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Author |
Pennisi, E. |
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Title |
Schizophrenia clues from monkeys |
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Year |
1997 |
Publication |
Science (New York, N.Y.) |
Abbreviated Journal |
Science |
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Volume  |
277 |
Issue |
5328 |
Pages |
900 |
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Keywords |
Animals; Antipsychotic Agents/pharmacology; Behavior, Animal/drug effects; *Cercopithecus aethiops; Clozapine/pharmacology; Cognition/drug effects; *Disease Models, Animal; Dopamine/*metabolism; Excitatory Amino Acid Antagonists/pharmacology; Memory/drug effects; Phencyclidine/*pharmacology; Prefrontal Cortex/*metabolism; Schizophrenia/chemically induced/drug therapy/*metabolism; Schizophrenic Psychology |
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English |
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0036-8075 |
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Notes |
PMID:9281070 |
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Call Number |
Equine Behaviour @ team @ |
Serial |
2844 |
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Author |
Pierce, M.M.; Nall, B.T. |
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Title |
Coupled kinetic traps in cytochrome c folding: His-heme misligation and proline isomerization |
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Journal Article |
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Year |
2000 |
Publication |
Journal of Molecular Biology |
Abbreviated Journal |
J Mol Biol |
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Volume |
298 |
Issue |
5 |
Pages |
955-969 |
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Keywords |
Amino Acid Sequence; Amino Acid Substitution/genetics; Binding Sites; Cytochrome c Group/*chemistry/genetics/*metabolism; *Cytochromes c; Enzyme Stability/drug effects; Fluorescence; Guanidine/pharmacology; Heme/*metabolism; Histidine/genetics/*metabolism; Hydrogen-Ion Concentration; Isomerism; Kinetics; Models, Molecular; Molecular Sequence Data; Mutation/genetics; Proline/*chemistry/metabolism; Protein Conformation/drug effects; Protein Denaturation/drug effects; *Protein Folding; Protein Renaturation; Saccharomyces cerevisiae/enzymology/genetics; Sequence Alignment; Thermodynamics |
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Abstract |
The effect of His-heme misligation on folding has been investigated for a triple mutant of yeast iso-2 cytochrome c (N26H,H33N,H39K iso-2). The variant contains a single misligating His residue at position 26, a location at which His residues are found in several cytochrome c homologues, including horse, tuna, and yeast iso-1. The amplitude for fast phase folding exhibits a strong initial pH dependence. For GdnHCl unfolded protein at an initial pH<5, the observed refolding at final pH 6 is dominated by a fast phase (tau(2f)=20 ms, alpha(2f)=90 %) that represents folding in the absence of misligation. For unfolded protein at initial pH 6, folding at final pH 6 occurs in a fast phase of reduced amplitude (alpha(2f) approximately 20 %) but the same rate (tau(2f)=20 ms), and in two slower phases (tau(m)=6-8 seconds, alpha(m) approximately 45 %; and tau(1b)=16-20 seconds, alpha(1b) approximately 35 %). Double jump experiments show that the initial pH dependence of the folding amplitudes results from a slow pH-dependent equilibrium between fast and slow folding species present in the unfolded protein. The slow equilibrium arises from coupling of the His protonation equilibrium to His-heme misligation and proline isomerization. Specifically, Pro25 is predominantly in trans in the unligated low-pH unfolded protein, but is constrained in a non-native cis isomerization state by His26-heme misligation near neutral pH. Refolding from the misligated unfolded form proceeds slowly due to the large energetic barrier required for proline isomerization and displacement of the misligated His26-heme ligand. |
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Center for Biomolecular Structure, Department of Biochemistry, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA |
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0022-2836 |
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PMID:10801361 |
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Call Number |
refbase @ user @ |
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3853 |
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Author |
Crosby, M.B.; Svenson, J.L.; Zhang, J.; Nicol, C.J.; Gonzalez, F.J.; Gilkeson, G.S. |
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Title |
Peroxisome proliferation-activated receptor (PPAR)gamma is not necessary for synthetic PPARgamma agonist inhibition of inducible nitric-oxide synthase and nitric oxide |
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Journal Article |
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Year |
2005 |
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The Journal of pharmacology and experimental therapeutics |
Abbreviated Journal |
J Pharmacol Exp Ther |
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312 |
Issue |
1 |
Pages |
69-76 |
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Keywords |
Animals; Cell Line; Gene Expression/drug effects; Macrophages/drug effects/metabolism; Mice; Mice, Inbred C57BL; Nitric Oxide/*metabolism; Nitric Oxide Synthase/*metabolism; Nitric Oxide Synthase Type II; PPAR delta/metabolism; PPAR gamma/*agonists/deficiency; Thiazolidinediones/pharmacology |
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Abstract |
Peroxisome proliferation-activated receptor (PPAR)gamma agonists inhibit inducible nitric-oxide synthase (iNOS), tumor necrosis factor-alpha, and interleukin-6. Because of these effects, synthetic PPARgamma agonists, including thiazolidinediones, are being studied for their impact on inflammatory disease. The anti-inflammatory concentrations of synthetic PPARgamma agonists range from 10 to 50 microM, whereas their binding affinity for PPARgamma is in the nanomolar range. The specificity of synthetic PPARgamma agonists for PPARgamma at the concentrations necessary for anti-inflammatory effects is thus in question. We report that PPARgamma is not necessary for the inhibition of iNOS by synthetic PPARgamma agonists. RAW 264.7 macrophages possess little PPARgamma, yet lipopolysaccharide (LPS)/interferon (IFN)gamma-induced iNOS was inhibited by synthetic PPARgamma agonists at 20 microM. Endogenous PPARgamma was inhibited by the transfection of a dominant-negative PPARgamma construct into murine mesangial cells. In the transfected cells, synthetic PPARgamma agonists inhibited iNOS production at 10 microM, similar to nontransfected cells. Using cells from PPARgamma Cre/lox conditional knockout mice, baseline and LPS/IFNgamma-induced nitric oxide levels were higher in macrophages lacking PPARgamma versus controls. However, synthetic PPARgamma agonists inhibited iNOS at 10 microM in the PPARgamma-deficient cells, similar to macrophages from wild-type mice. These results indicate that PPARgamma is not necessary for inhibition of iNOS expression by synthetic PPARgamma agonists at concentrations over 10 microM. Intrinsic PPARgamma function, in the absence of synthetic agonists, however, may play a role in inflammatory modulation. |
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Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA |
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0022-3565 |
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PMID:15356214 |
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Call Number |
refbase @ user @ |
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73 |
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