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The activation of the Agrobacterium virulence system is known to be induced by certain phenolic compounds. We have tested the vir-inducing ability of fifty compounds, by using a virB-lacZ gene fusion, and analysed the relationship between structure and activity of these compounds. In this way we have identified several new vir-inducers: coniferylalcohol, 3,5-dimethoxy-4-hydroxybenzene, homovanillic acid, ferulic acid, 3-ethoxy-4-hydroxybenzaldehyde and guaiacol, all of which are compounds with strong or moderate activity and four compounds with weak vir-inducing activity. In view of the specificity of vir-inducers, our data extended observations of others and enabled us to define the specific structural features of a vir-inducer molecule. In addition we show here that induction of the octopine Ti vir-genes is (i) optimal at 29 degrees C and totally abolished at 37 degrees C, and (ii) strongly inhibited at low concentrations of sodium chloride. The implications for plant transformation are discussed.
Mol Microbiol 1989 Jul
PMID:Specificity of signal molecules in the activation of Agrobacterium virulence gene expression. 279 34

A deviation from physiological osmolality (300 mOsm/kg H2O) can lead to genotoxic effects. A 30-min treatment of V79 hamster cells with hypotonic sodium chloride of 60 mOsm/kg H2O or with diluted culture medium of the same osmolality induces extraordinarily high frequencies of chromosomal aberrations. In this study, multiple fixation times over a 24-hr period were used to identify cells in various stages of the cell cycle at the time of treatment and to find out whether or not hypotonic conditions are able to induce aberrations in all cell cycle stages. Because of the aberration pattern observed, it is suggested that hypotonic treatment acts as an S-independent agent, like X-rays or restriction endonucleases. Whether the aberrations originate from directly induced DNA damage or from a release of DNase after lysosomal breakdown is discussed.
Environ Mol Mutagen 1989
PMID:Induction of chromosomal aberrations by hypotonic culture conditions is independent of the S-phase in V79 hamster cells. 291 Jul 3

The novel iodinated ligand [125I]-N-(p-aminophenethyl)spiroperidol ([125I]NAPS) was used to identify the D-2 dopamine receptor in the intermediate lobe of the rat pituitary gland. The binding of [125I]NAPS was of high affinity and saturable, given that the dissociation constant and the maximal binding were 34.7 +/- 4.8 pM and 21.1 +/- 2.5 fmol/mg of protein, respectively. The ability of dopaminergic agonists and antagonists to compete with [125I]NAPS varied markedly with incubation temperature. The marked decrease of the molar potency associated with increasing incubation temperature in the competitive displacement curve suggested that the binding of five agonists, dopamine, (-)-apomorphine, (-)-n-propylnorapomorphine, N-0434, and LY-171555, to the D-2 dopamine receptor was enthalpy-driven, with a negative change in entropy. In contrast, the binding of three antagonists, fluphenazine, (+)-butaclamol, and domperidone, was entropy-driven, with positive change in entropy, suggesting less temperature-sensitive change in the molar potency. Several molecules gave unanticipated results; the molar potency of two dopamine agonists, bromocriptine and lisuride, was much less temperature-sensitive than the other agonists used in this study. The thermodynamic parameters for the atypical agonists indicated entropy-driven binding. Conversely, the molar potency of (+)-apomorphine, a dopamine receptor antagonist, was markedly affected by incubation temperature, indicating enthalpy-driven binding. Another antagonist, YM-09151-2, was affected by the inclusion of sodium chloride in the assay system: in the absence of sodium chloride, the drug was relatively weak and displayed enthalpy-driven binding; in the presence of sodium chloride, its molar potency was increased and its binding manner turned into entropy-driven.
Mol Pharmacol 1988 Feb
PMID:Binding of [125I]-N-(p-aminophenethyl)spiroperidol to the D-2 dopamine receptor in the neurointermediate lobe of the rat pituitary gland: a thermodynamic study. 296 8

