Roles of glutamate transporters in the nervous system
| Project/Area Number |
07044292
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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 Institution | Kyorin University |
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Principal Investigator |
KANAI Yoshikatsu Kyorin University, School of Medicine, Lecturer, 医学部, 講師 (60204533)
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| Co-Investigator(Kenkyū-buntansha) |
TATE Naoko Kyorin University, School of Medicine, 医学部, 助手 (00201955)
TAKEDA Michio Kyorin University, School of Medicine, 医学部, 助手 (40255401)
ENDOU Hitoshi Kyorin University, School of Medicine, 医学部, 教授 (20101115)
NUSSBERGER Stephan Harvard Medical School, 医学部, 助手
HEDIGER Matt ハーバード大学, 医学部, 助教授
HEDIGEL Matthias a Harvard Medical School
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| Project Period (FY) |
1995
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| Project Status |
Completed (Fiscal Year 1995)
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| Budget Amount *help |
¥4,700,000 (Direct Cost: ¥4,700,000)
Fiscal Year 1995: ¥4,700,000 (Direct Cost: ¥4,700,000)
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| Keywords | Glutamate / Transporter / Central nervous system / neuro transmission / neurotoxicity / excitotoxicity / membrane transport |
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| Research Abstract |
It has been proposed that glutamate transporters play critical roles in the termination of synaptic transmission and the maintenance of extracellular glutamate concentration below neurotoxic level. In this project, we have addressed the questions on the role of glutamate transporters in the nervous system utilizing molecular biology methodologies.
Stoichiometric analyzes of the glutamate transporter EAAC1 revealed that one glutamate is cotransported with two Na^+ and countertransported with one K^+ and OH-. Based on this stoichiometry, it was estimated that glutamate transporter has a high capacity to concentrate glutamate, confirming the role of the transporters maintaining extracellular glutamate concentration.
Chimera analysis based on the differential sensitivity of EAAC1 and GLT-1 to glutamate uptake inhibitor dihydrokainate addressed the region of glutamate transporter proteins which seems to be a glutamate binding site. In addition, the cloning and functional characterization of a
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new isoform of Na^+-dependent neutral amino acid transporter provided useful information on the sites for glutamate and Na^+ bindings.
To understand the mechanisms of regulation of expression of glutamate transporter genes, we isolated 15kb genomic DNA fragment which seems to contain the promotor region of EAAC1. The analysis of the nucleotide sequence and a CAT assay to study the regulatory region of the gene are in process.
The in situ hybridization study indicated that EAAC1 is expressed exclusively in neurons in rat central nervous system. The gene knockout experiment using an antisense oligo DNA intracerebroventricular administration technique revealed that the knockout of neuronal glutamate transporter EAAC1 elicits epileptic seizure on rat, which is in contrast with the glial transporter knockouts inducing neuronal cell death.
The results of this projected research will trigger the researches addressing the pathophysiology of disorders in which glutamate transport disturbance is involved and the development of drugs which specifically modify glutamate transporter function. Less
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Report
(1 results)
Research Products
(20 results)
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[Publications] Kanai, Y,Nussberger, S,Romero, MF,Boron, WF,Hebert, SC and Hediger, MA: "Electrogenic properties of the epithelial and neuronal high affinity glutamate transporter" The Journal of Biological Chemistry. 270. 16561-16568 (1995)
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[Publications] Rothstein, JD,Dykes-Hoberg, M,Pardo, CA,Bristol, LA,JinL,Kuncl, RW,Kanai, Y,Hediger, MA,Wang, Y,Schielke, J., and Welty, DF: "Antisense knockout of glutamate transporters reveals a predominant role of astroglial glutamate transport in excitotoxicity and clearance of extracellular glutamate" Neuron. (in press).
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