Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of several N-sulfonyl-polyamines, including N1-dansyl-spermine (N1-DnsSpm) and N1-(n-octanesulfonyl)-spermine (N1-OsSpm), were studied at recombinant N-methyl-D-aspartate (NMDA) receptors expressed in Xenopus laevis oocytes. N1-DnsSpm and N1-OsSpm inhibited NMDA receptors and were approximately 1000-fold more potent than spermine in oocytes voltage-clamped at -70 mV. Block by N1-DnsSpm and N1-OsSpm was strongly voltage dependent, being more pronounced at hyperpolarized membrane potentials. With the Woodhull model of voltage-dependent channel block, the values of Kd(0) were 779 microM, 882 microM, and 7.4 mM and those of z delta were 2.58, 2.57, and 1.07 for N1-DnsSpm, N1-OsSpm, and spermine, respectively. This suggests that an increase in the voltage dependence of block together with an increase in affinity contributes to the increased potencies of N1-DnsSpm and N1-OsSpm compared with spermine. Sensitivity to N1-DnsSpm was reduced by mutation NR1(N616Q) and was increased by mutations NR1(N616G) and NR2A(N615G). The NR1(N616G) and NR2A(N615G) mutations decreased the Kd(0) value of N1-DnsSpm without affecting z delta, whereas the NR1(N616Q) mutation reduced z delta. These mutations may alter the accessibility of part of the polyamine binding site within the channel pore or directly alter the properties of that site. Block by N1-DnsSpm (0.3 microM) was almost complete at -100 mV, and there was no relief of block at extreme negative membrane potentials (-100 to -200 mV) at wild-type NR1/NR2A channels. In contrast, block by N1-DnsSpm was partially relieved at extreme negative potentials at receptors containing NR1(N616G) or NR2A(N615G), suggesting that N1-DnsSpm can permeate these mutant channels but not wild-type NR1/NR2A channels. This is hypothesized to be due to an increase in the pore size of channels containing NR1(N616G) or NR2A(N615G), which allows passage of the bulky head group of N1-DnsSpm. In contrast to N1-DnsSpm, N1-OsSpm could easily permeate wild-type NR1/NR2A channels, presumably because the head group of N1-OsSpm can pass through the narrowest part of the channel pore. N-Sulfonyl-polyamines such as N1-DnsSpm and N1-OsSpm represent a new class of polyamine antagonists with which to study glutamate receptor ion channels.
Mol Pharmacol 1997 May
PMID:N1-dansyl-spermine and N1-(n-octanesulfonyl)-spermine, novel glutamate receptor antagonists: block and permeation of N-methyl-D-aspartate receptors. 914 25

The chi(-1) subunit is a recently identified member of a new class of the ionotropic glutamate receptor family that attenuates NMDA receptor current. We have generated a polyclonal C-terminal antibody to the chi(-1) subunit which recognizes a 135-kDa protein in membranes prepared from chi(-1) transfected HEK-293 cells and in rat brain. In the post-natal day 7 (P7) rat brain, Western blot analysis revealed a 135-kDa band in the thalamus and cortex but not the striatum, cerebellum or peripheral tissues. De-glycosylation of the chi(-1) subunit in both transfected cell lines and in the brain reduced the 135-kDa band to 110 kDa, near the predicted molecular weight of the chi(-1) subunit. These studies demonstrate the chi(-1) subunit is expressed as a glycosylated protein subunit in a distribution that parallels that observed for chi(-1) mRNA by in situ hybridization.
Brain Res Mol Brain Res 1997 Jun
PMID:An anti-chi-1 antibody recognizes a heavily glycosylated protein in rat brain. 919 Oct 81

We have detected immunoreactivities of AMPA receptor subunits GluR1-4 in post-synaptic density (PSD) fraction and tested whether they can be phosphorylated by endogenous kinases. Incubation of PSD with Ca2+ and calmodulin increased phosphorylation of GluR1 and GluR2/3. The phosphorylation of GluR1 was largely blocked by a Ca2+/calmodulin-dependent protein kinase type II inhibitor. Thus Ca2+/calmodulin-dependent phosphorylation of glutamate receptor may be a mechanism underlying enhanced post-synaptic receptor responsiveness in LTP.
Brain Res Mol Brain Res 1997 Jun
PMID:Calcium- and calmodulin-dependent phosphorylation of AMPA type glutamate receptor subunits by endogenous protein kinases in the post-synaptic density. 919 Nov 13

