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The 6th (2006) Yamazaki-Teiichi Prize Winner Biological Science & Technology

Study of Excitatory Neurotransmission System Based on Novel Molecular Probes

winner Winner
Keiko Shimamoto
History
Mar. 1984 Graduated from Dept. of Chemistry, School of Science, Osaka Univ.
Mar. 1986 Completed Masters Course at Osaka Univ. Graduate School of Science (Organic Chemistry Major)
Apr. 1986 Suntory Institute for Bioorganic Research (SUNBOR), Researcher
Dec. 1991 Received Ph.D. Degree from Osaka Univ. Graduate School of Science
Jul. 2001 SUNBOR, Senior Chemist
Apr. 2005 SUNBOR, Senior Researcher
Present

Reason for award

The cells that make up our bodies maintain the homeostasis of life through the exchange of various signal molecules. The activities of the central nervous system control complex physical and mental activities by means of an advanced signal network and hold the key to maintaining balanced vital activities. Glutamate in particular, plays an extremely large role in this signal processing system. Although various methods have been applied to learn about its activities, it was Keiko Shimamoto who succeeded in establishing an inhibitor of the functional molecules that work within cells. Glutamate acts on receptors to induce a variety of functions, and the world has engaged in fierce competition to analyze those receptors, in kind. Amidst this move, Ms. Shimamoto focused on the Glutamate transporters, which transports glutamate, and developed the blocker threo-β-benzyloxyaspartate (TBOA). She conceived of converting an inhibitor to a blocker by introducing a substituent to the chemical structure of the substrate molecules to block the transport and thus succeeded in developing TBOA. (She has succeeded in enhancing TBOA activity around 1,000 times through additional chemical modification and continues to make a wider range of research possible at present.)
The TBOA that Ms. Shimamoto created is currently the only known drug that can selectively block the glutamate transporters. Since its announcement in 1998, TBOA has been used to open new possibilities in research on neural activity --including the analysis of changes in glutamate concentrations when the transporters are blocked and the associated receptor activity and the elucidation of the requirements for neuronal cell death -- and is widely applied at present. When the transporters are blocked with TBOA, the phenomena of a rapid rise in glutamate concentration, enhanced excitation and duration in the receptors, and increased cerebellar long-term depression (LTD) have been observed. These results indicate that the transporters controls receptor functions, and this entirely new research could not have been done without a selective blocker. Meanwhile, neuropathic pain (allodynia) and neuronal cell death caused by glutamate efflux under ischemic conditions have been blocked using TBOA. Along with providing evidence of the transporter's involvement in the cause of disease, these results present the possibility for its control to serve as a target for discovering new drugs. In addition, up until now, the role of the glutamate transporters was thought to be nothing more than the removal of waste following excitation by glutamate receptors , but the results made clear with TBOA show that the transporter's role is both to protect the neurons from neurotoxicity induced by glutamate and to actively modify signal transmission, presenting new concepts. In addition, Ms. Shimamoto has also made affinity columns for purifying transporter proteins and synthesized analogues containing heavy atoms for crystal analysis; she is leading the way in elucidating three-dimensional structural function for these protein molecules.
The drug that Ms. Shimamoto developed has already established itself as a standard substance for research pertaining to neurotransmission and is used around the world. Initially, Ms. Shimamoto synthesized it herself and distributed it widely to researchers around the world at their request, but at present, TBOA and its analogous compounds are commercially available, making a substantial contribution to signal mechanism elucidation on the international level.

Background of research and development

Glutamate is a representative excitatory neutrotransmitter that is found in mammalian central nervous systems and that is deeply involved in higher order brain functions, such as memory and learning. However, because high concentrations of glutamate cause neuronal cell death through excessive excitation, under physiological conditions, the glutamate concentration in synapses is strictly controlled by the function of glutamate transporters that exist primarily in glial cells. Research to clarify how these transporters affect brain function and neurological disorders requires selective inhibitors of the transport activity. However, the selective inhibitors known to the present function as competitive substrates: although they inhibited glutamate uptake, there was uptake of the inhibitors themselves, instead, and the associated ion flux and heteroexchange of glutamate could not be attenuated. For this reason, in experiments using these inhibitors, accurate observation of the transporter functions was difficult, in principle.

Achievements

In order to block the transport, By introducing a substituent to the chemical structure of the substrate molecules, the prizewinner succeeded in converting an inhibitor into a blocker. By using the blocker, threo-β-benzyloxyaspartate (TBOA), discovered in this way, the extracellular concentration of glutamate can be accurately measured with transporter activity suppressed. In consequence, the mechanism by which neurons can avoid death caused by glutamate by having the transporter function was clearly proved for the first time. The availability of selective blocker TBOA has rapidly advanced research on the glutamate transporters, and clarification continues, particular on the role the glia serve in neurotransmission. TBOA is now an indispensable reagent to research on excitatory neurotransmission. The prizewinner also succeeded in enhancing TBOA activity around 1,000 times through chemical modification, making an even wider range of research possible. The molecular probe that was created with techniques of organic chemistry on the basis of the structure of TBOA, such as the introduction of light-sensitive protecting group and radiolabeling, is expected to further contribute to the analysis of transporter functions and the search for new drugs. Moreover, prior to engaging in this research, the prizewinner also developed glutamate receptor ligands and synthesized conformationally constrained glutamate derivatives to clarify the active conformation when receptors recognize glutamate. She also conducted intricate receptor research, synthesizing compounds that work selectively on specific types of receptors from among the multiple receptor types and functions.

Meaning of the achievements

Glutamate is a double-edge sword, working simultaneously as both a neurotransmitter and a neurotoxin. Knowing the mechanisms by which this molecule transmits signals and by which its concentration is regulated will conceivably both link to the elucidation of the mechanisms for important vital phenomena involving neurons, such as memory and learning, and contribute to revealing the etiologic causes of neurological disorders and to the development of medical treatments. Although many drugs that target glutamate receptors have been reported to the present, clarification of how glial cells serve in neural control in recent years has made it important to clarify the role of the glutamate transporters, which exists primarily in the glial cells. The TBOA that the prizewinner created selectively blocks glutamate transporters. TBOA is widely applied to open up new possibilities for research on neural activity, including analysis of changes in glutamate concentrations when the transporters are blocked and the associated receptor activity and the elucidation of the requirements for inducing neuronal cell death. It has already established itself as a standard substance for research pertaining to neurotransmission. Originally, the prizewinner synthesized it herself and distributed it widely to researchers throughout the world by request, but TBOA is now commercially available. Her research to create new molecular probes using chemistry as a basis is expected to contribute substantially not only to the elucidation of the mechanism of excitatory neurotransmission but to that of vital phenomena, as well.

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