardiovascular disorders, diabetes). Besides their role in physiology and pathophysiology platelets may be useful partial models for vascular smooth muscle cells.

Blood Platelets↗
PubMed1996

Endothelin-1: a scientist's curiosity, or a real player in ischemic heart disease?

Endothelin-1, the most potent endothelium-derived vasoconstrictor peptide identified so far, exerts multiple biologic effects that are potentially relevant for the pathogenesis of coronary atherosclerosis and ischemic heart disease. Since the discovery of the peptide, a good deal of experimental and clinical data have been accumulated to support an important role of endothelin-1 in ischemic heart disease. In experimental animals, exogenous endothelin-1 was found to cause coronary vasoconstriction and, at higher doses, ventricular fibrillation and death. Endothelin receptor subtypes have been demonstrated and pharmacologically characterized in the coronary vascular bed. The plasma levels of immunoreactive endothelin-1 were found to be increased in patients with coronary atherosclerosis, acute myocardial infarction, and angina. Given its growth-promoting and mitogenic action, endothelin-1 has also been suspected to participate in the mechanism of restenosis after PTCA. The purpose of this study was to critically review the experimental and clinical data supporting the involvement of endothelin-1 in ischemic heart disease and the results of more recent studies on the effects of endothelin-1 blockade on experimental myocardial necrosis and restenosis after PTCA.

Angioplasty, Balloon, Coronary↗
PubMed1992

Low structural specificity for nucleoside triphosphates as antagonists of ADP-induced platelet activation.

Although the platelet ADP receptor is thought to exhibit a high degree of structural selectivity, adenosine 5'-O-(thiotriphosphate) (ATP alpha S) is a potent inhibitor of ADP-induced platelet activation and has been recently shown to bind with high affinity (Kd 3 +/- 0.1 nM) to formaldehyde-fixed platelets and to be photoincorporated into an 18-kDa fragment beginning at Tyr-198 of glycoprotein (GP) IIb alpha (Greco, N. J., Yamamoto, N., Jackson, B. W., Tandon, N. N., Moos, M., Jr., and Jamieson, G. A. (1991) J. Biol. Chem. 266, 13627-13633). Further studies have now shown that guanosine 5'-O-(thiotriphosphate) (GTP alpha S) also binds to high affinity sites (Kd 4.7 +/- 0.9 nM; 13,600 +/- 1,140 sites/platelet) and to low affinity sites (Kd 470 +/- 85 nM; 135,900 +/- 19,400 sites/platelet). Competition binding studies showed that all GTP alpha S binding sites were accessible to ADP and vice versa. The corresponding pyrimidine nucleotide cytidine 5'-O-(thiotriphosphate) (CTP alpha S) was found to be similarly effective in competing in the binding of ADP and both 5'-O-(thiotriphosphates) as well as uridine 5'-O-(thiotriphosphate) (UTP alpha S) were potent inhibitors of platelet shape change and aggregation. Ultraviolet irradiation of platelets in the presence of either [35S]GTP alpha S or [35S]UTP alpha S resulted in their specific incorporation into the alpha chain of GPIIb as previously shown with [35S]ATP alpha S. These results show that the structure of the nucleotide base has little influence on its ability to occupy the ADP-binding site on platelets, to function as an inhibitor of ADP-induced activation or to be photoincorporated into GPIIb alpha.

Adenosine Diphosphate↗
PubMed1989

Culture of macrophages from bovine bone marrow.

Macrophages perform important immunoregulatory and host defense functions. Examination of this cell type in the bovine has been restricted because of lack of a means to obtain pure bovine macrophage populations reproducibly. We have developed a system for production of large numbers of macrophages from this species with greater than 99% purity. Stem cells were obtained from the bone marrow of neonatal calves and cultured in vitro in the presence of macrophage-colony-stimulating factor. Bovine bone marrow culture-derived macrophages were esterase-positive, expressed Fc receptors for aggregated IgG, and bovine macrophage differentiation markers. In addition, they displayed class I and class II major histocompatibility (MHC) antigens. The level of MHC antigen expressed could be further enhanced by treatment with recombinant bovine interferons. The macrophages exhibited expected functions, for example, Fc-mediated ingestion of opsonized sheep red blood cells. Augmentation of phagocytic capacity by either alpha or gamma interferon could also be demonstrated. The data reported here confirm that bone marrow culture is a convenient, reliable source of macrophages for investigations of this bovine cell type.

