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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| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-10-01
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| Series: | Redox Biology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231725002976 |
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| Summary: | 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. |
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| ISSN: | 2213-2317 |