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81.
In the pathogenesis of Parkinson’s disease and Huntington’s disease excitotoxicity may play an important role. The common
toxin model for Parkinson’s disease is MPTP, while for Huntington’s disease it is 3-NP. These toxins inhibit the mitochondrial
respiratory chain, resulting in an energy deficit. In the central nervous system, the amino acids act as neurotransmitters
and neuromodulators. The energy deficit caused by these neurotoxins may alter the concentrations of amino acids. Thus, it
can be claimed that the aminoacidergic neurotransmission can be changed by neurotoxins. To test this hypothesis we studied
the amino acid concentrations in different brain regions following MPTP or 3-NP administration. The two toxins were found
to produce similar changes. We detected marked decreases in most of the amino acid concentrations in the striatum and in the
cortex, while the levels in the cerebellum increased significantly. The decreased amino acid levels can be explained by the
reduced levels of ATP produced by these neurotoxins. In the cerebellum, where there is no detectable ATP loss, the elevated
amino acid levels may reflect a compensation of the altered neurotransmission. 相似文献
82.
Natalia Dominguez Jan R. T. van Weering Ricardo Borges Ruud F. G. Toonen Matthijs Verhage 《Journal of neurochemistry》2018,144(3):241-254
83.
N. E. Naftchi H. Maker E. Lapin J. Sleis A. Lajtha S. Leeman 《Neurochemical research》1988,13(4):305-309
Ten minutes after a single injection of 0.8 mg/kg nicotine SC (free base) the level of substance P-like immunoreactivity (SPLI) was reduced by 61–73% in rat caudate-putamen, nucleus accumbens, and olfactory tubercle, with smaller and not significant reductions in the frontal cortex, substantia nigra, and ventral tegmental area. The nicotinic receptor antagonist mecamylamine (1.0 mg/kg IP) prevented the reductions in SPLI. The rapidity and the degree of the changes in SPLI after nicotine exceed those previously reported for other agents and implicate substance P neurotransmission as a major component of nicotinic action.Preliminary data were presented at the 17th annual meeting of the American Society for Neurochemistry, Montreal, 1986 (1). 相似文献
84.
85.
Laura Caldinelli Gianluca Molla Silvia Sacchi Mirella S. Pilone Loredano Pollegioni 《Protein science : a publication of the Protein Society》2009,18(4):801-810
In the brain, the human flavoprotein D ‐amino acid oxidase (hDAAO) is involved in the degradation of the gliotransmitter D ‐serine, an important modulator of NMDA‐receptor‐mediated neurotransmission; an increase in hDAAO activity (that yields a decrease in D ‐serine concentration) was recently proposed to be among the molecular mechanisms leading to the onset of schizophrenia susceptibility. This human flavoenzyme is a stable homodimer (even in the apoprotein form) that distinguishes from known D ‐amino acid oxidases because it shows the weakest interaction with the flavin cofactor in the free form. Instead, cofactor binding is significantly tighter in the presence of an active site ligand. In order to understand how hDAAO activity is modulated, we investigated the FAD binding process to the apoprotein moiety and compared the folding and stability properties of the holoenzyme and the apoprotein forms. The apoprotein of hDAAO can be distinguished from the holoenzyme form by the more “open” tertiary structure, higher protein fluorescence, larger exposure of hydrophobic surfaces, and higher sensitivity to proteolysis. Interestingly, the FAD binding only slightly increases the stability of hDAAO to denaturation by urea or temperature. Taken together, these results indicate that the weak cofactor binding is not related to protein (de)stabilization or oligomerization (as instead observed for the homologous enzyme from yeast) but rather should represent a means of modulating the activity of hDAAO. We propose that the absence in vivo of an active site ligand/substrate weakens the cofactor binding, yielding the inactive apoprotein form and thus avoiding excessive D ‐serine degradation. 相似文献
86.
Solute carrier (SLC) membrane transporters remain a largely unexploited target class, despite their central roles in cell identity and metabolism. This gap is reflected in the lack of high-quality chemical ligands or probes and in the small number of compounds that have progressed toward clinical development. In this review, we discuss recent advancements in SLC ligand discovery as well as new candidates that have been added to the investigational toolkit, with a particular focus on first-in-class ligands and the cognate discovery strategies. The availability of new probes expands the opportunity to elucidate the functions of SLCs and their relevance in physiology and explores any future potential of SLC druggability. 相似文献
87.
