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Query: UNIPROT:P06889 (Mol)
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Vertebrate blood sera contain a factor that triggers oscillatory chloride currents in Xenopus oocytes through activation of the phosphoinositide/Ca2+ second system. The active serum component consists of lipids bound to an isoform of serum albumin that we have named active serum albumin (ASA). In undifferentiated PC12 cells, micromolar concentrations of ASA inhibit the early morphological changes induced by NGF, whereas in differentiated PC12 cells ASA caused a rapid withdrawal of neurites, which was reversible and dependent upon culture age. In contrast to normal serum, plasma and thrombin did not cause neurite retraction. Preincubation of ASA with monospecific antibodies to serum albumin suppressed its ability to induce neurite retraction in a dose dependent fashion. As in the oocyte, ASA activated the phosphatidylinositol second messenger system of PC12 cells, causing a several fold increase in Ins1,4,5P3 levels within minutes of application. The Ins1,4,5P3 increase was also blocked, in a titratable fashion, when ASA was preincubated with monospecific antibodies to serum albumin. This suggests that ASA-induced neurite retraction in PC12 cells may depend, at least in part, on activation of the phosphatidylinositol second messenger system. Results involving albumin-depleted sera show that ASA is the main factor responsible for serum vulnerability of neurites in PC12 cells. These findings point to some limitations in the use of serum in culture media, and raise the possibility that the serum factor may impair neuronal plasticity in disorders that are accompanied by the activation of blood coagulation together with a breakdown of the blood-brain barrier.
Brain Res Mol Brain Res 1992 Aug
PMID:The effect of active serum albumin on PC12 cells: I. Neurite retraction and activation of the phosphoinositide second messenger system. 132 92

In the preceding paper it was shown that an isoform of serum albumin (ASA; active serum albumin) causes a rapid retraction of neurites and increases intracellular content of Ins1,4,5P3 in PC12 cells. Here we examined whether ASA's effects in nerve growth factor-differentiated PC12 cells were mediated through the Ins1,4,5P3/Ca2+ second messenger pathway by monitoring intracellular Ca2+ (Ca2+i) with Fura2. It was found that ASA caused a dose-dependent increase in Ca2+i. In Ca(2+)-free medium, the increase in Ca2+i elicited by ASA was smaller, but the rise in Ins1,4,5P3 content was not appreciably changed. The small Ca2+i increase seen in Ca(2+)-free medium was probably due to the release of Ca2+ from Ins1,4,5P3-sensitive intracellular stores. In Ca(2+)-containing medium the Ca2+ transient induced by ASA was not affected by organic Ca2+ channel blockers, but decreased when Co2+, Mn2+ or Zn2+ were present in the extracellular medium. The effect of other ligands, such as carbachol and bradykinin, whose receptors are coupled to the phosphoinositide system was also investigated. Carbachol at concentrations from 2 to 200 microM, and bradykinin at a concentration of 2 microM did not cause neurite retraction, whereas 200 microM bradykinin caused an approximately 40% decrease in neurite length. Thapsigargin, a Ca(2+)-ATPase inhibitor, caused a sustained elevation of Ca2+i and retraction of neurites, whereas depolarization of the cells by high K+ gave only a transient elevation of Ca2+i, and no neurite retraction. Therefore, a sustained elevation in Ca2+i might be a sufficient trigger to induce neurite retraction in differentiated PC12 cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Brain Res Mol Brain Res 1992 Aug
PMID:The effect of active serum albumin on PC12 cells: II. Intracellular Ca2+ transients and their role in neurite retraction. 132 93

