Synthesis and Biological Activities of Aryl-Ether-, Biaryl-, and Fluorene-Aspartic Acid and Diaminopropionic Acid Analogues as Potent Inhibitors of the High-Affinity Glutamate Transporter EAAT-2.

ChemInform ◽  
2006 ◽  
Vol 37 (8) ◽  
Author(s):  
Alexander Greenfield ◽  
Cristina Grosanu ◽  
John Dunlop ◽  
Beal McIlvain ◽  
Tikva Carrick ◽  
...  
Keyword(s):  
Aspartic Acid ◽  
Biological Activities ◽  
Glutamate Transporter ◽  
Aryl Ether ◽  
High Affinity ◽  
Diaminopropionic Acid

scholarly journals A single residue, aspartic acid 95, in the delta opioid receptor specifies selective high affinity agonist binding.

1993 ◽  
Vol 268 (31) ◽  
pp. 23055-23058
Author(s):  
H Kong ◽  
K Raynor ◽  
K Yasuda ◽  
S.T. Moe ◽  
P.S. Portoghese ◽  
...  
Keyword(s):  
Aspartic Acid ◽  
Opioid Receptor ◽  
Delta Opioid Receptor ◽  
Agonist Binding ◽  
High Affinity

Conformationally restricted inhibitors of the high affinity -glutamate transporter

1993 ◽  
Vol 3 (1) ◽  
pp. 115-121 ◽  
Author(s):  
Richard J. Bridges ◽  
Frank E. Lovering ◽  
John M. Humphrey ◽  
Mark S. Stanley ◽  
Tracy N. Blakely ◽  
...  
Keyword(s):  
Glutamate Transporter ◽  
Conformationally Restricted ◽  
High Affinity

scholarly journals Constitutive and Regulated Shedding of Soluble FGF Receptors Releases Biologically Active Inhibitors of FGF-2

2021 ◽  
Vol 22 (5) ◽  
pp. 2712
Author(s):  
Anne Hanneken ◽  
Maluz Mercado ◽  
Pamela Maher
Keyword(s):  
Cell Surface ◽  
Ligand Binding ◽  
Cellular Proliferation ◽  
Biological Activities ◽  
Biological Properties ◽  
Matrix Metalloproteases ◽  
Biologically Active ◽  
Ectodomain Shedding ◽  
High Affinity

The identification of soluble fibroblast growth factor (FGF) receptors in blood and the extracellular matrix has led to the prediction that these proteins modulate the diverse biological activities of the FGF family of ligands in vivo. A recent structural characterization of the soluble FGF receptors revealed that they are primarily generated by proteolytic cleavage of the FGFR-1 ectodomain. Efforts to examine their biological properties are now focused on understanding the functional consequences of FGFR-1 ectodomain shedding and how the shedding event is regulated. We have purified an FGFR-1 ectodomain that is constitutively cleaved from the full-length FGFR-1(IIIc) receptor and released into conditioned media. This shed receptor binds FGF-2; inhibits FGF-2-induced cellular proliferation; and competes with high affinity, cell surface FGF receptors for ligand binding. FGFR-1 ectodomain shedding downregulates the number of high affinity receptors from the cell surface. The shedding mechanism is regulated by ligand binding and by activators of PKC, and the two signaling pathways appear to be independent of each other. Deletions and substitutions at the proposed cleavage site of FGFR-1 do not prevent ectodomain shedding. Broad spectrum inhibitors of matrix metalloproteases decrease FGFR-1 ectodomain shedding, suggesting that the enzyme responsible for constitutive, ligand-activated, and protein kinase C-activated shedding is a matrix metalloprotease. In summary, shedding of the FGFR-1 ectodomain is a highly regulated event, sharing many features with a common system that governs the release of diverse membrane proteins from the cell surface. Most importantly, the FGFR ectodomains are biologically active after shedding and are capable of functioning as inhibitors of FGF-2.

scholarly journals Cellular distribution of a high-affinity glutamate transporter in the nervous system of the cabbage looperTrichoplusia ni

2002 ◽  
Vol 205 (17) ◽  
pp. 2605-2613 ◽  
Author(s):  
Richard B. Gardiner ◽  
Kyrre Ullensvang ◽  
Niels C. Danbolt ◽  
Stanley Caveney ◽  
B. Cameron Donly
Keyword(s):  
Nervous System ◽  
Glial Cells ◽  
Trichoplusia Ni ◽  
Neuromuscular Junctions ◽  
Glutamate Transporter ◽  
Extracellular Fluid ◽  
Sensory Nerves ◽  
Cabbage Looper ◽  
Microscopical Examination ◽  
High Affinity

