UNIPROT:P50583 - FACTA Search

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Query: UNIPROT:P50583 (asymmetrical)
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ADP ribosylation factor 6 (Arf6) is a small GTPase that regulates dendritic differentiation possibly through the organization of actin cytoskeleton and membrane traffic. Here, we characterized IQ-ArfGEF/BRAG1, a guanine nucleotide exchange factor (GEF) for Arf6, in the mouse brain. In vivo Arf pull down assay demonstrated that IQ-ArfGEF/BRAG1 activated Arf6 more potently than Arf1. IQ-ArfGEF/BRAG1 mRNA was abundantly expressed in the brain with higher levels in forebrain structures and cerebellar granule cells. In hippocampal neurons, IQ-ArfGEF/BRAG1 mRNA was localized not only at neuronal cell bodies but also at dendritic processes, indicating its dendritic transport and localization. Immunoprecipitation and in vitro binding experiments revealed that IQ-ArfGEF/BRAG1 formed a protein complex with N-methyl-d-aspartate (NMDA)-type glutamate receptors through the interaction with a postsynaptic density (PSD) scaffold protein, PSD-95. Immunohistochemical analysis demonstrated that IQ-ArfGEF/BRAG1 was localized preferentially at the postsynaptic density of asymmetrical synapses on dendritic spines, but was lacking at GABAa receptor-carrying inhibitory synapses. Taken together, IQ-ArfGEF/BRAG1 forms a postsynaptic protein complex containing PSD-95 and NMDA receptors at excitatory synapses, where it may function as a GEF for Arf6.
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PMID:IQ-ArfGEF/BRAG1 is a guanine nucleotide exchange factor for Arf6 that interacts with PSD-95 at postsynaptic density of excitatory synapses. 1816 4

Subpallial structures are highly conserved across the different vertebrate species. They are instrumental in the neural processing relevant to adaptive learning, decision making, motivation and behavioural strategies. Of the striatal regions, our attention has been focussed on the medial and ventral striatum (MSt), now parcellated into subregions, and also including the nucleus accumbens (Ac). Similar to mammals, the avian Ac and MSt receive glutamatergic input from the pallium and dopaminergic input from the substantia nigra and ventral tegmental area. Coincidence between glutamatergic and dopaminergic synaptic activities in the ventral/medial striatum, including the Ac, is required for memory to be formed for a given pairing of stimulus and a hedonic quality or behavioural salience. The underlying mechanism involves the activation of NMDA and dopaminergic receptors, as well as the phosphorylation of dopamine-cAMP-regulated phosphoprotein (DARPP-32). Using quantitative electron microscopy of chick specimens double-labelled against glutamate and DARPP-32 we observed direct synaptic connections between glutamate immunoreactive axon terminals and DARPP-32 labelled dendrites in the MSt and also in the posterolateral telencephalon (nidopallium caudolaterale, a prefrontal cortex equivalent region) and the hippocampus. Glutamate immunoreactive axons synapsed with both DARPP-32 immunoreactive (DARPP-32+) and DARPP-32 negative (DARPP-32-) dendrites, forming asymmetrical junctions, in all brain regions observed. The existence of direct synaptic contacts between excitatory amino acid containing axon terminals and DARPP-32 containing dopaminoceptive neurons of the chicken MSt underlines the functional homology with mammalian striatal systems.
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PMID:The organisation of the basal ganglia in the domestic chick (Gallus domesticus): anatomical localisation of DARPP-32 in relation to glutamate. 1849 30

There is evidence that brain lateralization underlying hemispheric specialization can be observed also at biochemical level. However, hemispheric differences in nitric oxide mediator system have not yet been evaluated. The hippocampus and planum temporale are highly asymmetrical regions but the degree of their laterality is altered in demented or psychotic people. In the study, l-glutamate/l-arginine/l-citrulline concentrations, nitric oxide synthase activities/expressions and nitrites/nitrates levels were estimated in autoptic hippocampi. Right/left laterality in endothelial synthase activity and in nitrites/nitrates was observed in controls. Lateral changes were estimated in patients with Alzheimer disease (a marked increase in activities of constitutive synthases and in expression of inducible enzyme in the left side) and schizophrenia (an increase in activities of all enzymes especially in the right side). Significant shifts from positive to negative correlations were found between laterality of some components of nitric oxide pathway and of planum temporale volumetry under pathological conditions. The hippocampal nitric oxide system appears to be globally right/left lateralized, especially via actions of highly asymmetrical endothelial synthase. The results suggest a specific involvement of all synthases in the development of selected diseases and show that lateral analyses are of sufficient sensitivity to reveal subtle links. The volumetric asymmetry of the planum temporale as a marker of handedness is not probably simply linked to brain laterality at biochemical level but reflects alterations due to pathological processes.
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PMID:Lateralization of hippocampal nitric oxide mediator system in people with Alzheimer disease, multi-infarct dementia and schizophrenia. 1864 32

