| Author |
Yamawaki, Shigeto Uegaki, Koichi Lume, Maria Mizui, Toshiyuki Kojima, Masami Kumanogoh, Haruko Takahashi, Masami Ishikawa, Yasuyuki Itami, Chiaki Matsumoto, Tomoya Shiosaka, Sadao Saarma, Mart Hara, Tomoko |
| Description |
Author Affiliation: Mizui T ( Biomedical Research Institute (BMD), National Institute of Advanced Industrial Science and Technology (AIST), Osaka 563-8577, Japan); Ishikawa Y ( Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Kawaguchi 332-0012, Japan); Kumanogoh H ( Biomedical Research Institute (BMD), National Institute of Advanced Industrial Science and Technology (AIST), Osaka 563-8577, Japan); Lume M ( Institute of Biotechnology, University of Helsinki, FIN-00014, Helsinki, Finland); Matsumoto T ( Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Kawaguchi 332-0012, Japan); Hara T ( Biomedical Research Institute (BMD), National Institute of Advanced Industrial Science and Technology (AIST), Osaka 563-8577, Japan); Yamawaki S ( Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Kawaguchi 332-0012, Japan); Takahashi M ( Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Kawaguchi 332-0012, Japan); Shiosaka S ( Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Kawaguchi 332-0012, Japan); Itami C ( Department of Physiology, Faculty of Medicine, Saitama Medical University, Saitama 350-0495, Japan); Uegaki K ( Biomedical Research Institute (BMD), National Institute of Advanced Industrial Science and Technology (AIST), Osaka 563-8577, Japan); Saarma M ( Institute of Biotechnology, University of Helsinki, FIN-00014, Helsinki, Finland); Kojima M ( Biomedical Research Institute (BMD), National Institute of Advanced Industrial Science and Technology (AIST), Osaka 563-8577, Japan); |
| Abstract |
Most growth factors are initially synthesized as precursor proteins and subsequently processed into their mature form by proteolytic cleavage, resulting in simultaneous removal of a pro-peptide. However, compared with that of mature form, the biological role of the pro-peptide is poorly understood. Here, we investigated the biological role of the pro-peptide of brain-derived neurotrophic factor (BDNF) and first showed that the pro-peptide is expressed and secreted in hippocampal tissues and cultures, respectively. Interestingly, we found that the BDNF pro-peptide directly facilitates hippocampal long-term depression (LTD), requiring the activation of GluN2B-containing NMDA receptors and the pan-neurotrophin receptor p75(NTR). The BDNF pro-peptide also enhances NMDA-induced -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor endocytosis, a mechanism crucial for LTD expression. Thus, the BDNF pro-peptide is involved in synaptic plasticity that regulates a mechanism responsible for promoting LTD. The well-known BDNF polymorphism valine for methionine at amino acid position 66 (Val66Met) affects human memory function. Here, the BDNF pro-peptide with Met mutation completely inhibits hippocampal LTD. These findings demonstrate functional roles for the BDNF pro-peptide and a naturally occurring human BDNF polymorphism in hippocampal synaptic depression. |