SUMMARYGlutamate functions as a neurotransmitter in the central nervous system(CNS) and neuromuscular junctions in insects. High-affinity glutamate transporters are responsible for keeping the resting levels of excitatory amino acids below the synaptic activation threshold by removing them from the extracellular fluid, thereby preventing them from reaching toxic levels. Peptides representing the N- and C-terminal regions of a glutamate transporter cloned from the cabbage looper caterpillar (Trichoplusia ni) were synthesized and used to generate polyclonal antibodies. The antibodies produced immunohistochemical staining in both muscular and nervous system T. ni tissues. Neuromuscular junctions in the skeletal muscles produced the most intense labelling, but no visceral muscle or sensory nerves were labelled. In the CNS, the neuropile of the ganglia, but not the connectives, gave a diffuse staining. Electron microscopical examination of ganglia and neuromuscular junctions showed that the plasma membrane of glial cells, but not that of neurons was labelled, in agreement with the notion that most of the glutamate uptake sites in this insect are in glial cells.

The COOH-terminal nuclear localization sequence of interferon gamma regulates STAT1 alpha nuclear translocation at an intracellular site

2000 ◽  
Vol 113 (15) ◽  
pp. 2771-2781
Author(s):  
P.S. Subramaniam ◽  
J. Larkin ◽  
M.G. Mujtaba ◽  
M.R. Walter ◽  
H.M. Johnson
Keyword(s):  
Nuclear Localization ◽  
Nuclear Import ◽  
Nuclear Translocation ◽  
Biological Activities ◽  
Nuclear Localization Sequence ◽  
Receptor Complex ◽  
Ifn Gamma ◽  
High Affinity ◽  
Gamma Receptor ◽  
Localization Sequence

We have recently shown that the nuclear localization of IFN gamma is mediated by a polybasic nuclear localization sequence (NLS) in its C terminus. This NLS is required for the full expression of biological activity of IFN gamma, both extracellularly and intracellularly. We now show that this NLS plays an integral intracellular role in the nuclear translocation of the transcription factor STAT1 alpha activated by IFN gamma. Treatment of IFN gamma with antibodies to the C-terminal region (95–133) containing the NLS blocked the induction of STAT1 alpha nuclear translocation. The antibodies had no effect on nuclear translocation of STAT1 alpha in IFN gamma treated cells. A deletion mutant of human IFN gamma, IFN gamma (1–123), which is devoid of the C-terminal NLS region was found to be biologically inactive, but was still able to bind to the IFN gamma receptor complex on cells with a K(d) similar to that of the wild-type protein. Deletion of the NLS specifically abolished the ability of IFN gamma(1–123) to initiate the nuclear translocation of STAT1 alpha, which is required for the biological activities of IFN gamma following binding to the IFN gamma receptor complex. Thus, the NLS region appears to contribute minimally to extracellular high-affinity receptor-ligand binding, yet exerts a strong functional role in STAT1 alpha nuclear localization. A high-affinity site for the interaction of the C-terminal NLS domain of IFN gamma with a K(d) approx. 3 × 10(−8) M(−1) has been described by previous studies on the intracellular cytoplasmic domain of the IFN gamma receptor alpha-chain. To examine the role of the NLS at the intracellular level, we microinjected neutralizing antibodies raised against the C-terminal NLS domain of IFN gamma into the cytoplasm of cells before treatment of cells with IFN gamma. These intracellular antibodies specifically blocked the nuclear translocation of STAT1 alpha following the subsequent treatment of these cells extracellularly with IFN gamma. These data show that the NLS domain of IFN gamma interacts at an intracellular site to regulate STAT1 alpha nuclear import. A C-terminal peptide of murine IFN gamma, IFN gamma(95–133), that contains the NLS motif, induced nuclear translocation of STAT1 alpha when taken up intracellularly by a murine macrophage cell line. Deletion of the NLS motif specifically abrogated the ability of this intracellular peptide to cause STAT1 alpha nuclear translocation. In cells activated with IFN gamma, IFN gamma was found to as part of a complex that contained STAT1 alpha and the importin-alpha analog Npi-1, which mediates STAT1 alpha nuclear import. The tyrosine phosphorylation of STAT1 alpha, the formation of the complex IFN gamma/Npi-1/STAT1 alpha complex and the subsequent nuclear translocation of STAT1 alpha were all found to be dependent on the presence of the IFN gamma NLS. Thus, the NLS of IFN gamma functions intracellularly to directly regulate the activation and ultimate nuclear translocation STAT1 alpha.

Sign in / Sign up

Export Citation Format

Share Document