Animals↗
PubMed1994

Redistribution of plasma membrane proteins by electroosmosis elicits cytosolic calcium response in tumor mast cells.

Activation of mast cells and basophils by binding of ligands that crosslink and micro-aggregate cell surface receptors leads to a series of responses including a phosphoinositide cascade, elevation of intracellular free calcium ([Ca2+]i), morphological changes in the cell plasma membrane, and ultimately, exocytosis of granules containing histamine and other mediators of the allergic response. In rat basophilic leukemia (RBL) cells, a tumor mast cell line, stimulation by immunoglobulin E receptor crosslinking induces these responses. In order to determine whether redistribution or aggregation of cell surface proteins is sufficient to induce a response in these cells without extrinsic crosslinking, we have redistributed cell surface proteins by electroosmotic segregation and looked for second messenger [Ca2+]i responses. Video imaging of calcium ion activity using the fluorescent calcium sensitive dye fura-2 revealed the effects of receptor motion and aggregation induced by application of small (10 V/cm) electric fields. A synchronous, monotonic rise in [Ca2+]i generally occurs within a few minutes after a steady field has been applied, while the redistribution of surface proteins is still in progress. The oscillations in [Ca2+]i characteristic of antigen-stimulated cells are not seen, nor are any effects observed in weak alternating fields (0.02, 60 Hz). The observed rise in [Ca2+]i induced by static electric fields is attributed to perturbation of [Ca2+]i regulation by the large-scale redistribution of membrane constituents induced by surface electroosmosis.

Animals↗
PubMed1999

Protease-activated receptor 1 is the primary mediator of thrombin-stimulated platelet procoagulant activity.

The activation of human platelets by thrombin is mediated primarily by protease-activated receptors (PARs). PAR1 and PAR4 are present on human platelets and are activated by the hexapeptides SFLLRN and GYPGQV, respectively. To further characterize the involvement of PAR1 and PAR4 in platelet activation, the ability of SFLLRN or GYPGQV to generate annexin V binding to newly exposed phospholipids on the platelet surface and generate procoagulant activity has been examined. Exposure of phosphatidylserine and phosphatidylethanolamine on platelets, as determined by an increase in annexin V binding, was strongly stimulated by SFLLRN, thrombin, and collagen, but only to a minor extent by GYPGQV. In a clotting assay initiated with factor VIIa, soluble tissue factor, and calcium, the clotting time in the absence of platelets was >5 min. In the presence of unstimulated platelets, the clotting time was 200 +/- 20 sec. In the presence of platelets activated with SFLLRN or collagen, the clotting time decreased to 100 +/- 10 sec. This shortening of the clotting time is equivalent to about a 5-fold increase in coagulant activity when stimulated platelets are compared with unstimulated platelets and activated platelets are used as a reference. These results indicate that thrombin initiates a very strong response in platelets through PAR1, leading to exposure of anionic phospholipids that support blood clotting. The response mediated by PAR4, however, was limited to platelet aggregation and similar to that triggered in platelets by weaker agonists such as ADP or epinephrine.

Annexin A5↗
PubMed2003

Humanin peptides block calcium influx of rat hippocampal neurons by altering fibrogenesis of Abeta(1-40).

Humanin peptides (including HN, HNG and other mutants) were reported previously that antagonize neurotoxicity caused by various familial Alzheimer's disease (FAD) genes and Abeta derivatives. Herein, we describe the aggregation dynamics and the representative morphological characteristics of Abeta(1-40) after different time of addition humanin peptides, which revealed that (a) the interactions of both HN and HNG with Abeta(1-40) induced quick and significant increase of light-scattering intensity, and (b) HNG also caused obvious morphological alteration from fibrillary to amorphous. In the meantime, the experiments also revealed that the interaction of HNG with Abeta(1-40) could decrease Abeta(1-40)-induced calcium rise, an initial event accompanying Abeta(1-40)-induced apoptosis of cultured neurons. Our results indicate that HNG can protect neurons by altering Abeta(1-40) morphology.

Amino Acid Sequence↗
PubMed1989

Studies on the mechanism of expression of secreted fibrinogen on the surface of activated human platelets.