The purpose of these studies was to evaluate structural and functional changes in a model of hypertension-induced cardiac hypertrophy in which vasodilator therapy prevented the increase in blood pressure. Uninephrectomized weanling (125 g) Sprague-Dawley rats received a Silastic implant containing deoxycorticosterone acetate (DOCA, 150 mg/kg) subcutaneously and were given drinking water containing sodium chloride and potassium chloride. Vasodilator antihypertensive treatment (hydralazine; HYD) was started immediately after DOCA implantation. The rise in blood pressure was prevented in DOCA + HYD (124 +/- 5.4 mm Hg, +/- S.E.M.) compared to DOCA (213 +/- 7.5 mm Hg), and blood pressure was not different from control (CON; 118 +/- 5.5 mm Hg). Hydralazine lowered blood pressure in CON + HYD (102 + 3.9 mm Hg) but this decrease was not significant (P greater than 0.05). Hydralazine treatment prevented hypertension in DOCA + HYD but did not prevent development of cardiac hypertrophy (heart weight/body weight of DOCA + HYD 3.99 +/- 0.1 vs. DOCA 4.15 +/- 0.1; CON, 3.23 +/- 0.2 and CON + HYD 3.27 +/- 0.1). Coronary flow reserve measured by adenosine vasodilatation in a modified Langendorff isolated perfused rat heart model, was decreased in hearts from DOCA rats (41% increase in flow above baseline) compared to controls (CON, 132%; CON + HYD 139%), and was significantly improved in DOCA + HYD (98%). Morphometric evaluation of perfusion-fixed coronary arteries demonstrated a significant increase in the slope of the regression line comparing the square root of medial area vs. outer diameter in DOCA (0.619) compared to CON (0.501) and CON + HYD (0.491). Blood vessels from DOCA + HYD were not different from control (0.503). These studies suggest that significant alterations in coronary vascular structure and function occur in hypertension-induced cardiac hypertrophy. The coronary vasculature is responsive to blood pressure, independent of cardiac hypertrophy, although coronary deficits do remain after antihypertensive therapy.
J Mol Cell Cardiol 1988 Oct
PMID:Coronary vascular function and morphology in hydralazine treated DOCA salt rats. 297 41

There is conflicting evidence concerning the state of the actin protofilaments in the membrane cytoskeleton of the human red cell. To resolve this uncertainty, we have analysed their characteristics with respect to nucleation of G-actin polymerization. The effects of cytochalasin E on the rate of elongation of the protofilaments have been measured in a medium containing 0.1 M-sodium chloride and 5 mM-magnesium chloride, using pyrene-labelled G-actin. At an initial monomer concentration far above the critical concentration for the negative ("pointed") end of F-actin, high concentrations of cytochalasin reduce the elongation rate of free F-actin by about 70%. The residual rate is presumed to correspond to the elongation rate at the negative ends. By contrast, the elongation rate on red cell ghosts or cytoskeletons falls to zero, allowing for the background of self-nucleated polymerization of the G-actin. The critical concentration of the actin in the red cell membrane has been measured after elongation of the filaments by added pyrenyl-G-actin in the same solvent. It was found to be 0.07 microM, compared with 0.11 microM under the same conditions for actin alone. This is consistent with prediction for the case of blocked negative ends on the red cell actin. The rate of elongation of actin filaments, free and in the red cell membrane cytoskeleton, has been measured as a function of the concentration of an added actin-capping protein, plasma gelsolin, with a high affinity for the positive ends. The elongation rate falls linearly with increasing gelsolin concentration until it approaches a minimum when the gelsolin has bound to all positive filament ends. The elongation rate at this point corresponds to the activity of the negative ends, and its ratio to the unperturbed polymerization rate (in the absence of capping proteins) is indistinguishable from zero in the case of ghosts, but about 1 : 4 in the case of F-actin. When ATP is replaced in the system by ADP, so that the critical concentrations at the two filament ends are equalized, the difference is equally well-marked: for F-actin, the rate at the equivalence point is about 40% of that in the absence of capping protein, whereas for ghosts the nucleated polymerization rate at the equivalence point is again zero, indicating that under these conditions the negative ends contribute little or not at all to the rate of elongation.(ABSTRACT TRUNCATED AT 400 WORDS)
J Mol Biol 1986 Oct 05
PMID:Study of actin filament ends in the human red cell membrane. 302 84