Cholinergic interneurons are the only known source of acetylcholine in the rat nucleus accumbens (nAcb); yet there is little anatomical data about their mode of innervation and the origin of their excitatory drive. We characterized the cholinergic and thalamic innervations of nAcb with choline acetyltransferase (ChAT) immunocytochemistry and anterograde transport of Phaseolus vulgaris-leucoagglutinin (PHA-L) from the midline/intralaminar/paraventricular thalamic nuclei. The use of a monoclonal ChAT antiserum against whole rat ChAT protein allowed for an optimal visualization of the small dendritic branches and fine varicose axons of cholinergic interneurons. PHA-L-labeled thalamic afferents were heterogeneously distributed throughout the core and shell regions of nAcb, overlapping regionally with cholinergic somata and dendrites. At the ultrastructural level, several hundred single-section profiles of PHA-L and ChAT-labeled axon terminals were analyzed for morphology, synaptic frequency, and the nature of their synaptic targets. The cholinergic profiles were small and apposed to various neuronal elements, but rarely exhibited a synaptic membrane specialization (5% in single ultrathin sections). Stereological extrapolation indicated that less than 15% of these cholinergic varicosities were synaptic. The PHA-L-labeled profiles were comparatively large and often synaptic (37% in single ultrathin sections), making asymmetrical contacts primarily with dendritic spines (>90%). Stereological extrapolation indicated that all PHA-L-labeled terminals were synaptic. In double-labeled material, some PHA-L-labeled terminals were directly apposed to ChAT-labeled somata or dendrites, but synapses were never seen between the two types of elements. These observations demonstrate that the cholinergic innervation of rat nAcb is largely asynaptic. They confirm that the afferents from midline/intralaminar/paraventricular thalamic nuclei to rat nAcb synapse mostly on dendritic spines, presumably of medium spiny neurons, and suggest that the excitatory drive of nAcb cholinergic interneurons from thalamus is indirect, either via substance P release from recurrent collaterals of medium spiny neurons and/or by extrasynaptic diffusion of glutamate.
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PMID:Cholinergic innervation and thalamic input in rat nucleus accumbens. 1877 52

Following activation of Gq protein-coupled receptors, phospholipase C yields a pair of second messengers, i.e. diacylglycerol (DAG) and inositol 1,4,5-trisphosphate. The former activates protein kinase C and the latter mobilizes Ca(2+) from intracellular store. DAG kinase (DGK) then phosphorylates DAG to produce another second messenger (phosphatidic acid). Of 10 mammalian DGK isozymes, DGKbeta is expressed in dopaminergic projection fields with the highest level in the striatum and its particular splice variant is differentially expressed in patients with bipolar disorder. To gain molecular anatomical evidence for its signaling role, we investigated the cellular expression and subcellular localization of DGKbeta in the striatum of rat brain. DGKbeta was expressed in medium spiny neurons constituting the striatonigral and striatopallidal pathways, whereas striatal interneurons were below the detection threshold. DGKbeta was distributed in somatodendritic elements of medium spiny neurons and localized in association with the smooth endoplasmic reticulum and plasma membrane or in the narrow cytoplasmic space between them. In particular, DGKbeta exhibited dense accumulation at perisynaptic sites on dendritic spines forming asymmetrical synapses. The characteristic anatomical localization was consistent with exclusive enrichment of DGKbeta in the microsomal and postsynaptic density fractions. Intriguingly, DGKbeta was very similar in immunohistochemical and immunochemical distribution to Gq-coupled receptors, such as metabotropic glutamate receptors 1 and 5, and also to other downstream molecules involving DAG metabolism, such as phospholipase C beta and DAG lipase. These findings suggest that abundant DGKbeta is provided to perisynaptic sites of medium spiny neurons so that it can effectively produce phosphatidic acid upon activation of Gq-coupled receptors and modulate the cellular state of striatal output neurons.
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PMID:Diacylglycerol kinase beta accumulates on the perisynaptic site of medium spiny neurons in the striatum. 1908 71

