title: Point mutation in syntaxin-1A causes abnormal vesicle recycling, behaviors, and short term plasticity.
abstract: Syntaxin-1A is a t-SNARE that is involved in vesicle docking and vesicle fusion; it is important in presynaptic exocytosis in neurons because it interacts with many regulatory proteins. Previously, we found the following: 1) that autophosphorylated Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), an important modulator of neural plasticity, interacts with syntaxin-1A to regulate exocytosis, and 2) that a syntaxin missense mutation (R151G) attenuated this interaction. To determine more precisely the physiological importance of this interaction between CaMKII and syntaxin, we generated mice with a knock-in (KI) syntaxin-1A (R151G) mutation. Complexin is a molecular clamp involved in exocytosis, and in the KI mice, recruitment of complexin to the SNARE complex was reduced because of an abnormal CaMKII/syntaxin interaction. Nevertheless, SNARE complex formation was not inhibited, and consequently, basal neurotransmission was normal. However, the KI mice did exhibit more enhanced presynaptic plasticity than wild-type littermates; this enhanced plasticity could be associated with synaptic response than did wild-type littermates; this pronounced response included several behavioral abnormalities. Notably, the R151G phenotypes were generally similar to previously reported CaMKII mutant phenotypes. Additionally, synaptic recycling in these KI mice was delayed, and the density of synaptic vesicles was reduced. Taken together, our results indicated that this single point mutation in syntaxin-1A causes abnormal regulation of neuronal plasticity and vesicle recycling and that the affected syntaxin-1A/CaMKII interaction is essential for normal brain and synaptic functions in vivo.
authors.affiliation: From the Departments of Neurochemistry and Molecular Cell Biology and.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Norikazu
authors.initials: N
authors.lastname: Katayama
authors.forename: Kosei
authors.initials: K
authors.lastname: Takeuchi
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Togano
authors.forename: Rieko
authors.initials: R
authors.lastname: Itoh
authors.forename: Michiko
authors.initials: M
authors.lastname: Sato
authors.forename: Maya
authors.initials: M
authors.lastname: Yamazaki
authors.forename: Manabu
authors.initials: M
authors.lastname: Abe
authors.forename: Toshiya
authors.initials: T
authors.lastname: Sato
authors.forename: Kanako
authors.initials: K
authors.lastname: Oda
authors.forename: Minesuke
authors.initials: M
authors.lastname: Yokoyama
authors.forename: Keizo
authors.initials: K
authors.lastname: Takao
authors.forename: Masahiro
authors.initials: M
authors.lastname: Fukaya
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Miyakawa
authors.forename: Masahiko
authors.initials: M
authors.lastname: Watanabe
authors.forename: Kenji
authors.initials: K
authors.lastname: Sakimura
authors.forename: Toshiya
authors.initials: T
authors.lastname: Manabe
authors.forename: Michihiro
authors.initials: M
authors.lastname: Igarashi
mesh_terms: D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D005089:Exocytosis / Q000235:genetics*; D055879:Gene Knock-In Techniques; D006624:Hippocampus / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D009473:Neuronal Plasticity / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D017354:Point Mutation / Q000235:genetics*; D060066:Protein Interaction Maps; D009435:Synaptic Transmission / Q000235:genetics; D013572:Synaptic Vesicles / Q000235:genetics / Q000378:metabolism; D050827:Syntaxin 1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; D050827:Syntaxin 1; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2
keywords: Calcium/Calmodulin-dependent Protein Kinase (CaMK); Exocytosis; SNARE Proteins; Synaptic Plasticity; Synaptosomes