Arginine-481 is located in the putative agonist-binding region preceding the putative transmembrane segment M1 of the alpha1-subunit of the AMPA-selective glutamate receptor (GluR) channel. This amino acid is completely conserved among GluR proteins. A site-directed mutagenesis study using a baculovirus expression system showed that substitution of glutamate, glutamine and lysine for arginine-481 of the recombinant alpha1-subunit protein abolishes binding to [3H]AMPA completely. The present study provides the first direct experimental evidence that the conserved charged arginine-481 residue is essential, directly or indirectly, for the acquisition of ligand-binding activity by the receptor protein.
Brain Res Mol Brain Res 1997 Jul
PMID:Arginine-481 mutation abolishes ligand-binding of the AMPA-selective glutamate receptor channel alpha1-subunit. 922 33

L-Glutamic acid is a major excitatory neurotransmitter in the mammalian central nervous system. The termination of the glutamatergic transmission and the clearance of the excessive, neurotoxic concentrations of glutamate is ensured by a high affinity glutamate uptake system. Four homologous types of Na/K-dependent high affinity glutamate transporters, glutamate/aspartate transporter, glutamate transporter 1, excitatory amino acid carrier 1, and excitatory amino acid transporter 4, have recently been cloned and were assigned to a separate gene family, together with two neutral amino acid carriers, alanine/serine/cysteine transporter 1/serine/alanine/threonine transporter and adipocyte amino acid transporter. The genomic organization of these transporters is still under investigation. Very little is known about the nature of the factors and molecular mechanisms that regulate developmental, regional, and cell type-specific expression of the glutamate transporters and their aberrant functioning in neurodegenerative diseases (e.g., amyotrophic lateral sclerosis and Alzheimer's disease). Some experimental conditions (e.g., ischemia, corticostriatal lesions, hyperosmolarity, culturing conditions) and several naturally occurring and synthetic compounds (e.g., glutamate receptor agonists, dopamine, alpha1- and beta-adrenergic agonists, cAMP, phorbol esters, arachidonic acid, nitric oxide, oxygen free radicals, amyloid beta-peptide, tumor necrosis factor-alpha, glucocorticosteroids, unidentified neuronal factors) affect the molecular expression and activity of glutamate transporters. Further elucidation of the molecular events that link epigenetic signals with transcriptional and post-transcriptional mechanisms (e.g., alternative splicing, translation and post-translational modifications) is crucial for the development of selective pharmacological tools and strategies interfering with the expression of the individual glutamate transporters.
Mol Pharmacol 1997 Jul
PMID:High affinity glutamate transporters: regulation of expression and activity. 922 6

Polyamines and polyamine conjugates display a diverse range of important biological functions, ranging from antibiotics to immunosuppressants and glutamate receptor antagonists. For these reasons, polyamines provide an excellent template/scaffold for combinatorial chemistry. In this paper we present methods for the solid-phase immobilisation of polyamines for use in synthetic and combinatorial chemistry and describe how they have been employed in the preparation of a number of important polyamine conjugates and polyamine libraries. Thus, we have designed, synthesised and utilised a number of polyamine linkers for both solution and resin screening combinatorial application.
Mol Divers 1997
PMID:Synthetic methods for polyamine linkers and their application to combinatorial chemistry. 923 47

The levels of nerve growth factor (NGF) mRNA can be regulated in vitro and in vivo in the hippocampal formation by events associated with pharmacological activation of glutamate receptors. In the present study, the level of NGF mRNA in the hippocampal formation was examined following an intrahippocampal injection of 1 nmole fluorocitrate, which temporarily inhibits the astrocyte metabolic activity in vivo. Consistent with previous findings, fluorocitrate treatment significantly increased glutamate levels and decreased glutamine levels in the dentate gyrus as determined by in vivo microdialysis. The increased ratio of glutamate to glutamine was followed by a significant increase in NGF mRNA expression selectively in dentate gyrus granule cells. The effects of increasing glutamate levels were blocked by pretreatment with 50 nmole 2-amino-5-phosphonovalerate (AP5), a competitive antagonist that acts at the N-methyl-D-aspartate (NMDA) glutamate receptor subtype. These findings suggest that NGF mRNA expression is regulated, in part, by changes in endogenous glutamate levels, partially through enhanced excitatory neurotransmission through NMDA receptors.
Mol Cells 1997 Jun 30
PMID:Endogenous glutamate levels regulate nerve growth factor mRNA expression in the rat dentate gyrus. 926 33