beta-Hexosaminidases, potent mitogens in bovine tracheal myocytes (BTM), stimulate a rapid and transient increase in intracellular cyclic adenosine monophosphate (cAMP) accumulation. The objective of this study was to elucidate the contribution of cAMP in hexosaminidase-induced airway muscle proliferation. Rate of DNA synthesis was measured by 3H-thymidine incorporation in quiescent cells prepared by a low-serum treatment (0.4%) for 48 h after reaching confluency in microtiter wells. cAMP accumulation was measured in acetylated cell extracts in the presence of isobutyl methylxanthine (100 microM) by radioimmunoassay using 125I-cAMP as tracer. Exposure of quiescent cells to purified human placental hexosaminidase B (5 micrograms/ml, 50 nM) caused a significant transient increase in cAMP accumulation (49 to 107 fmol/micrograms protein, or a 20- to 70-fold increase from basal level). Maximum increase occurred at 15 min followed by a rapid decline in cAMP accumulation within 30 min after exposure to hexosaminidase. Similar results were obtained in cells treated with neoglycoprotein mannose bovine serum albumin (100 to 500 nM). The increase in cAMP accumulation was inhibited by mannan (mannose receptor blocker, 0.1 mg/ml), as well as phenylisopropyladenosine (PIA; A1 receptor agonist that inhibits adenylyl cyclase, 0.1 to 1.0 microM). The increase in 3H-thymidine incorporation induced by hexosaminidase B was also inhibited by mannan and PIA. Exposure to 8-(4-chlorophenylthio)-cAMP (cpt-cAMP; a cell-permeable analog of cAMP, 100 microM) or forskolin (a direct activator of catalytic subunit of adenylyl cyclase, 24 microM) up to 6 h enhanced 3H-thymidine incorporation. In contrast, a prolonged exposure (18 to 30 h) to these agents inhibited 3H-thymidine incorporation.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1992 Dec
PMID:Dual regulation by cAMP of beta-hexosaminidase-induced mitogenesis in bovine tracheal myocytes. 133 45

The quantitative immunological technique of microcomplement fixation was used to examine serum albumin evolution among members of the order Crocodylia. The cross-reactivity of the albumin antisera and antigens employed in this study had been examined previously using the qualitative technique of immunodiffusion. The phylogenetic conclusions derived from these two data sets are highly congruent, including support of the families Alligatoridae and Crocodylidae, with the placement of Gavialis as the sister taxon of Tomistoma. Both methods provide similar information on the relative amounts of amino acid sequence divergence between albumin molecules; however, the data obtained from microcomplement fixation comparisons are more discriminating than those derived from immunodiffusion. The estimated divergence times within the Crocodylia derived from the fossil record are examined in light of divergence times predicted by the microcomplement fixation-based albumin clock. The traditional phylogenetic placement of Gavialis outside the remaining extant crocodilians is inconsistent with all molecular data sets and we suggest that a careful reexamination of both the extant and the fossil morphological data is warranted.
Mol Phylogenet Evol 1992 Sep
PMID:Crocodilian evolution: insights from immunological data. 134 35

Plasmodium yoelii nigeriensis infection in mice caused an increase in uptake of 125I-labeled bovine serum albumin, 51Cr-labeled erythrocytes and Evans blue dye from peripheral circulation into the brain. Isolated cerebral microvessels which were characterized in terms of their morphology under scanning electron microscope and enhancement of the specific activities of biochemical markers, viz. alkaline phosphatase, gamma-glutamyl transpeptidase, and monoamine oxidase, showed significant decrease in these activities due to P. yoelii nigeriensis infection. On the other hand, relatively minor (statistically insignificant) changes occurred in the first two enzyme specific activities in the cerebral cortex and monoamine oxidase registered an increase in this tissue due to infection. Histological examination of the cerebral tissue of infected animals by light and electron microscopy showed broken blood vessel walls and leakage of erythrocytes into extravascular space, some of which contained intraerythrocytic malarial parasite in a state of cell division.
Exp Mol Pathol 1992 Aug
PMID:Aberrations in cerebral vascular functions due to Plasmodium yoelii nigeriensis infection in mice. 135 26

