Chemie und Pharmazie - Open Access LMU - Teil 02/02

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Die Universitätsbibliothek (UB) verfügt über ein umfangreiches Archiv an elektronischen Medien, das von Volltextsammlungen über Zeitungsarchive, Wörterbücher und Enzyklopädien bis hin zu ausführlichen Bibliographien und mehr als 1000 Datenbanken reicht. Auf iTunes U stellt die UB unter anderem eine Auswahl an elektronischen Publikationen der Wissenschaftlerinnen und Wissenschaftler an der LMU bereit. (Dies ist der 2. von 2 Teilen der Sammlung 'Chemie und Pharmazie - Open Access LMU'.)

  1. 10/01/1994

    Membrane Association of Lipoprotein Lipase and a cAMP-Binding Ectoprotein in Rat Adipocytes

    Chemie und Pharmazie - Open Access LMU - Teil 02/02

  2. 09/01/1994

    Stimulation of a glycosyl-phosphatidylinositol-specific phospholipase by insulin and the sulfonylurea, glimepiride, in rat adipocytes depends on increased glucose transport

    Chemie und Pharmazie - Open Access LMU - Teil 02/02

  3. 08/30/1994

    Stimulation of glucose utilization in 3T3 adipocytes and rat diaphragm in vitro by the sulphonylureas, glimepiride and glibenclamide, is correlated with modulations of the cAMP regulatory cascade

    The long-term hypoglycemic activity of sulphonylurea drugs has been attributed, in part at least, to the stimulation of glucose utilization in extra-pancreatic tissues. The novel sulphonylurea, glimepiride, gives rise to a longer lasting reduction in the blood sugar level in dogs and rabbits compared to glibenclamide (Geisen K, Drug Res38: 1120–1130, 1988). This cannot be explained adequately by elevated plasma insulin levels. This study investigated whether this prolonged hypoglycemic phase was based on the drug's abilities to stimulate glucose utilization and affect the underlying regulatory mechanisms in insulin-sensitive cells in vitro. It was found that in the absence of added insulin, glimepiride and glibenclamide (1–50 μM) stimulated lipogenesis (3T3 adipocytes) and glycogenesis (isolated rat diaphragm) not, vert, similar4.5- and 2.5-fold, respectively, and reduced the isoproterenol-stimulated lipolysis (rat adipocytes) up to 40–60%. The increased glucose utilization was correlated with a 3–4-fold higher 2-deoxyglucose transport rate and amount of GLUT4 at the plasma membrane, as well as with increased activities of key metabolic enzymes (glycerol-3-phosphate acyltransferase, glycogen synthase) within the same concentration range. Furthermore, the low Km cAMP-specific phosphodiesterase was activated 1.8-fold, whereas the cytosolic cAMP level and protein kinase A activity ratios were significantly lowered after incubation of isoproterenol-stimulated rat adipocytes with the sulphonylureas. In many of the aspects studied the novel sulphonylurea, glimepiride, exhibited slightly lower ed50-values than glibenclamide. This study demonstrates correlations existing between drug-induced stimulation of glucose transport/metabolism and cAMP degradation/protein kinase A inhibition as well as between the relative efficiencies of glimepiride and glibenclamide in inducing thse extra-pancreatic processes. Therefore, it is suggested that the stimulation of glucose utilization by sulphonylureas is mediated by a decrease of cAMP-dependent phosphorylation of GLUT4 and glucose metabolizing enzymes. The therapeutic relevance of extra-pancreatic effects of sulphonylureas, in general, and of the differences between glimepiride and glibenclamide as observed in vitro in this work, in particular, remain to be elucidated.

  4. 05/11/1994

    Differential interaction of glimepiride and glibenclamide with the β-cell sulfonylurea receptor II