Interaction of amiloride with adrenergic receptors was studied using radioligand binding techniques. Amiloride competed for [3H]prazosin binding to alpha 1-adrenergic receptors on rat renal cortical membranes and BC3H-1 muscle cell membranes. Non-linear regression analysis of radioligand binding isotherms showed that amiloride increased Kd without a change in Bmax, suggesting the drug binds competitively in a mutually exclusive manner with the radioligand at the receptor-binding site. Similarly, amiloride competitively blocked [125I]iodocyanopindolol binding to beta-adrenergic receptors on both tissues. The addition of guanylyl 5'-imidodiphosphate or sodium chloride did not alter the interaction of amiloride with alpha 1- or beta-adrenergic receptors. The interaction of amiloride with alpha 2-adrenergic receptors was more complex and revealed an allosteric site. In both rat renal cortical membranes and intact human platelets, amiloride increased the Kd for [3H]rauwolscine binding, as well as decreasing the apparent Bmax. In binding experiments where amiloride competed for [3H]rauwolscine-binding sites, pseudo-Hill slopes of less than 1.0 were obtained for both platelet and renal alpha 2 receptors. In addition, amiloride increased the rate of [3H]rauwolscine dissociation from renal alpha 2 receptors. In the presence of 100-120 mM sodium chloride, the Ki for amiloride competition was decreased an average of 54% in renal membranes; in contrast, sodium increased the Kd of the agonist epinephrine. Taken together, these data support the hypothesis that alpha 2-adrenergic receptors, but not alpha 1- or beta-adrenergic receptors, have an allosteric site to which amiloride binds and which we propose to be a cation-binding site.
Mol Pharmacol 1987 Jul
PMID:Interactions of amiloride with alpha- and beta-adrenergic receptors: amiloride reveals an allosteric site on alpha 2-adrenergic receptors. 303 3

DNA interaction with an alkylating antitumor drug N,N',N"-triethylenethiophosphoramide (thiotepa) in water-salt solutions at 37 degrees C has been studied by UV-spectroscopy, heat denaturation and electron microscopy methods. Changes of the DNA melting curve parameters provide information on the kinetics of alkylation. The dependence of the alkylation rate on DNA and thiotepa concentrations shows that the alkylation reaction is biomolecular. The increase of sodium chloride concentration from 10(-3) to 10(-1) M is accompanied by a drastic decrease of the alkylation rate. Thiotepa binding results in destabilization of the DNA secondary structure and formation of cross-links. An increased amount of bounded thiotepa results in DNA denaturation; prolonged alkylation causes breaks in the sugar-phosphate backbone. The results of the work are discussed in connection with the literature data on DNA interaction with thiotepa in vivo.
Mol Biol (Mosk)
PMID:[DNA interaction with the antitumor agent thiophosphamide]. 308 47

Transport of the glutathione S-conjugate, S-(1,2-dichlorovinyl)glutathione (DCVG), was studied in renal basal-lateral membrane vesicles and isolated rat kidney cells. The time course of S-(1,2-dichlorovinyl)glutathione uptake in membrane vesicles exhibited an overshoot in the presence of sodium, indicating transport against a concentration gradient. The initial rate of uptake with membrane potential clamped at 0 mV was stimulated 2.5-fold by an inwardly directed gradient of 100 mM sodium chloride. Hyperpolarization of the membrane potential to -60 mV in the presence of sodium stimulated uptake another 2.7-fold, indicating that cotransport of sodium and S-(1,2-dichlorovinyl)glutathione is electrogenic. Sodium-dependent DCVG uptake was inhibited by glutathione, glutathione disulfide, and gamma-glutamylglutamate, but not by the corresponding cysteine S-conjugate, S-(1,2-dichlorovinyl)cysteine, indicating that the transport system is specific for the gamma-glutamyl moiety. Probenecid was also a potent inhibitor of sodium-dependent uptake. S-(1,2-dichlorovinyl)glutathione inhibited sodium-dependent uptake of glutathione in a concentration-dependent manner. Thus, these results show that uptake of DCVG and glutathione is mediated by the same sodium-coupled system. Uptake of S-(1,2-dichlorovinyl)glutathione was also demonstrated in isolated kidney cells; in the presence of sodium, cells accumulated approximately 4-fold more DCVG than in the absence of sodium. This basal-lateral membrane transport system can enable efficient delivery of circulating S-(1,2-dichlorovinyl)glutathione to kidney cells and may, therefore, contribute to its potent and selective nephrotoxicity. In addition, it suggests that renal clearance of glutathione conjugates may include transport from the blood through epithelial cells into the lumen as well as direct filtration through the glomerulus.
Mol Pharmacol 1985 Sep
PMID:Uptake of the glutathione conjugate S-(1,2-dichlorovinyl)glutathione by renal basal-lateral membrane vesicles and isolated kidney cells. 383 97

