Point mutation in syntaxin-1A causes abnormal vesicle recycling, behaviors, and short term plasticity

Yumi Watanabe, Norikazu Katayama, Kosei Takeuchi, Tetsuya Togano, Rieko Itoh, Michiko Sato, Maya Yamazaki, Manabu Abe, Toshiya Sato, Kanako Oda, Minesuke Yokoyama, Keizo Takao, Masahiro Fukaya, Tsuyoshi Miyakawa, Masahiko Watanabe, Kenji Sakimura, Toshiya Manabe, Michihiro Igarashia

Research output: Contribution to journalArticle

11 Citations (Scopus)

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 Ca2+/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.

Original languageEnglish
Pages (from-to)34906-34919
Number of pages14
JournalJournal of Biological Chemistry
Volume288
Issue number48
DOIs
Publication statusPublished - 29-11-2013

Fingerprint

Syntaxin 1
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Recycling
Point Mutation
Plasticity
Qa-SNARE Proteins
SNARE Proteins
Exocytosis
Neuronal Plasticity
Phenotype
Clamping devices
Synaptic Vesicles
Modulators
Neurons
Missense Mutation
Brain
Synaptic Transmission
Fusion reactions
Mutation
Proteins

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Watanabe, Y., Katayama, N., Takeuchi, K., Togano, T., Itoh, R., Sato, M., ... Igarashia, M. (2013). Point mutation in syntaxin-1A causes abnormal vesicle recycling, behaviors, and short term plasticity. Journal of Biological Chemistry, 288(48), 34906-34919. https://doi.org/10.1074/jbc.M113.504050
Watanabe, Yumi ; Katayama, Norikazu ; Takeuchi, Kosei ; Togano, Tetsuya ; Itoh, Rieko ; Sato, Michiko ; Yamazaki, Maya ; Abe, Manabu ; Sato, Toshiya ; Oda, Kanako ; Yokoyama, Minesuke ; Takao, Keizo ; Fukaya, Masahiro ; Miyakawa, Tsuyoshi ; Watanabe, Masahiko ; Sakimura, Kenji ; Manabe, Toshiya ; Igarashia, Michihiro. / Point mutation in syntaxin-1A causes abnormal vesicle recycling, behaviors, and short term plasticity. In: Journal of Biological Chemistry. 2013 ; Vol. 288, No. 48. pp. 34906-34919.
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Watanabe, Y, Katayama, N, Takeuchi, K, Togano, T, Itoh, R, Sato, M, Yamazaki, M, Abe, M, Sato, T, Oda, K, Yokoyama, M, Takao, K, Fukaya, M, Miyakawa, T, Watanabe, M, Sakimura, K, Manabe, T & Igarashia, M 2013, 'Point mutation in syntaxin-1A causes abnormal vesicle recycling, behaviors, and short term plasticity', Journal of Biological Chemistry, vol. 288, no. 48, pp. 34906-34919. https://doi.org/10.1074/jbc.M113.504050

Point mutation in syntaxin-1A causes abnormal vesicle recycling, behaviors, and short term plasticity. / Watanabe, Yumi; Katayama, Norikazu; Takeuchi, Kosei; Togano, Tetsuya; Itoh, Rieko; Sato, Michiko; Yamazaki, Maya; Abe, Manabu; Sato, Toshiya; Oda, Kanako; Yokoyama, Minesuke; Takao, Keizo; Fukaya, Masahiro; Miyakawa, Tsuyoshi; Watanabe, Masahiko; Sakimura, Kenji; Manabe, Toshiya; Igarashia, Michihiro.

In: Journal of Biological Chemistry, Vol. 288, No. 48, 29.11.2013, p. 34906-34919.

Research output: Contribution to journalArticle

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T1 - Point mutation in syntaxin-1A causes abnormal vesicle recycling, behaviors, and short term plasticity

AU - Watanabe, Yumi

AU - Katayama, Norikazu

AU - Takeuchi, Kosei

AU - Togano, Tetsuya

AU - Itoh, Rieko

AU - Sato, Michiko

AU - Yamazaki, Maya

AU - Abe, Manabu

AU - Sato, Toshiya

AU - Oda, Kanako

AU - Yokoyama, Minesuke

AU - Takao, Keizo

AU - Fukaya, Masahiro

AU - Miyakawa, Tsuyoshi

AU - Watanabe, Masahiko

AU - Sakimura, Kenji

AU - Manabe, Toshiya

AU - Igarashia, Michihiro

PY - 2013/11/29

Y1 - 2013/11/29

N2 - 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 Ca2+/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.

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