The ultrastructure of the retinorecipient layers of the lamprey optic tectum was analysed using tract tracing techniques combined with GABA and glutamate immunocytochemistry. Two types of neurons were identified; a population of large GABA-immunonegative cells, and a population of smaller, highly GABA-immunoreactive interneurons, some of whose dendrites contain synaptic vesicles (DCSV). Five types of axon terminals were identified and divided into two major categories. The first of these are GABA-immunonegative, highly glutamate-immunoreactive, contain round synaptic vesicles, make asymmetrical synaptic contacts, and can in turn be divided into AT1 and AT2 terminals. The AT1 terminals are those of the retinotectal projection. The origin of the nonretinal AT2 terminals could not be determined. AT1 and AT2 terminals establish synaptic contacts with DCSV, with dendrites of the retinopetal neurons (DRN), and with conventional dendritic (D) profiles. The terminals of the second category are GABA-immunoreactive and can similarly be divided into AT3 and AT4 terminals. The AT3 terminals contain pleiomorphic synaptic vesicles and make symmetrical synaptic contacts for the most part with glutamate-immunoreactive D profiles. The AT4 terminals contain rounded synaptic vesicles and make asymmetrical synaptic contacts with DRN, with DCSV, and with D profiles. A fifth, rarely observed category of terminals (AT5) contain both clear synaptic vesicles and a large number of dense-core vesicles. Synaptic triads involving AT1, AT2 or AT4 terminals are rare. Our findings are compared to these of previous studies of the fine structure and immunochemical properties of the retinorecipient layers of the optic tectum or superior colliculus of Gnathostomes.
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PMID:Synaptic circuitry in the retinorecipient layers of the optic tectum of the lamprey (Lampetra fluviatilis). A combined hodological, GABA and glutamate immunocytochemical study. 1925 25

A new class of dendron-like polypeptide/linear poly(epsilon-caprolactone) block copolymers with asymmetrical topology (i.e., dendron-like poly(gamma-benzyl-l-glutamate)/linear PCL copolymers having 2(m) PBLG branches, m = 0, 1, 2, and 3; denoted as PCL-Dm-PBLG) was for the first time synthesized via the combination of controlled ring-opening polymerization (ROP) of epsilon-caprolactone, click chemistry, and the ROP of gamma-benzyl-l-glutamate N-carboxyanhydride (BLG-NCA). The linear hydroxyl-terminated PCL (PCL-OH) was synthesized by controlled ROP of epsilon-caprolactone and then transformed into clickable azide-terminated PCL (PCL-N(3)). The PCL-N(3) precursor was further click conjugated with propargyl focal point PAMAM-typed dendrons (i.e., Dm having 2(m) primary amine groups) to generate PCL-dendrons (PCL-Dm) using CuBr/PMDETA as catalyst in dimethylformamide solution at 35 degrees C. Finally, PCL-Dm was used as macroinitiator for the ROP of BLG-NCA monomer to produce the targeted PCL-Dm-PBLG block copolymers. Their molecular structures and physical properties were characterized in detail by FT-IR, NMR, matrix assisted laser desorption ionization time-of-flight mass spectrometry, gel permeation chromatography, differential scanning calorimetry, and wide-angle X-ray diffraction. To the best of our knowledge, this is the first report that describes the synthesis of dendron-like polypeptide/linear PCL block copolymers with asymmetrical topology via the combination of ROP and click chemistry. Consequently, this provides a versatile strategy for the synthesis of biodegradable and biomimetic dendron-like polypeptide-based biohybrids.
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PMID:Versatile strategy for the synthesis of dendronlike polypeptide/linear poly(epsilon-caprolactone) block copolymers via click chemistry. 1932 56

