S-nitros(yl)ation of CaMKIIα and its precision redox regulation by SNOTAC plays a critical role in learning and memory
Ca2+/calmodulin-dependent protein kinase II α (CaMKIIα) and nitric oxide (NO) both play vital roles in learning and memory; however, the underlying mechanisms connecting them have remained elusive. To address this question, our study surprisingly observed that during learning and memory tasks, S-nit...
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Elsevier
2025-10-01
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| Series: | Redox Biology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231725002976 |
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| author | Boyu Chu Xinhua Qiao Hui Ye Xiaoli Cui Shuli Zhang Wenting Su Yuying Zhang Chuanxin Sun Xuanhao Wu Tiepeng Wang Hua Li Jianbing Wu Zhangjian Huang Chang Chen |
| author_facet | Boyu Chu Xinhua Qiao Hui Ye Xiaoli Cui Shuli Zhang Wenting Su Yuying Zhang Chuanxin Sun Xuanhao Wu Tiepeng Wang Hua Li Jianbing Wu Zhangjian Huang Chang Chen |
| author_sort | Boyu Chu |
| collection | DOAJ |
| description | Ca2+/calmodulin-dependent protein kinase II α (CaMKIIα) and nitric oxide (NO) both play vital roles in learning and memory; however, the underlying mechanisms connecting them have remained elusive. To address this question, our study surprisingly observed that during learning and memory tasks, S-nitrosation of CaMKIIα, a key redox-based post-translational modification, significantly increased in mouse hippocampus. We then constructed mice with mutations in the major S-nitrosation sites of CaMKIIα (C280/289V) and found that the mutant mice exhibited remarkable cognitive impairments and attenuated long-term potentiation (LTP). Mechanistically, we demonstrated that the SNO-CaMKIIα mutation increased presynaptic release probability by increasing the interaction and the phosphorylation of synapsin I (Syn1). Excessive vesicle release in the resting state leads to invalid postsynaptic activation, resulting in reduced variability in postsynaptic AMPAR-mediated transmission and impaired response capacity of learning and memory. This reduction of response capacity was also detected in naturally aging mice, indicating it may serve as a determining factor underlying cognitive impairments. Furthermore, we developed the S-nitrosation targeting chimera (SNOTAC), a precision redox modulator designed to enhance the interaction between CaMKIIα and nNOS. Intranasal administration of SNOTAC increased the CaMKIIα S-nitrosation level in mouse hippocampus and successfully rescued learning and memory impairment. These findings establish that redox modification, CaMKIIα S-nitrosation, plays a vital, yet previously unrecognized role in the physiological processes of learning and memory. Moreover, the SNOTAC strategy pioneers a novel paradigm for precision redox intervention, highlighting the potential of targeted redox modulation for cognitive impairment. |
| format | Article |
| id | doaj-art-a42e8da8a5cb41c1ab7e5079511906e3 |
| institution | Kabale University |
| issn | 2213-2317 |
| language | English |
| publishDate | 2025-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj-art-a42e8da8a5cb41c1ab7e5079511906e32025-08-20T03:45:10ZengElsevierRedox Biology2213-23172025-10-018610378410.1016/j.redox.2025.103784S-nitros(yl)ation of CaMKIIα and its precision redox regulation by SNOTAC plays a critical role in learning and memoryBoyu Chu0Xinhua Qiao1Hui Ye2Xiaoli Cui3Shuli Zhang4Wenting Su5Yuying Zhang6Chuanxin Sun7Xuanhao Wu8Tiepeng Wang9Hua Li10Jianbing Wu11Zhangjian Huang12Chang Chen13National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China; University of Chinese Academy of Sciences, Beijing, 100049, ChinaNational Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, ChinaState Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 211198, ChinaNational Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China; University of Chinese Academy of Sciences, Beijing, 100049, ChinaNational Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China; University of Chinese Academy of Sciences, Beijing, 100049, ChinaBeijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing, 102206, China; Laboratory for Clinical Medicine, Capital Medical University, Beijing, 100069, ChinaNational Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, ChinaNational Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, ChinaNational Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China; University of Chinese Academy of Sciences, Beijing, 