《Cell reports》2020,30(2):409-420.e6
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88.
The effect of angiotensin II on catecholamine release from bovine adrenal medulla has been investigated. In retrogradely perfused, isolated bovine adrenal glands, angiotensin II increased basal efflux of catecholamines, but the presence of angiotensin II did not increase the release of catecholamines evoked either by bolus injections of the secretagogue carbachol or by depolarization with a perfusing solution containing a raised concentration of K+. In chromaffin cells maintained in primary tissue culture, angiotensin II increased 3H release from cells preloaded with [3H]-noradrenaline but did not enhance the release evoked by carbachol or by depolarization with K+. The increase in 3H release evoked by angiotensin II from chromaffin cells in tissue culture was inhibited by its analogue antagonist Sar1,Ala8-angiotensin II (saralasin) and was entirely dependent on the presence of Ca2+ in the experimental medium. These findings suggest that, in the chromaffin cells of the bovine adrenal medulla, angiotensin II acts on specific receptors to cause a calcium-dependent catecholamine release but triggers no additional response that acts synergistically with depolarizing or nicotinic stimuli to augment catecholamine release. 相似文献
89.
Sanae Iwana Tomoya Kawazoe Hwan KI. Park Koichiro Tsuchiya Koji Ono Kazuko Yorita 《Journal of enzyme inhibition and medicinal chemistry》2013,28(6):901-911
D-Amino acid oxidase (DAO), a potential risk factor for schizophrenia, has been proposed to be involved in the decreased glutamatergic neurotransmission in schizophrenia. Here we show the inhibitory effect of an antipsychotic drug, chlorpromazine, on human DAO, which is consistent with previous reports using porcine DAO, although human DAO was inhibited to a lesser degree (Ki = 0.7 mM) than porcine DAO. Since chlorpromazine is known to induce phototoxic or photoallergic reactions and also to be transformed into various metabolites, we examined the effects of white light-irradiated chlorpromazine on the enzymatic activity. Analytical methods including high-resolution mass spectrometry revealed that irradiation triggered the oligomerization of chlorpromazine molecules. The oligomerized chlorpromazine showed a mixed type inhibition with inhibition constants of low micromolar range, indicative of enhanced inhibition. Taken together, these results suggest that oligomerized chlorpromazine could act as an active substance that might contribute to the therapeutic effects of this drug. 相似文献
90.
Vesicle uncoating regulated by SH3-SH3 domain-mediated complex formation between endophilin and intersectin at synapses
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Ira Milosevic Maria Jäpel Marielle Eichhorn‐Grünig Olga Vorontsova Jelena Bacetic Tanja Maritzen Oleg Shupliakov Christian Freund Volker Haucke 《EMBO reports》2015,16(2):232-239
Neurotransmission involves the exo-endocytic cycling of synaptic vesicle (SV) membranes. Endocytic membrane retrieval and clathrin-mediated SV reformation require curvature-sensing and membrane-bending BAR domain proteins such as endophilin A. While their ability to sense and stabilize curved membranes facilitates membrane recruitment of BAR domain proteins, the precise mechanisms by which they are targeted to specific sites of SV recycling has remained unclear. Here, we demonstrate that the multi-domain scaffold intersectin 1 directly associates with endophilin A to facilitate vesicle uncoating at synapses. Knockout mice deficient in intersectin 1 accumulate clathrin-coated vesicles at synapses, a phenotype akin to loss of endophilin function. Intersectin 1/endophilin A1 complex formation is mediated by direct binding of the SH3B domain of intersectin to a non-canonical site on the SH3 domain of endophilin A1. Consistent with this, intersectin-binding defective mutant endophilin A1 fails to rescue clathrin accumulation at neuronal synapses derived from endophilin A1-3 triple knockout (TKO) mice. Our data support a model in which intersectin aids endophilin A recruitment to sites of clathrin-mediated SV recycling, thereby facilitating vesicle uncoating. 相似文献