1,720,997 research outputs found
New targets for pharmacological intervention in the glutamatergic synapse
No full textExcitotoxicity is thought to be a major mechanism in many human disease states such as ischemia, trauma, epilepsy and chronic neurodegenerative disorders. Briefly, synaptic overactivity leads to the excessive release of glutamate that activates postsynaptic cell membrane receptors, which upon activation open their associated ion channel pore to produce ion influx. To date, although molecular basis of glutamate toxicity remain uncertain, there is general agreement that N-methyl-d-aspartate (NMDA) subtype of ionotropic glutamate receptors plays a key role in mediating at least some aspects of glutamate neurotoxicity. On this view, research has focused in the discovery of new compounds able to either reduce glutamate release or activation of postsynaptic NMDA receptors. Although NMDA receptor antagonists prevent excitotoxicity in cellular and animal models, these drugs have limited usefulness clinically. Side effects such as psychosis, nausea, vomiting, memory impairment, and neuronal cell death accompany complete NMDA receptor blockade, dramatizing the crucial role of the NMDA receptor in normal neuronal processes. Recently, however, well-tolerated compounds such as memantine has been shown to be able to block excitotoxic cell death in a clinically tolerated manner. Understanding the biochemical properties of the multitude of NMDA receptor subtypes offers the possibility of developing more effective and clinically useful drugs. The increasing knowledge of the structure and function of this postsynaptic NMDA complex may improve the identification of specific molecular targets whose pharmacological or genetic manipulation might lead to innovative therapies for brain disorders
An in-vivo approach of uncoupling ADAM10 from its cargo protein: a way towards amyloid production
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Calcium-calmodulin-dependent protein kinase II phosphorylation modulates PSD-95 binding to NMDA receptors
No full textAt the postsynaptic membrane of excitatory synapses, NMDA-type receptors are bound to scaffolding and signalling proteins that regulate the strength of synaptic transmission. The cytosolic tails of the NR2A and NR2B subunits of NMDA receptor bind to calcium-calmodulin-dependent protein kinase II (CaMKII) and to members of the MAGUK family such as PSD-95. In particular, although NR2A and NR2B subunits are highly homologous, the sites of their interaction with CaMKII as well as the regulation of this binding differ. We identified PSD-95 phosphorylation as a molecular mechanism responsible for the dynamic regulation of the interaction of both PSD-95 and CaMKII with the NR2A subunit. CaMKII-dependent phosphorylation of PSD-95 occurs both in vitro, in GST-PSD-95 fusion proteins phosphorylated by purified active CaMKII, and in vivo, in transfected COS-7 as well as in cultured hippocampal neurons. We identified Ser73 as major phosphorylation site within the PDZ1 domain of PSD-95, as confirmed by point mutagenesis experiments and by using a phospho-specific antibody. PSD-95 Ser73 phosphorylation causes NR2A dissociation from PSD-95, while it does not interfere with NR2B binding to PSD-95. These results identify CaMKII-dependent phosphorylation of the PDZ1 domain of PSD-95 as a mechanism regulating the signalling transduction pathway downstream NMDA receptor
ADENOSINE MODULATES THE DOPAMINERGIC FUNCTION IN THE NIGRO-STRIATAL SYSTEM BY INTERACTING WITH STRIATAL DOPAMINE DEPENDENT ADENYLATE-CYCLASE
No full textBehavioral and pharmacological evidences suggest that dopaminergic mechanisms in striatum might be counteracted by adneosine or potentiated by its pharmacological antagonists methylxanthines. To test whether adenosine modulation of the dopaminergic function could be, at least in part, due to an interaction at the level of the adenylate cyclase complex, we studied the effects of the adenosine analog R-Phenyl-isopropil-adenosine (R-PIA) on basal and dopamine-sensitive adenylate cyclase in rat striatum. R-PIA, which interacts with both adenosine A1-inhibitory and A2-stimulatory receptors, dose-dependently inhibited the stimulation induced by dopamine, and seemed to utilize the same pool of enzyme linked to dopaminergic D1 receptors. Two experimental approaches leading to supersensitivity of striatal dopaminergic receptors, (i.e., 6-hydroxy-dopamine injection in substantia nigra and reserpine administration) also induced upregulation of adenosine-dependent adenylate cyclase in striatum, and altered R-PIA modulation of dopamine-sensitive adenylate cyclase. Conversely, after subchronic treatment with neuroleptics such as haloperidol or sulpiride, upregulation of 3H-Spiroperidol binding in striatum was not associated with changes of R-PIA dependent adenylate cyclase in this area. It is concluded that adenosine might modulate post-synaptic responses to dopamine via adenosine receptors which functionally interact with dopaminergic D1 receptors in striatum
IN VIVO MODULATION OF STRIATAL PHOSPHOPROTEINS BY DOPAMINERGIC AGENTS
No full textProtein phosphorylation in the brain represents a common target for several second messenger systems. A phosphoprotein (DARPP-32) specifically regulated by cAMP and dopamine has been detected in neurons bearing dopamine D-1 receptors, where it plays a key role in eliciting cAMP-mediated intracellular responses. The endogenous phosphorylation of this cytosolic protein is markedly affected after in vivo acute treatment with the selective D-1 agonist, SKF 38393. The amount of the DARPP-32 dephospho-form measured by a back-phosphorylation assay was decreased by about 30% in agonist-treated animals. This effect was completely counteracted by the concomitant administration of the selective D-1 antagonist, SCH 23390, but not by a selective D-2 antagonist. This first demonstration of in vivo modulation of the phosphorylation state of DARPP-32 could, as a biochemical approach, represent a useful tool to gain further insight into the cascade of biochemical events elicited by specific dopaminergic drugs
Combined biomarkers for early Alzheimer disease diagnosis
No full textFew public health problems have captured the attention of the biomedical and lay communities alike as has Alzheimer Disease (AD). Several questions remain still open in disease management, as the necessity to delineate disease process from "normal ageing". In the last few years, Mild Cognitive Impairment (MCI) has received significant attention, thus it represents the major risk factor for AD. Not all people diagnosed as having MCI, however, will develop AD, hence there is a need to reliably predict progression. To this aim, different biomarkers have been proposed with the attempt to identify MCI people who already have pre-clinical AD. Neuropsychological assessment, peripheral and CSF biomarkers as well as neuroimaging findings (both structural and functional) have reported variable accuracy values, but better results have been obtained by combined biomarker approach. In this review, we summarise the most recent findings on combined biomarkers and their usefulness in clinical practice for the early and preclinical diagnosis of A
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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