Ca²⁺/calmodulin-dependent kinase IIα (CaMKIIα) is essential for synaptic plasticity and learning by decoding synaptic Ca²⁺ oscillations. Despite decades of extensive research, new mechanisms underlying CaMKIIα’s function in synapses are still being discovered. Here, we discover that Shank3 is a specific binding partner for autoinhibited CaMKIIα. We demonstrate that Shank3 and GluN2B, via combined actions of Ca²⁺ and phosphatases, reciprocally bind to CaMKIIα. Under basal condition, CaMKIIα is recruited to the Shank3 subcompartment of postsynaptic density (PSD) via phase separation. Rise of Ca²⁺ concentration induces GluN2B-mediated recruitment of active CaMKIIα and formation of the CaMKIIα/GluN2B/PSD-95 condensates, which are autonomously dispersed upon Ca²⁺ removal. Protein phosphatases control the Ca²⁺-dependent shuttling of CaMKIIα between the two PSD subcompartments and PSD condensate formation. Activation of CaMKIIα further enlarges the PSD assembly and induces structural LTP. Thus, Ca²⁺-induced and phosphatase-checked shuttling of CaMKIIα between distinct PSD nano-domains can regulate phase separation-mediated PSD assembly and synaptic plasticity.

Ca ²⁺ /钙调蛋白依赖性激酶 IIα (CaMKIIα) 通过解码突触 Ca ²⁺振荡对突触可塑性和学习至关重要。尽管进行了数十年的广泛研究，但仍在发现 CaMKIIα 在突触中的功能的新机制。在这里，我们发现 Shank3 是自动抑制的 CaMKIIα 的特异性结合伙伴。我们证明 Shank3 和 GluN2B，通过 Ca ²⁺和磷酸酶的联合作用，相互结合到 CaMKIIα。在基础条件下，CaMKIIα 通过相分离被募集到突触后密度 (PSD) 的 Shank3 亚室。Ca ^{2+ 的}上升浓度诱导 GluN2B 介导的活性 CaMKIIα 募集和 CaMKIIα/GluN2B/PSD-95 缩合物的形成，这些缩合物在 Ca ²⁺去除后自动分散。蛋白磷酸酶控制CaMKIIα 在两个 PSD 亚室之间的 Ca ²⁺依赖性穿梭和 PSD 冷凝物形成。CaMKIIα 的激活进一步扩大了 PSD 组装并诱导了结构性 LTP。因此，Ca ²⁺诱导和磷酸酶检查的 CaMKIIα 在不同 PSD 纳米域之间的穿梭可以调节相分离介导的 PSD 组装和突触可塑性。