100049, ChinaNational Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, ChinaBeijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing, 102206, China; Laboratory for Clinical Medicine, Capital Medical University, Beijing, 100069, ChinaState Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 211198, ChinaState Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 211198, China; School of Pharmacy, Xinjiang Key Laboratory of Biopharmaceuticals and Medical Devices, Key Laboratory of Active Components of Xinjiang Natural Medicine and Drug Release Technology, Engineering Research Center of Xinjiang and Central Asian Medicine Resources, Xinjiang Medical University, Urumqi, 830054, China; Corresponding author. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China.National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China; University of Chinese Academy of Sciences, Beijing, 100049, China; Corresponding author. National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.Ca2+/calmodulin-dependent protein kinase II α (CaMKIIα) and nitric oxide (NO) both play vital roles in learning and memory; however, the underlying mechanisms connecting them have remained elusive. To address this question, our study surprisingly observed that during learning and memory tasks, S-nitrosation of CaMKIIα, a key redox-based post-translational modification, significantly increased in mouse hippocampus. We then constructed mice with mutations in the major S-nitrosation sites of CaMKIIα (C280/289V) and found that the mutant mice exhibited remarkable cognitive impairments and attenuated long-term potentiation (LTP). Mechanistically, we demonstrated that the SNO-CaMKIIα mutation increased presynaptic release probability by increasing the interaction and the phosphorylation of synapsin I (Syn1). Excessive vesicle release in the resting state leads to invalid postsynaptic activation, resulting in reduced variability in postsynaptic AMPAR-mediated transmission and impaired response capacity of learning and memory. This reduction of response capacity was also detected in naturally aging mice, indicating it may serve as a determining factor underlying cognitive impairments. Furthermore, we developed the S-nitrosation targeting chimera (SNOTAC), a precision redox modulator designed to enhance the interaction between CaMKIIα and nNOS. Intranasal administration of SNOTAC increased the CaMKIIα S-nitrosation level in mouse hippocampus and successfully rescued learning and memory impairment. These findings establish that redox modification, CaMKIIα S-nitrosation, plays a vital, yet previously unrecognized role in the physiological processes of learning and memory. Moreover, the SNOTAC strategy pioneers a novel paradigm for precision redox intervention, highlighting the potential of targeted redox modulation for cognitive impairment.http://www.sciencedirect.com/science/article/pii/S2213231725002976CaMKIIαS-nitrosation/S-nitrosylationLearning and memoryAge-related cognitive impairmentResponse capacityPresynaptic release probability |
| spellingShingle | Boyu Chu Xinhua Qiao Hui Ye Xiaoli Cui Shuli Zhang Wenting Su Yuying Zhang Chuanxin Sun Xuanhao Wu Tiepeng Wang Hua Li Jianbing Wu Zhangjian Huang Chang Chen S-nitros(yl)ation of CaMKIIα and its precision redox regulation by SNOTAC plays a critical role in learning and memory Redox Biology CaMKIIα S-nitrosation/S-nitrosylation Learning and memory Age-related cognitive impairment Response capacity Presynaptic release probability |
| title | S-nitros(yl)ation of CaMKIIα and its precision redox regulation by SNOTAC plays a critical role in learning and memory |
| title_full | S-nitros(yl)ation of CaMKIIα and its precision redox regulation by SNOTAC plays a critical role in learning and memory |
| title_fullStr | S-nitros(yl)ation of CaMKIIα and its precision redox regulation by SNOTAC plays a critical role in learning and memory |
| title_full_unstemmed | S-nitros(yl)ation of CaMKIIα and its precision redox regulation by SNOTAC plays a critical role in learning and memory |
| title_short | S-nitros(yl)ation of CaMKIIα and its precision redox regulation by SNOTAC plays a critical role in learning and memory |
| title_sort | s nitros yl ation of camkiiα and its precision redox regulation by snotac plays a critical role in learning and memory |
| topic | CaMKIIα S-nitrosation/S-nitrosylation Learning and memory Age-related cognitive impairment Response capacity Presynaptic release probability |
| url | http://www.sciencedirect.com/science/article/pii/S2213231725002976 |
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