Monoclonal antibodies to cyclosporine A (Cs), a potent immunosuppressant, were generated in BALB/c mice using a novel antigen prepared by linking Cs to a protein carrier via a photoactive cross-linking reagent, 4-benzoylbenzoic acid (BBa). Twenty-two monoclonal anti-Cs antibodies were generated, using Cs-BBa-bovine serum albumin (Cs-BBa-BSA) as the immunogen. They were characterized with respect to affinity by Scatchard analysis of a radioimmunoassay (RIA), and with respect to specificity by an ELISA in which a series of singly substituted Cs derivatives were examined as inhibitors. McAb affinities ranged from 5 x 10(-8) M to 2 x 10(-10) M. Based on ELISA inhibition data with Cs analogs, and on the binding to two Cs-BSA conjugates in which opposite sides of the Cs molecule are exposed, the antibodies fell into five epitope recognition groups. Binding to Cs was also studied by ELISA in competition with cyclophilin (CyP), a Cs-binding protein whose epitope specificity has been well characterized. Competition by CyP was found to correlate with antibody specificity, not with affinity, i.e. CyP competed best with antibodies having specificities most similar to that of CyP. Epitope mapping can, therefore, be accomplished in a system in which two different species of binding proteins compete for the same antigen. This type of characterization may be useful in identifying antibodies whose combining sites mimic those of a receptor.
Mol Immunol 1992 Jan
PMID:Novel monoclonal antibodies to cyclosporine A: characterization and epitope mapping with cyclosporine analogs and cyclophilin. 137 May 70

Erythrocytes (E) play a central role in handling circulating immune complexes (IC) in primates. E capture IC via complement receptors, type 1 (CR1) which can bind to C3b and C4b ligand sites generated on IC during activation of the complement cascade. The present study was designed to explore how the immunochemical properties of IC affected their interactions with human E. Model IC were constructed by combining murine monoclonal anti-dinitrophenyl (DNP) antibodies with DNP-bovine serum albumin. A panel of 10 independently-derived monoclonal IgG1, IgG2a, IgG2b, IgG3, IgM and IgA antibodies were used to construct IC and their interactions with human E were examined in vitro. The data reveal that IC constructed with the different monoclonal antibodies differed with respect to their rate of binding to E, the peak magnitude of IC binding to E, and the rate and extent of IC release from E. IC containing IgG1 antibodies (IgG1 IC), IgG2a IC, IgG2b IC, and IgA IC all bound rapidly to E, whereas IgG3 IC and IgM IC were bound relatively slowly to E. The peak magnitude of IC binding to E correlated directly with their binding rate. There was an inverse correlation between the antigen/antibody ratio of the IC and the magnitude of IC binding to E. The rate of release of the various types of IC from E also differed. IgG2a IC and IgG2b IC displayed the most rapid maximum release rates while IgG3 IC had the slowest peak release rate. IgM IC and IgA IC were also released relatively slowly from E. IgG1 IC had an intermediate release rate. There was no direct correlation between the maximum release rate and either the maximum binding rate or the peak magnitude of IC binding to E. While there were some clonotypic differences in binding and release rates between IC made with different IgG2a, IgG3 and IgM antibodies, antibody isotype appears to be of fundamental importance with respect to both the binding of IC to E and the release of IC from E. These data indicate that the immunochemical properties of IC can profoundly affect their interactions with human E and that the panel of IC constructed with monoclonal antibodies can serve as a useful model to explore these interactions.
Mol Immunol
PMID:Isotypic and clonal variations in the interactions between model monoclonal immune complexes and the human erythrocyte CR1 receptor. 138 41

