1997 Fiscal Year Final Research Report Summary
PHARMACOLOGICAL STRATEGIES FOR GLUTAMATE SIGNALING
| Project/Area Number |
08044326
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| Research Category |
Grant-in-Aid for international Scientific Research
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| Allocation Type | Single-year Grants |
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| Section | Joint Research |
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| Research Field |
Biological pharmacy
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| Research Institution | SETSUNAN UNIVERSITY |
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Principal Investigator |
YONEDA Yukio SETSUNAN UNIVERSITY,DEPARTMENT OF PHARMACOLOGY,PROFESSOR, 薬学部, 教授 (50094454)
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| Co-Investigator(Kenkyū-buntansha) |
MAX Recasens モンペリエ大学, 理学部, 教授
OGITA Kiyokazu SETSUNAN UNIVERSITY,DEPARTMENT OF PHARMACOLOGY,LECTURER, 薬学部, 講師 (90169219)
RECASENS Max UNIVERSITY OF MONTPELLIER,DEPARTMENT OF CEREBRAL PLASTISITY,PROFESSOR
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| Project Period (FY) |
1996 – 1997
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| Keywords | GLUTAMATE SIGNALING / IONOTROPIC RECEPTORS / METABOTROPIC RECEPTORS / NMDA RECEPTOR / GLYCINE DOMAIN / PHOSPHOLIPASE C / PHOSPHATIDYLINOSITOL / CADMIUM IONS |
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| Research Abstract |
In the mammalian central nervous system, extracellular signals carried by glutamate (Glu) are transduced into intracellular signals through Glu receptors located on cellular mambranes. These receptors for Glu are nowadays classified into two major categories such as metabotropic and ionotropic receptors according to their unique intracellular signal transduction systems. In this international research collaboration, we have aimed at discovery and development of a drug useful for the treatment and therapy of a variety of neuropsychiatric disorders through biochemical and mpharmacological evaluations of both subclasses of Glu receptors. Receptor binding studies on the ionotropic subclass revealed that 5,7-dichloroquinoxaline-2.3-dione 8DCQX) is a potent displacer of ligand binding to a glycine recognition domain on the ion channel associated with the N-methyl-D-aspartate (NMDA)-sensitive subtype. However, DCQX did not significantly affect binding of either a variety of radioligands for other recognition domains on the NMDA channel, or radioligands for the non-NMDA receptors. These results suggest that DCQX is a specific antagonist with high affinity fot the glycine recognition domain on the NMDA receptor. On the other hand, Glu was effective in stimulating hydrolysis of phosphatidylinositol in synaptoneurosomes of brains from newborn but not adult rats. The hydrolysis by Glu was markedly inhibited by the addition of cadmiun ions which did not affect the hydrolysis by carbachol at all. Therefore, cadmiun ions may have selective inhibitory actions on the metabotropic subclass of Glu receptors. Our final goal is to develop pharmacological strategies for the discovery of medicines of great clinical benefits through evaluation of biochemical andmpharmacological properties of both subclasses.
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