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M protein, a classical bacterial virulence determinant, forms complexes with fibrinogen that induce vascular leakage 总被引:10,自引:0,他引:10
Herwald H Cramer H Mörgelin M Russell W Sollenberg U Norrby-Teglund A Flodgaard H Lindbom L Björck L 《Cell》2004,116(3):367-379
Increased vascular permeability is a key feature of inflammatory conditions. In severe infections, leakage of plasma from the vasculature induces a life-threatening hypotension. Streptococcus pyogenes, a major human bacterial pathogen, causes a toxic shock syndrome (STSS) characterized by excessive plasma leakage and multi-organ failure. Here we find that M protein, released from the streptococcal surface, forms complexes with fibrinogen, which by binding to beta2 integrins of neutrophils, activate these cells. As a result, neutrophils release heparin binding protein, an inflammatory mediator inducing vascular leakage. In mice, injection of M protein or subcutaneous infection with S. pyogenes causes severe pulmonary damage characterized by leakage of plasma and blood cells. These lesions were prevented by treatment with a beta2 integrin antagonist. In addition, M protein/fibrinogen complexes were identified in tissue biopsies from a patient with necrotizing fasciitis and STSS, further underlining the pathogenic significance of such complexes in severe streptococcal infections. 相似文献
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—Cortex slices of rat brain were incubated with glucose mixed-labelled with 3H and 14C in the 6-position and the 3H/14C ratios of lactate, acetate, citrate and acetylcholine were determined. The values obtained were: lactate 0·95, acetate 0·85, citrate 0·65 and acetylcholine 0·67 when expressed in relation to a glucose 3H/14C ratio of 1·00. When brain slices were incubated with [2-14C, 2-3H]acetate in the presence of unlabelled glucose, labelled acetylcholine was formed with a 3H/14C ratio not significantly different from the labelled substrate. The results indicate that citrate is a precursor to the acetyl moiety of acetylcholine. 相似文献
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EXPRESSION OF cfos IN THE MEDULLA OBLONGATA AFTER CAROTID BARORECEPTOR
ACTIVATION BYELEVATED INTRASINUS PRESSURE AND ADENOSINE 总被引:2,自引:1,他引:1
在14只隔离灌流颈动脉窦区的大鼠,观察了窦内压(ISP)升高和灌流腺苷(adenosine,Ado)激活压力感受器时延髓内cfos蛋白的表达。结果显示:在孤束核、最后区、延髓腹外侧头端区和中缝苍白核可见Fos蛋白样免疫阳性反应(FLI)神经元分布,且其数量随ISP升高而增多。在给定ISP下,颈动脉窦内灌流Ado,可使上述区域中FLI表达明显增多。根据以上结果,得出如下结论:cfos在压力感受器反射延髓通路中的表达,可由ISP增高和灌流Ado而增强,表明Ado对压力感受器反射有易化作用。 相似文献
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Abstract— Alkyl, phenyl, phenylalkyl and pyridiniumalkyl derivatives of choline were studied as substrates for choline acetyltransferase from bovine brain. When one methyl group of choline was replaced by an ethyl group, pK m (negative logarithm of apparent K m ) decreased, whereas V max was not significantly changed in comparison with choline. The n-propyl derivative showed an even lower pK m with unchanged V max Further elongation of the n-alkyl chain had little effect on the substrate parameters until the n-decyl derivative was reached, when a pronounced decrease of V max occurred. The highest n-alkyl homologue studied, n-pentadecyl choline, was a very poor substrate. Phenylcholine was also a poor substrate, but introduction of an alkyl chain between the phenyl group and the quaternary nitrogen resulted in compounds with better substrate properties, although they were still inferior to choline. The lowest homologue of the pyridiniumalkyl cholines studied, pyridiniumpropylcholine, had a very low pK m and a lower V m in comparison with choline. Increasing the chain length of the alkyl residue resulted in an increase of pK m , whereas V max was little affected. The results demonstrate that replacement of one methyl group of choline with a more bulky substituent resulted in impaired substrate properties, presumably due to steric effects. No evidence was obtained for hydrophobic interactions between the enzyme and non-polar substituents in the choline analogues studied. 相似文献
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DETERMINATION OF ACETYLCOENZYME A IN BRAIN 总被引:3,自引:3,他引:0
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Molecular characterization of the ligand binding site of the human galanin receptor type 2, identifying subtype selective interactions 总被引:1,自引:0,他引:1
To define the specific role of the galanin receptors when mediating the effect of galanin, effective tools for distinct activation and inhibition of the different receptor subtypes are required. Several of the physiological effects modulated by galanin are implicated to be mediated via the GalR2 subtype and have been distinguished from GalR1 effects by utilizing the Gal(2–11) peptide, recognizing only GalR2 and GalR3. In this study, we have performed a mutagenesis approach on the GalR2 subtype and present, for the first time, a molecular characterization of the interactions responsible for ligand binding and receptor activation at this receptor subtype. Our results identify four residues, His252 and His253 located in transmembrane domain 6 and Phe264 and Tyr271 in the extracellular loop 3, to be of great significance. We show evidence for the N-terminal tail of GalR2 to participate in ligand binding and that selective binding of Gal(2–11) includes interaction with the Ile256 residue, located at the very top of TM 6. In conclusion, we present a mutagenesis study on GalR2 and confer interactions responsible for ligand binding and receptor activation as well as selective recognition of the Gal(2–11) peptide at this receptor subtype. The presented observations could be of major importance for the design and development of new and improved peptide and non-peptide ligands, selectively activating the GalR2 subtype. 相似文献
7.