    Glimepiride is a novel sulfonylurea for the treatment of type II-diabetic patients exhibiting different receptor binding kinetics to β-cell membranes with 8–9-fold higher koff rate and 2.5–3-fold higher kon rate compared to glibenclamide (see accompanying paper (Müller, G. et al. (1994) Biochim. Biophys. Acta 1191, 267–277)). To elucidate the molecular basis for this differential behaviour of glimepiride and glibenclamide, direct photoaffinity labeling studies using β-cell tumor membranes were performed. [3H]Glimepiride was specifically incorporated into a membrane polypeptide of Mr = 65000 under conditions, which led to predominant labeling of a 140 kDa protein by [3H]glibenclamide (Kramer, W. et al. (1988) FEBS Lett. 229, 355–359). Labeling of the 140 kDa protein by [3H]glibenclamide was inhibited by unlabeled glimepiride and, vice versa, glibenclamide inhibited labeling of the 65 kDa protein by [3H]glimepiride. The 65 kDa protein was also specifically photolabeled by the sulfonylurea [125I]35623, whereas an 4-azidobenzoyl derivative of glibenclamide, N3-[3H]33055, exclusively labeled a 33 kDa protein. Competitive Scatchard analysis of [3H]glimepiride-binding and [3H]glibenclamide-binding to RINm5F cell membranes using glibenclamide and glimepiride, respectively, as heterologous displacing compounds yielded non-linear plots. These findings may be explained by cooperative interactions between the 140 and 65 kDa sulfonylurea-binding proteins. The possibility that sulfonylureas of different structure have different access to the 140 and 65 kDa receptor proteins due to the β-cell membrane barrier was investigated by photoaffinity labeling of solubilized β-cell membrane proteins. Interestingly, solubilization of β-cell tumor membranes led to a shift of specific [3H]glibenclamide binding from the 140 kDa to the 65 kDa binding protein, exclusively, and to an increased labeling of the 65 kDa protein by [3H]glimepiride. The labeling of a unique protein is in agreement with similar Kd values measured for both sulfonylurcas upon solubilization of β-cell tumor and RINm5F cell membranes (see accompanying paper). Furthermore, competitive Scatchard plots of [3H]glimepiride binding to solubilized RINm5F cell membrane proteins in the presence of glibenclamide and vice versa approximate linearity suggesting loss of cooperativity between the 140 kDa glibenclamide-binding and 65 kDa glimepiride-binding proteins upon solubilization. The physiological significance of the differential interaction of glimepiride and glibenclamide with different binding proteins was also substantiated by photoaffinity labeling of RINm5F cells leading to labeling of a 140 kDa protein by [3H]glibenclamide and of a 65 kDa protein by [3H]glimepiride. In conclusion, this report presents the first evidence that different sulfonylurea drugs bind to different components of the sulfonylurea receptor complex which are characterized by different accessibility for the drugs.

  5. 03/01/1994

    4′-Amino-benzamido-taurocholic Acid Selectively Solubilizes Glycosyl-phosphatidylinositol-Anchored Membrane Proteins and Improves Lipolytic Cleavage of Their Membrane Anchors by Specific Phospholipases

    Glycosyl-phosphatidylinositol-anchored membrane proteins (GPI-proteins) are normally identified either by cleavage of the lipid anchor using (glycosyl)phosphatidylinositol-specific phospholipases C or D (GPI-PLs) or by metabolic labeling of the lipid moiety with specific building blocks. Therefore, methods for discrimination between transmembrane proteins and GPI-proteins on the basis of their physicochemical properties are desirable. Here we are presenting a selective extraction method for typical well-characterized mammalian GPI-proteins, e.g., acetylcholine esterase, alkaline phosphatase, 5′-nucleotidase, and lipoprotein lipase, using a derivative of taurocholate. The results were compared to those obtained with well-characterized transmembrane proteins, e.g., insulin receptor and hydroxymethyl glutaryl coenzyme A-reductase, glucose transporters, or aminopeptidase M and several commercially available detergents. With regard to total membrane proteins, it was possible to selectively enrich GPI-proteins up to 8- to 14-fold by using concentrations between 0.1 and 0.3% of 4′-NH2-amino-7β-benzamido-taurocholic acid (BATC). In addition, the cleavage specificity and efficiency of (G)PI-PLs were increased in the presence of identical concentrations of BATC compared to commonly used detergents, e.g., Nonidet P-40. Therefore, the present study shows that the use of BATC facilitates the identification of glycosyl-phosphatidylinositol-anchored membrane proteins.

  6. 01/01/1994

    Another member of the cyclic nucleotide-gated channel family, expressed in testis, kidney, and heart.

    Cyclic nucleotide-gated cation channels are essential in visual and olfactory signal transduction. An additional member of the cGMP-gated channel family, termed CNG-3, has been cloned from bovine kidney. Its deduced amino acid sequence is 60% and 62% identical with the CNG-channel proteins from bovine rod outer segment and bovine olfactory epithelium, respectively. Northern analysis and sequences amplified by the PCR showed that the CNG-3 mRNA is present in testis, kidney, and heart. Calcium permeated the expressed channel in the presence of extracellular Mg2+ and Na+ at membrane potentials from -100 to +45 mV. It is likely that CNG-3 protein is responsible for cGMP-induced Ca2+ entry in cells other than sensory cells.

  7. 01/01/1994

    Asymmetric electrophilic α-amidoalkylation - 10. A new camphorimide derived chiral auxiliary for the Asymmetric Synthesis with N-acyliminium ions - preparation of aracemic 2-Substituted Piperidines.

    Chemie und Pharmazie - Open Access LMU - Teil 02/02

  8. 01/01/1994

    Bimetallic Complexes in Zeolites. Reactivity of Tetracarbonyl(trimethylstannyl)cobalt in Acidic Zeolite Y

    Chemie und Pharmazie - Open Access LMU - Teil 02/02

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Die Universitätsbibliothek (UB) verfügt über ein umfangreiches Archiv an elektronischen Medien, das von Volltextsammlungen über Zeitungsarchive, Wörterbücher und Enzyklopädien bis hin zu ausführlichen Bibliographien und mehr als 1000 Datenbanken reicht. Auf iTunes U stellt die UB unter anderem eine Auswahl an elektronischen Publikationen der Wissenschaftlerinnen und Wissenschaftler an der LMU bereit. (Dies ist der 2. von 2 Teilen der Sammlung 'Chemie und Pharmazie - Open Access LMU'.)

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