In order to label D2 dopamine receptors selectively and covalently by means of a photosensitive compound, azidoclebopride was synthesized directly from clebopride. The dissociation constant (KD) of clebopride for the D2 dopamine receptor (canine brain striatum) was 1.5 nM, while that for azidoclebopride was 21 nM. The affinities of both clebopride and azidoclebopride were markedly reduced in the absence of sodium chloride. In the presence of ultraviolet light, azidoclebopride inactivated D2 dopamine receptors irreversibly, as indicated by the inability of the receptors to bind [3H]spiperone. Maximal photoinactivation of about 60% of the D2 dopamine receptors occurred at 1 microM azidoclebopride; 30% of the receptors were inactivated at 80 nM azidoclebopride (pseudo-IC50). Dopamine agonists selectively protected the D2 receptors from being inactivated by azidoclebopride, the order of potency being (-)-N-n-propylnorapomorphine greater than apomorphine greater than (+/-)-6,7-dihydroxy-2-aminotetralin greater than (+)-N-n-propylnorapomorphine greater than dopamine greater than noradrenaline greater than serotonin. Similarly, dopaminergic antagonists prevented the photoinactivation of D2 receptors by azidoclebopride with the following order of potency: spiperone greater than (+)-butaclamol greater than haloperidol greater than clebopride greater than (-)-sulpiride greater than (-)-butaclamol. The degree of D2 dopamine receptor photoinduced inactivation by azidoclebopride was not significantly affected by scavengers such as p-aminobenzoic acid and dithiothreitol. Furthermore, irradiation of striatal membranes with a concentration of azidoclebopride sufficient to inactivate dopamine D2 receptors by 60% did not significantly reduce dopamine D1, serotonin (S2), benzodiazepine, alpha 1- or beta-noradrenergic receptors. This study describes the use of a novel and selective photoaffinity ligand for brain dopamine D2 receptors. The molecule, in radiolabeled form, may aid in the molecular characterization of these receptors.
Mol Pharmacol 1985 Feb
PMID:A photoaffinity ligand for dopamine D2 receptors: azidoclebopride. 396 68

Reversible binding of warfarin to defatted serum albumin was studied by equilibrium dialysis at pH 7.4, in a 66 mM sodium phosphate buffer at 37 degrees. The binding isotherm could be described by two stoichiometric binding constants, K1 in the range 141,000 to 192,000 M-1 and K2 at 39,000 to 57,000 M-1. At least two additional molecules could be bound but gave indeterminate binding constants. The product K3 X K4 was about 4.7 X 10(7) M-2. Different site models were possible, either one high affinity and several low affinity sites, or two high affinity sites, cooperative, independent, or anticooperative, together with two low affinity sites. Binding affinity for the first warfarin molecule did not vary with pH in the interval from 6 to 9. The affinity decreased with increasing concentrations of sodium sulfate, sodium chloride, and calcium chloride, depending upon ionic strength. Specific effects of chloride and calcium ions were not observed. Light absorption spectra indicated that the warfarin anion was bound to albumin. All observations were consistent with a binding process involving albumin and the warfarin anion, without participation of hydrogen ions and not influenced by the N-B conformational transition of albumin.
Mol Pharmacol 1985 Feb
PMID:Interaction of warfarin with human serum albumin. A stoichiometric description. 396 70


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