SAD-B Phosphorylation of CAST Controls Active Zone Vesicle Recycling for Synaptic Depression.
Short-term synaptic depression (STD) is a common form of activity-dependent plasticity observed widely in the nervous system. Few molecular pathways that control STD have been described, but the active zone (AZ) release apparatus provides a possible link between neuronal activity and plasticity. Here, we show that an AZ cytomatrix protein CAST and an AZ-associated protein kinase SAD-B coordinately regulate STD by controlling reloading of the AZ with release-ready synaptic vesicles. SAD-B phosphorylates the N-terminal serine (S45) of CAST, and S45 phosphorylation increases with higher firing rate. A phosphomimetic CAST (S45D) mimics CAST deletion, which enhances STD by delaying reloading of the readily releasable pool (RRP), resulting in a pool size decrease. A phosphonegative CAST (S45A) inhibits STD and accelerates RRP reloading. Our results suggest that the CAST/SAD-B reaction serves as a brake on synaptic transmission by temporal calibration of activity and synaptic depression via RRP size regulation.
Department of Physiology, Tokyo Medical University, Tokyo 160-8402, Japan. Electronic address: mochida@tokyo-med.ac.jp.
Sumiko
S
Mochida
Department of Biochemistry, Faculty of Medicine/Graduate School of Medicine, University of Yamanashi, Yamanashi 409-3898, Japan.
Yamato
Y
Hida
Department of Physiology, Tokyo Medical University, Tokyo 160-8402, Japan.
Shota
S
Tanifuji
Department of Biochemistry, Faculty of Medicine/Graduate School of Medicine, University of Yamanashi, Yamanashi 409-3898, Japan.
Akari
A
Hagiwara
Department of Biochemistry, Faculty of Medicine/Graduate School of Medicine, University of Yamanashi, Yamanashi 409-3898, Japan.
Shun
S
Hamada
Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan.
Manabu
M
Abe
Department of Physiology, Tokyo Medical University, Tokyo 160-8402, Japan.
Huan
H
Ma
Department of Biochemistry, Faculty of Medicine/Graduate School of Medicine, University of Yamanashi, Yamanashi 409-3898, Japan.
Misato
M
Yasumura
Department of Clinical and Molecular Pathology, Faculty of Medicine/Graduate School of Medicine, University of Toyama, Toyama 930-0194, Japan.
Isao
I
Kitajima
Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan.
Kenji
K
Sakimura
Department of Biochemistry, Faculty of Medicine/Graduate School of Medicine, University of Yamanashi, Yamanashi 409-3898, Japan. Electronic address: tohtsuka@yamanashi.ac.jp.
Toshihisa
T
Ohtsuka
D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D002462:Cell Membrane / Q000502:physiology; D003598:Cytoskeletal Proteins / Q000737:chemistry / Q000378:metabolism*; D004705:Endocytosis; D057809:HEK293 Cells; D006801:Humans; D017774:Long-Term Potentiation; D008564:Membrane Potentials / Q000502:physiology; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D017783:Superior Cervical Ganglion / Q000166:cytology; D013572:Synaptic Vesicles / Q000378:metabolism*
D003598:Cytoskeletal Proteins; C505599:Erc2 protein, mouse; C496826:Brsk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D002118:Calcium
phosphorylation; presynaptic active zone; short-term plasticity; sympathetic neuron; synaptic vesicle