Affinity purified anti-fibrinogen (anti-Fg) Fab fragments were used to study the mechanism of expression of alpha-granule fibrinogen on activated platelets. Low amounts of the radiolabeled anti-Fg Fab bound to unstimulated or adenosine diphosphate (ADP)-stimulated cells. They readily bound to platelets stimulated with collagen, alpha-thrombin or gamma-thrombin in the presence of divalent cations. At 1 n mol/L alpha-thrombin or 25 nmol/L gamma-thrombin, platelet fibrinogen was expressed on the surface of the cells notwithstanding the presence of AP-2, a monoclonal antibody to the glycoprotein (GP) IIb-IIIa complex, or the synthetic peptides Arg-Gly-Asp-Ser and gamma 400-411, all substances that prevented the binding of plasma fibrinogen to platelets. These results suggest that platelet fibrinogen may interact with its receptors during its translocation from the alpha-granules to the plasma membrane and, thus, not occupy the same sites as those available for plasma fibrinogen on the surface of the cell. Furthermore, we found that platelet fibrinogen was expressed on the thrombin-stimulated platelets of a Glanzmann's thrombasthenia variant that failed to bind plasma fibrinogen. Normal platelets stimulated with 5 nmol/L alpha-thrombin bound increased amounts of the anti-fg Fab, the additional expression being inhibited by the anti-GP IIb-IIIa monoclonal antibody or by Gly-Pro-Arg-Pro, an inhibitor of fibrin polymer formation. This suggests that rebinding to externally located GP IIb-IIIa complexes becomes important once fibrin is formed.

Binding Sites, Antibody↗
PubMed1997

gamma-AChR/epsilon-AChR switch at agrin-induced postsynaptic-like apparatus in skeletal muscle.

We transfected the extrajunctional region of denervated soleus muscles in adult rats with neural agrin cDNA to induce myofibers to form postsynaptic-like apparatus containing acetylcholine receptor (AChR) aggregates. By 1 week approximately 30% of the AChR aggregates contained a mixture of epsilon-AChRs and gamma-AChRs while approximately 70% had only gamma-AChRs. If the transfected muscles were reinnervated in the original junctional region, the postsynaptic-like apparatus, despite the absence of apposed axon terminals, gradually came to have only epsilon-AChRs. We conclude that at the postsynaptic apparatus of ectopic neuromuscular junctions formed by a foreign nerve implanted into the extra-junctional region of denervated muscles, agrin secreted by the axon terminal plays a direct role in the gamma-AChR/epsilon-AChR switch that occurs as the apparatus reaches maturity. Our findings, together with results from other studies, indicate further that agrin and acetylcholine are the only nerve-derived factors required for this switch.

Agrin↗
PubMed1985

Peripheral adrenoceptors and serotonin receptors in depression. Changes associated with response to treatment with trazodone or amitriptyline.

Changes in platelet and lymphocyte adrenoceptor densities, platelet serotonin uptake and aggregatory response to serotonin were assessed in a group of moderately depressed patients before and during treatment with either trazodone or amitriptyline. Platelet serotonin receptor activity and uptake were lower before the start of treatment in all patients than in those patients responding to treatment. The densities of alpha 2- and beta-adrenoceptors tended to be higher in the patients before treatment and returned to control values after effective therapy. There were no major differences in the biochemical changes between the patients treated with trazodone or amitriptyline. When the biochemical data was correlated with the clinical history of the patients, it was found that only endogenously depressed patients, and not those with non-endogenous depression, had a significantly reduced platelet serotonin uptake rate. In addition, female depressives had a slightly lower platelet 5-HT aggregatory response than males irrespective to the type of depression.

Adolescent↗
PubMed1990

Evidence for a role of serotonin in initiation of coronary arterial thrombosis in dog and man.

We report recently published results in dogs by Torr et al. in which the accumulation of platelet thrombi in canine coronary arteries was abolished by the specific serotonin 5HT2 receptor antagonist, ritanserin. The serotonin blockade by ritanserin also prevented the re-establishment of thrombi by adrenaline infusion. 61 humans with critical coronary artery stenoses shown by coronary angiography were divided into control and serotonin antagonist (31 ketanserin administration) groups. While awaiting coronary artery bypass grafting or angioplasty, 7 of the subjects in the control group had coronary arterial occlusions, 4 of whom died. The only occlusion in the serotonin antagonism group occurred in a subject who died suddenly after 2 years of study. The probability of the occlusion rate in subjects subjected to serotonin antagonism being the same as that of the control subjects was less than 0.0245, by Fisher's exact test. It is concluded that serotonin may be as important in mediating coronary thrombosis in man as it is in animals.

Animals↗