Fbxo45, a novel ubiquitin ligase, regulates synaptic activity.
Neurons communicate with each other through synapses. To establish the precise yet flexible connections that make up neural networks in the brain, continuous synaptic modulation is required. The ubiquitin-proteasome system of protein degradation is one of the critical mechanisms that underlie this process, playing crucial roles in the regulation of synaptic structure and function. We identified a novel ubiquitin ligase, Fbxo45, that functions at synapses. Fbxo45 is evolutionarily conserved and selectively expressed in the nervous system. We demonstrated that the knockdown of Fbxo45 in primary cultured hippocampal neurons resulted in a greater frequency of miniature excitatory postsynaptic currents. We also found that Fbxo45 induces the degradation of a synaptic vesicle-priming factor, Munc13-1. We propose that Fbxo45 plays an important role in the regulation of neurotransmission by modulating Munc13-1 at the synapse.
Tada
Hirobumi
H
From the Department of Physiology, Keio University School of Medicine, Tokyo 160-8582; the Department of Physiology, Yokohama City University School of Medicine, Kanagawa 236-0004; the Bridgestone Laboratory of Developmental and Regenerative Neurobiology, Keio University School of Medicine, Tokyo 160-8582.
Okano
Hirotaka James
HJ
From the Department of Physiology, Keio University School of Medicine, Tokyo 160-8582; SORST (Solution Oriented Research for Science and Technology), the Japan Science and Technology Agency, Saitama 332-0012. Electronic address: hjokano@sc.itc.keio.ac.jp.
Takagi
Hiroshi
H
the Laboratory for Molecular Gerontology, Mitsubishi Kagaku Institute of Life Sciences Setou Group, Tokyo 194-8511.
Shibata
Shinsuke
S
From the Department of Physiology, Keio University School of Medicine, Tokyo 160-8582.
Yao
Ikuko
I
the Laboratory for Molecular Gerontology, Mitsubishi Kagaku Institute of Life Sciences Setou Group, Tokyo 194-8511.
Matsumoto
Masaki
M
the Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, and; CREST (Core Research for Evolutional Science and Technology), the Japan Science and Technology Agency, Saitama 332-0012.
Saiga
Toru
T
the Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, and; CREST (Core Research for Evolutional Science and Technology), the Japan Science and Technology Agency, Saitama 332-0012.
Nakayama
Keiichi I
KI
the Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, and; CREST (Core Research for Evolutional Science and Technology), the Japan Science and Technology Agency, Saitama 332-0012.
Kashima
Haruo
H
the Department of Neuropsychiatry, Keio University School of Medicine, Tokyo 160-8582.
Takahashi
Takuya
T
the Department of Physiology, Yokohama City University School of Medicine, Kanagawa 236-0004.
Setou
Mitsutoshi
M
the Laboratory for Molecular Gerontology, Mitsubishi Kagaku Institute of Life Sciences Setou Group, Tokyo 194-8511; the Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, and; the Department of Molecular Anatomy, Hamamatsu University School of Medicine, Shizuoka 431-3192, Japan. Electronic address: setou@hama-med.ac.jp.
Okano
Hideyuki
H
From the Department of Physiology, Keio University School of Medicine, Tokyo 160-8582; the Bridgestone Laboratory of Developmental and Regenerative Neurobiology, Keio University School of Medicine, Tokyo 160-8582; SORST (Solution Oriented Research for Science and Technology), the Japan Science and Technology Agency, Saitama 332-0012. Electronic address: hidokano@sc.itc.keio.ac.jp.
D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D019556:COS Cells; D002460:Cell Line; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D019706:Excitatory Postsynaptic Potentials; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D015151:Immunoblotting; D017403:In Situ Hybridization; D051379:Mice; D016253:Microscopy, Immunoelectron; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000502:physiology* / Q000648:ultrastructure; D011485:Protein Binding; D034622:RNA Interference; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013569:Synapses / Q000378:metabolism / Q000502:physiology; D009435:Synaptic Transmission / Q000235:genetics / Q000502:physiology*; D054875:Ubiquitination
D044783:F-Box Proteins; C542381:Fbxo45 protein, mouse; D009419:Nerve Tissue Proteins; D044786:S-Phase Kinase-Associated Proteins; C503321:Unc13a protein, mouse