Ageta-Ishihara Natsumi, Mizukami Masato, Kinoshita Itsuki, Asami Yurika, Nishioka Tomoki, Bito Haruhiko, Kaibuchi Kozo, Kinoshita Makoto
Department of Biomolecular Science, Faculty of Science, Toho University, 2-2-1 Miyama, Funabashi, 274-8510, Chiba, Japan.
Department of Molecular Biology, Division of Biological Sciences, Graduate School of Science, Nagoya University, Chikusa-ku, Nagoya, 464-8602, Japan.
Mol Brain. 2025 May 15;18(1):43. doi: 10.1186/s13041-025-01215-9.
Cytoskeletal remodeling drives morphological changes. Septin cytoskeleton assembles into hetero-oligomers. We previously demonstrated that late-phase long-term potentiation (L-LTP) induces smooth endoplasmic reticulum (sER) extension into dendritic spines via septin 3 (SEPT3), contributing to greater postsynaptic Ca responses and enhanced activation of synaptically induced Ca signaling. Sept3 mice exhibit a reduced number of sER-containing spines and show impaired long-term spatial/object memory despite normal short-term memory. Additionally, SEPT3 binds the motor protein myosin-Va (MYO5A) upon elevated Ca²⁺ concentrations, facilitating sER extension from the dendritic shaft into the spine. MYO5A localizes on the sER membrane, while SEPT3 remains at the spine base, accumulating on sER upon electroconvulsive stimulation (ECS). However, the mechanism underlying SEPT3's delocalization from the spine base and its cooperative role with MYO5A in sER extension remains unclear. In this study, we demonstrate that SEPT3 is phosphorylated in a stimulation-dependent manner. Phosphorylation at Thr211 releases SEPT3 from the spine base, enabling sER extension with constitutively active MYO5A mutant (MYO5A-CCtr). These findings provide molecular insight into the role of SEPT3 phosphorylation in regulating sER dynamics that sustain long-term spine activation.
细胞骨架重塑驱动形态变化。Septin细胞骨架组装成异源寡聚体。我们先前证明，晚期长时程增强（L-LTP）通过septin 3（SEPT3）诱导平滑内质网（sER）延伸至树突棘，从而导致更大的突触后钙反应并增强突触诱导的钙信号激活。Sept3小鼠含有sER的棘突数量减少，尽管短期记忆正常，但长期空间/物体记忆受损。此外，在Ca²⁺浓度升高时，SEPT3与运动蛋白肌球蛋白-Va（MYO5A）结合，促进sER从树突轴延伸至棘突。MYO5A定位于sER膜上，而SEPT3保留在棘突基部，在电惊厥刺激（ECS）时在sER上积累。然而，SEPT3从棘突基部脱离定位的机制及其与MYO5A在sER延伸中的协同作用仍不清楚。在本研究中，我们证明SEPT3以刺激依赖的方式磷酸化。苏氨酸211位点的磷酸化使SEPT3从棘突基部释放，从而使sER能够与组成型活性MYO5A突变体（MYO5A-CCtr）一起延伸。这些发现为SEPT3磷酸化在调节维持长期棘突激活的sER动态中的作用提供了分子见解。