G protein-coupled receptors are known to form homo- and heteromers at the plasma membrane, but the stoichiometry of these receptor oligomers are relatively unknown. Here, by using bimolecular fluorescence complementation, we visualized for the first time the occurrence of heterodimers of metabotropic glutamate mGlu(5) receptors (mGlu(5)R) and dopamine D(2) receptors (D(2)R) in living cells. Furthermore, the combination of bimolecular fluorescence complementation and bioluminescence resonance energy transfer techniques, as well as the sequential resonance energy transfer technique, allowed us to detect the occurrence receptor oligomers containing more than two protomers, mGlu(5)R, D(2)R and adenosine A(2A) receptor (A(2A)R). Interestingly, by using high-resolution immunoelectron microscopy we could confirm that the three receptors co-distribute within the extrasynaptic plasma membrane of the same dendritic spines of asymmetrical, putative glutamatergic, striatal synapses. Also, co-immunoprecipitation experiments in native tissue demonstrated the existence of an association of mGlu(5)R, D(2)R and A(2A)R in rat striatum homogenates. Overall, these results provide new insights into the molecular composition of G protein-coupled receptor oligomers in general and the mGlu(5)R/D(2)R/A(2A)R oligomer in particular, a receptor oligomer that might constitute an important target for the treatment of some neuropsychiatric disorders.
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PMID:Metabotropic glutamate type 5, dopamine D2 and adenosine A2a receptors form higher-order oligomers in living cells. 1934 74

A highly sensitive and selective glutamate microbiosensor based on polypyrrole (PPy), multiwalled carbon nanotubes (MWCNT) and glutamate oxidase (GluOx) deposited on the transducer platinum electrode (Pt) is described. The sensor consists of a permselective membrane of polypyrrole for the rejection of interferences, followed by a layer of multiwalled carbon nanotubes and glutamate oxidase deposited by asymmetrical alternating current electrophoretic deposition (AC-EPD). The biosensor has a high sensitivity (3.84 nA/(microMmm(2))), low response to interferences such as ascorbic acid, uric acid and acetaminophen, a fast response time (7s), low detection limit (approximately 0.3 microM), a linear range of 140 microM and a satisfactory stability. In order to improve the linear range and the stability, a thin layer of polyurethane (PU) was applied to the Pt/PPy/MWCNT/GluOx sensor. The resulting sensor with the PU outer membrane showed an increase in the linear range up to approximately 500 microM glutamate and has a better stability at the expense of a decrease in sensitivity (2.5 nA/(microMmm(2))) and an increase in the response time (15s).
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PMID:Highly sensitive and selective glutamate microbiosensor based on cast polyurethane/AC-electrophoresis deposited multiwalled carbon nanotubes and then glutamate oxidase/electrosynthesized polypyrrole/Pt electrode. 2003 83

While stressors are known to increase medial prefrontal cortex (PFC) glutamate (GLU) levels, the mechanism(s) subserving this response remain to be elucidated. We used microdialysis and local drug applications to investigate, in male Long-Evans rats, whether the PFC GLU stress response might reflect increased interhemispheric communication by callosal projection neurons. We report here that tail-pinch stress (20 min) elicited comparable increases in GLU in the left and right PFC that were sodium and calcium dependent and insensitive to local glial cystine-GLU exchanger blockade. Unilateral ibotenate-induced PFC lesions abolished the GLU stress response in the opposite hemisphere, as did contralateral mGlu(2/3) receptor activation. Local dopamine (DA) D(1) receptor blockade in the left PFC potently enhanced the right PFC GLU stress response, whereas the same treatment applied to the right PFC had a much weaker effect on the left PFC GLU response. Finally, the PFC GLU stress response was attenuated and potentiated, respectively, following alpha(1)-adrenoreceptor blockade and GABA(B) receptor activation in the opposite hemisphere. These findings indicate that the PFC GLU stress response reflects, at least in part, activation of callosal neurons located in the opposite hemisphere and that stress-induced activation of these neurons is regulated by GLU-, DA-, norepinephrine-, and GABA-sensitive mechanisms. In the case of DA, this control is asymmetrical, with a marked regulatory bias of the left PFC DA input over the right PFC GLU stress response. Together, these findings suggest that callosal neurons and their afferentation play an important role in the hemispheric specialization of PFC-mediated responses to stressors.
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PMID:Interhemispheric regulation of the medial prefrontal cortical glutamate stress response in rats. 2051 37

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