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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
1
|
| pubmed:dateCreated |
1989-8-11
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| pubmed:abstractText |
Guanine nucleotides were shown to alter N-methyl-d-aspartate (NMDA) receptor-effector coupling by competitive antagonism at the glutamate binding site, rather than via interaction with an intracellularly located GTP-binding protein. Thus, in contrast to known G-protein linked receptors, micromolar concentrations of guanine nucleotides and their analogs decreased both agonist [( 3H]glutamate) and antagonist [( 3H]-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid binding to the NMDA receptor complex. The most potent compound, the GDP analog guanosine-5'-O-(2-thiodiphosphate) (GDP beta S), was studied in detail. GDP beta S exhibited almost 200-fold selectivity for the glutamate recognition site vs. the strychnine-insensitive glycine binding site. IC50 values were 2.7 +/- 1.4 and 484 +/- 97 microM, respectively. GDP beta S also inhibited N-[1-(2-thienyl)cyclohexyl-3H]piperidine binding (IC50 was 28.0 +/- 3.7 microM) in an NMDA-reversible fashion. [3H]-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid saturation binding studies revealed an increase in Kd from 263 +/- 49 (control) to 552 +/- 134 nM (8 microM GDP beta S) without any change in maximum binding (4.94 +/- 0.34 and 5.19 +/- 0.58 pmol/mg of protein, respectively). GDP beta S was also a competitive inhibitor of the following NMDA-stimulated responses: elevation of cyclic GMP in neonatal rat cerebellar slices, release of preloaded [3H]norepinephrine from superfused rat hippocampal slices and elevation of cytosolic calcium concentration in fura-2-loaded cultured rat forebrain neurons. IC50 values were 78.4, 53.4 and 1.6 microM, respectively. Finally, GDP beta S resembled known NMDA receptor antagonists in its ability to block NMDA receptor-induced seizures after i.c.v. administration.(ABSTRACT TRUNCATED AT 250 WORDS)
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| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
|
| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Aspartic Acid,
http://linkedlifedata.com/resource/pubmed/chemical/Calcium,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclic GMP,
http://linkedlifedata.com/resource/pubmed/chemical/Guanine Nucleotides,
http://linkedlifedata.com/resource/pubmed/chemical/N-Methylaspartate,
http://linkedlifedata.com/resource/pubmed/chemical/Norepinephrine,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, N-Methyl-D-Aspartate,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Neurotransmitter
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| pubmed:status |
MEDLINE
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| pubmed:month |
Jul
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| pubmed:issn |
0022-3565
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| pubmed:author | |
| pubmed:issnType |
Print
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| pubmed:volume |
250
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
162-9
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| pubmed:dateRevised |
2003-11-14
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| pubmed:meshHeading |
pubmed-meshheading:2545857-Animals,
pubmed-meshheading:2545857-Aspartic Acid,
pubmed-meshheading:2545857-Binding, Competitive,
pubmed-meshheading:2545857-Brain,
pubmed-meshheading:2545857-Calcium,
pubmed-meshheading:2545857-Cerebellum,
pubmed-meshheading:2545857-Cerebral Cortex,
pubmed-meshheading:2545857-Cyclic GMP,
pubmed-meshheading:2545857-Cytosol,
pubmed-meshheading:2545857-Guanine Nucleotides,
pubmed-meshheading:2545857-Hippocampus,
pubmed-meshheading:2545857-Intracellular Membranes,
pubmed-meshheading:2545857-Kinetics,
pubmed-meshheading:2545857-Male,
pubmed-meshheading:2545857-N-Methylaspartate,
pubmed-meshheading:2545857-Neurons,
pubmed-meshheading:2545857-Norepinephrine,
pubmed-meshheading:2545857-Rats,
pubmed-meshheading:2545857-Rats, Inbred Strains,
pubmed-meshheading:2545857-Receptors, N-Methyl-D-Aspartate,
pubmed-meshheading:2545857-Receptors, Neurotransmitter,
pubmed-meshheading:2545857-Synaptosomes
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| pubmed:year |
1989
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| pubmed:articleTitle |
Guanine nucleotides are competitive inhibitors of N-methyl-D-aspartate at its receptor site both in vitro and in vivo.
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| pubmed:affiliation |
Merrell Dow Research Institute, Cincinnati, Ohio.
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| pubmed:publicationType |
Journal Article
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