U. E. Sollenberg L. Lundström T. Bartfai Ü. Langel 《International journal of peptide research and therapeutics》2006,12(2):115-119
Galanin and its three receptors have been linked to a wide variety of physiological processes and are distributed in both the central and peripheral nervous systems. Further knowledge of the properties of galanin-activated signaling systems can best be obtained by the availability of peptide and non-peptide ligands that are selective for the different receptor subtypes. The current study describes binding and signaling data for the chimeric peptide, galanin-(2–13)-Glu-His-(Pro)3-(Ala-Leu)2-Ala-amide (M871). This compound binds to the galanin receptor type 2 with more than 30-fold higher affinity than to the galanin receptor type 1 and exhibits antagonist actions at galanin receptor type 2, blocking increased release of inositol phosphate produced by galanin in CHO cells. This peptide opens new possibilities for the study of galanin receptor physiology. 相似文献
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Linda Lundström Ulla Sollenberg Ariel Brewer Poli Francois Kouya Kang Zheng Xiao-Jun Xu Xia Sheng John K. Robinson Zsuzsanna Wiesenfeld-Hallin Zhi-Qing Xu Tomas Hökfelt Tamas Bartfai Ülo Langel 《International journal of peptide research and therapeutics》2005,11(1):17-27
The chimeric peptide M617, galanin(1–13)-Gln14-bradykinin(2–9)amide, is a novel galanin receptor ligand with increased subtype specificity for GalR1 and agonistic activity in cultured cells as well as in vivo. Displacement studies on cell membranes expressing hGalR1 or hGalR2 show the presence of a high affinity binding site for M617 on GalR1 (Ki=0.23±.12 nM) while lower affinity was seen towards GalR2 (Ki=5.71±1.28 nM) resulting in 25-fold specificity for GalR1. Activation of GalR1 upon stimulation with M617 is further confirmed by internalization of a GalR1-EGFP conjugate. Intracellular signaling studies show the ability of M617 to inhibit forskolin stimulated cAMP formation with 57% and to produce a 5-fold increase in inositol phosphate (IP) accumulation. Agonistic effects on signal transduction are shown on both receptors studied after treatment with M617 in the presence of galanin. In noradrenergic locus coeruleus neurons, M617 induces an outward current even in the presence of TTX plus Ca2+, high Mg2+, suggesting a postsynaptic effect. Intracerebroventricular (i.c.v.) administration of M617 dose-dependently stimulates food uptake in rats while, in contrast, M35 completely fails to affect the feeding behavior. Spinal cord flexor reflex is facilitated by intrathecal (i.t.) administration of M617 as well as galanin with no significant change upon pre-treatment with M617. M617 dose dependently antagonizes the spinal cord hyperexcitablility induced by C-fiber conditioning stimulus and does neither enhance nor antagonize the effect of galanin. These data demonstrate a novel galanin receptor ligand with subtype specificity for GalR1 and agonistic activity, both in vitro and in vivo. 相似文献
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Ulla E. Sollenberg Johan Runesson Rannar Sillard Ülo Langel 《International journal of peptide research and therapeutics》2010,16(1):17-22
The neuropeptide galanin is ascribed to a variety of biological effects, but selective compounds to examine the specific roles
of the three receptor subtypes are currently lacking. The recently introduced chimeric peptide ligands M617 and M871 target
the galanin receptors GalR1 and GalR2, respectively. These peptides have been used to examine receptor function in vitro and
in vivo, but their affinity to GalR3 has not been tested. Here, we report the binding affinity of these peptides at human
GalR3 and demonstrate that M617 binds GalR3 and stimulates this receptor in an agonistic manner, whereas M871 shows very low
affinity towards GalR3 (K
i 49.2 ± 9.4 nM and >10 μM, respectively). An l-alanine scan of M617 revealed the importance of the ligand C-terminus in GalR3 binding, which stands in contrast to the structural
requirements for binding to GalR1 and GalR2. These data provide insights into galanin receptor ligand binding that should
be considered when using these compounds in functional studies. 相似文献
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