By display of antibody repertoires on the surface of a filamentous bacteriophage and selection of the phage by binding to antigen, we can mimic immune selection. Recently, by tapping the repertoire of rearranged V-genes from the peripheral blood lymphocytes of unimmunised donors, we succeeded in making human antibody fragments with different specificities, including both haptens and proteins, from the same library of phage. Now we have built a repertoire of human VH genes from 49 human germline VH gene segments rearranged in vitro to create a synthetic third complementarity determining region (CDR) of five or eight residues. The rearranged VH genes were cloned with a human V lambda 3 light chain as single chain Fv fragments for phage display, and the library of phage panned by binding to each of two haptens, 2-phenyl-5-oxazolone (phOx) or 3-iodo-4-hydroxy-5-nitrophenyl-acetate (NIP) coupled to bovine serum albumin (BSA). Many different antibody fragments were isolated which bound specifically to hapten, some with affinities in the micromolar range. The in vitro "immune response" to the hapten NIP was dominated by the 9-1 segment (VH3 family), and that to phOx by the VH26 segment (VH3 family) with an invariant aromatic residue (Tyr, Phe, Trp) at residue 97 of CDR3. However, the isolation of phage against protein antigens proved more elusive, with a single phage binding to human tumour necrosis factor, and none to bovine serum albumin, turkey egg-white lysozyme or human thyroglobulin. Nevertheless, the work shows that human antibody fragments with specific binding activities can be made entirely in vitro.
J Mol Biol 1992 Sep 20
PMID:By-passing immunisation. Human antibodies from synthetic repertoires of germline VH gene segments rearranged in vitro. 140 59

The displacement of a series of 1,4-benzodiazepine (BDZ) drugs from a chiral stationary phase, based upon human serum albumin, for high performance liquid chromatography was investigated. The different displacement patterns obtained using various mobile phase additives could not be interpreted in terms of binding of the solutes to a single site. The observations were better described by considering the attachment of the BDZs to several loci on the protein. Two main mechanisms of binding were discerned, a nonstereoselective mode, which affected all solutes and seemed to occur at a large number of locations on the protein, and a highly stereoselective mode, which involved only one enantiomer of chiral BDZs and presumably one conformation of certain achiral solutes. The stereoselective binding mode encompassed at least four different sites, each of which displayed slightly different structural requirements. It is suggested that the nomenclature currently used to describe drug binding to human serum albumin may be misleading. Rather than the use of site I or site II, it may be preferable to adopt the terms type I and type II binding, according to the displacement patterns of the compound concerned. This approach would retain the conceptual simplicity of the current notation, while avoiding misleading implications of the exact molecular locus of binding.
Mol Pharmacol 1992 Sep
PMID:Stereochemical aspects of benzodiazepine binding to human serum albumin. I. Enantioselective high performance liquid affinity chromatographic examination of chiral and achiral binding interactions between 1,4-benzodiazepines and human serum albumin. 140 1

Previously determined retention data for a series of benzodiazepine (BDZ) derivatives, comprising nine achiral compounds, four single enantiomers, and 18 individual isomers of nine racemates, on a chiral stationary phase based on immobilized human serum albumin (HSA) were analyzed to define quantitative relationships between structure and enantiospecific retention. Structural parametrization of the agents was done by means of hydrophobic fragmental constants and electronic and steric parameters obtained by computational chemistry methods. A structural descriptor was identified, a submolecular measure of polarity about the stereogenic center, that accounted for the stronger electrostatic interactions of the second-eluting enantiomer with the HSA chiral stationary phase. Quantitative structure-enantiospecific retention relationships were derived for both enantiomeric series and for achiral compounds, and structural requirements for binding to HSA were determined. Two types of binding sites were postulated. For BDZs in the P-conformation, binding to HSA involved a hydrophobic region with steric restrictions. For BDZs in the M-conformation, a hydrophobic region was also involved, as well as a cationic region that interacted electrostatically with carbon C(3) of the diazepine system and substituents at that carbon. These differences lead to different binding patterns for BDZ enantiomers and provide a rationalization for the diversified behavior of individual BDZs that was observed in previous displacement studies.
Mol Pharmacol 1992 Sep
PMID:Stereochemical aspects of benzodiazepine binding to human serum albumin. II. Quantitative relationships between structure and enantioselective retention in high performance liquid affinity chromatography. 140 2


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