SUNTORY INSTITUTE FOR BIOORGANIC RESEARCH

Oct.2007

Research Summary

Memory and learning in the brain, body generation/regeneration and morphogenesis and the like are complex biological events involving multiple factors. It is postulated that each event is triggered by a small organic molecule, followed by a series of reactions and regulations. We are studying to elucidate the functions of small organic molecules which cause these events. As illustrated in the right, our research approach based on natural products science involves three processes: isolation and structural determination of bioactive compounds with bioassay, chemical synthesis of active compounds and their derivatives, and identification of proteins and tissues targeted by the compounds.

Major research Projects

1）Peptide hormones in the octopus brain

Neurohypophysial peptide hormones, oxytocin and vasopressin, and related peptides are widely distributed in vertebrates. Gonadotropin-releasing hormone (GnRH) is the core peptide in the hypothalamo-hypophysial- gonadal axis in mammals. We have identified oxytocin / vasopressin-related peptides and a GnRH-like peptide from the brain of octopus, Octopus vulgaris. We have revealed that these peptides are widely distributed in lobes of the octopus brain; this fact indicates that they have physiological functions not only as endocrine hormones but also as multifunctional neuropeptides.

Octopus, squid, and cuttlefish are species of the Cephalopod. Octopus possesses advanced brain with several hundred millions of neuronal cells and has hence earned the distinction of “primate of the sea”, the cell number being though less than those of birds and mammals but exceeds those of fish and reptiles. Our research goal is to elucidate roles of octopus brain hormones in memory, learning, emotion, and innate behavior, etc, and to lead knowledge of human brain functions.

1. Neuropeptides and Peptide Hormones in Cephalopods. Minakata, H. In Invertebrate Neuropeptides and Hormones: Basic Knowledge and Recent Advances (Satake H ed), pp. 111-126, Transworld Research Network, Kerala, India (2006)

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2）Amino acids regulating neurotransmission

Glutamate acts as a major neurotransmitter in mammalian central nervous systems, which is linked to memory and learning. Simultaneously, excess glutamate causes neuronal cell death. To clarify how receptors transmit signals by glutamate and how transporters terminate neurotransmission, specific molecules are required which selectively activate or inhibit these proteins. We have, so far, developed TBOA, the first molecule which can selectively block glutamate transporters. By using TBOA, it has been found that transporters not only remove excess glutamate but also positively modify signal transmission. We also synthesized molecular proves that showed 1000-fold more potent activity and that is labeled with radioactive atoms. Our compounds contribute to elucidation of higher brain mechanisms on the international level.

1. Glutamate Transporter Blockers for Elucidation of the Function of Excitatory Neurotransmission Systems.
   Shimamoto, K. Chem. Rec., 8, 182-199 (2008)

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3）Signaling molecules in hydra

In the freshwater cnidarian Hydra, there is circumstantial evidence that small diffusible molecules act as morphogens that are key factors in the regulation of patterning processes. For example, the novel peptide, Hym-301, is found to play a specific role in tentacle formation. Recently, we have found the novel function of acetylcholine that generally acts as a neurotransmitter in the nervous system of higher metazoans. These small molecules appear to have wide variety of developmental functions in controlling morphogenesis, regeneration and asexual reproduction by budding in Hydra. Novel signaling molecules identified in our project are likely to provide a new and effective means to explore the mechanisms that underlie developmental processes in Hydra and most likely will inform our understanding of their function in higher animals as well.

1. New perspectives on neuropeptides in Hydra. Takahashi, T., Hayakawa, E., Koizumi, O. and Fujisawa, T. In Invertebrate Neuropeptides and Hormones: Basic Knowledge and Recent Advances (Satake H ed), pp. 1-15, Transworld Research Network, Kerala, India (2006)
2. 1.A Novel Neuropeptide (FRamide) Family Identified by a Peptidomic Approach in Hydra Hayakawa, E., Takahashi, T., Nishimiya-Fujisawa, C. and Fujisawa, T. FEBS J., 274, 5438-5448 (2007)