期刊
CELL RESEARCH
卷 31, 期 1, 页码 37-51出版社
SPRINGERNATURE
DOI: 10.1038/s41422-020-00439-9
关键词
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类别
资金
- Simons Foundation [510178]
- RGC of Hong Kong [16101419, AoE-M09-12, C6004-17G]
- Minister of Science and Technology of China [2019YFA0508402]
CaMKIIα plays a crucial role in synapses by interacting with Shank3 and GluN2B, regulating synaptic plasticity through the modulation of Ca2+ concentration and phosphatases. The shuttling of CaMKIIα between specific PSD subcompartments and PSD condensates controlled by protein phosphatases contributes to PSD assembly enlargement and structural long-term potentiation.
Ca2+/calmodulin-dependent kinase II alpha (CaMKII alpha) is essential for synaptic plasticity and learning by decoding synaptic Ca2+ oscillations. Despite decades of extensive research, new mechanisms underlying CaMKII alpha's function in synapses are still being discovered. Here, we discover that Shank3 is a specific binding partner for autoinhibited CaMKII alpha. We demonstrate that Shank3 and GluN2B, via combined actions of Ca2+ and phosphatases, reciprocally bind to CaMKII alpha. Under basal condition, CaMKII alpha is recruited to the Shank3 subcompartment of postsynaptic density (PSD) via phase separation. Rise of Ca2+ concentration induces GluN2B-mediated recruitment of active CaMKII alpha and formation of the CaMKII alpha/GluN2B/PSD-95 condensates, which are autonomously dispersed upon Ca2+ removal. Protein phosphatases control the Ca2+-dependent shuttling of CaMKII alpha between the two PSD subcompartments and PSD condensate formation. Activation of CaMKII alpha further enlarges the PSD assembly and induces structural LTP. Thus, Ca2+-induced and phosphatase-checked shuttling of CaMKII alpha between distinct PSD nano-domains can regulate phase separation-mediated PSD assembly and synaptic plasticity.
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