Glycine is a major inhibitory neurotransmitter in the spinal cord and brainstem of vertebrates. Glycine is accumulated into synaptic vesicles by a proton-coupled transport system and released to the synaptic cleft after depolarization of the presynaptic terminal. The inhibitory action of glycine is mediated by pentameric glycine receptors (GlyR) that belong to the ligand-gated ion channel superfamily. The synaptic action of glycine is terminated by two sodium- and chloride-coupled transporters, GLYT1 and GLYT2, located in the glial plasma membrane and in the presynaptic terminals, respectively. Dysfunction of inhibitory glycinergic neurotransmission is associated with several forms of inherited mammalian myoclonus. In addition, glycine could participate in excitatory neurotransmission by modulating the activity of the NMDA subtype of glutamate receptor. In this article, we discuss recent progress in our understanding of the molecular mechanisms that underlie the physiology and pathology of glycinergic neurotransmission.
Mol Neurobiol 1997 Jun
PMID:Molecular biology of glycinergic neurotransmission. 929 60

All ionotropic glutamate receptor (iGluR) subunits analyzed so far are heavily N-glycosylated at multiple sites on their amino-terminal extracellular domains. Although the exact functional significance of this glycosylation remains to be determined, it has been suggested that N-glycosylation may be a precondition for the formation of functional ion channels. In particular, it has been argued that N-glycosylation is required for the formation of functional ligand binding sites. We analyzed heterologously expressed recombinant glutamate receptors (GluRs) of all three pharmacological subclasses of glutamate receptors, N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid, and kainate receptors. By expressing the GluR subunits in tunicamycin-treated, nonglycosylating Xenopus laevis oocytes, we determined that in neither case is N-glycosylation required for ion channel function, although for NMDA receptors, functional expression in the absence of N-glycosylation is very low. Furthermore, we analyzed and compared the interaction of the desensitization-inhibiting lectin concanavalin A (ConA) with all functional GluR subunits. We show that although ConA has its most pronounced effects on kainate receptors, it potentiates currents at most other receptor subtypes as well, including certain NMDA receptor subunits, although to a much lesser extent. One notable exception is the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor GluR2, which is not affected by ConA. Furthermore, we show that ConA acts directly via binding to the carbohydrate side chains of the receptor protein.
Mol Pharmacol 1997 Nov
PMID:N-Glycosylation is not a prerequisite for glutamate receptor function but Is essential for lectin modulation. 935 77

The alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptor channels are expressed ubiquitously in brain neurons and mediate fast excitatory neurotransmission. They are composed of four subunits, GluR1, GluR2, GluR3 and/or GluR4. We constructed recombinant adenoviruses encoding rat AMPA receptor subunit cDNAs, GluR1 (AxCAGluR1) and silently mutated GluR2 (AxCAGluR2X) with modified chicken beta-actin promoter and cytomegalovirus immediate-early enhancer. Using these adenoviral vectors, we transferred the GluR1 and GluR2 genes into PC12 cells that possess no functional AMPA receptor channels. PC12 cells infected with these viruses expressed GluR1 and GluR2 RNAs. Immunoblot analysis indicated that the expressed GluR1 and GluR2 proteins were equivalent to those of the rat brain. Functional expression of the AMPA receptor channels was examined using the whole-cell patch clamp technique. In AxCAGluR1-infected cells, the current-voltage (I-V) relationship of response to kainate, a non-desensitizing agonist of AMPA receptors, exhibited a strong inward rectification, indicating the formation of functional GluR1-homomeric channels. In cells infected with both AxCAGluR1 and AxCAGluR2X, the I-V relationship of kainate responses exhibited an outward rectification, indicating the formation of heteromeric GluR1/R2 channels. Immunocytochemical analysis revealed that the AMPA receptor subunit genes were transferred in more than 95% of the infected PC12 cells.
Brain Res Mol Brain Res 1997 Oct 15
PMID:Adenovirus-mediated expression of AMPA-type glutamate receptor channels in PC12 cells. 940 22


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