Synaptic memory and CaMKII.
Synaptic memory and CaMKII.
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DOI：
10.1152/physrev.00034.2022
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发表时间：
2023-10-01
影响因子：
33.6
通讯作者：
Schulman, Howard
中科院分区：
文献类型：
--
作者：
Nicoll, Roger A.;Schulman, Howard
钙/钙调蛋白依赖的蛋白激酶II(CaMKII)和长时程增强(LTP)是在十年内被发现的，自那以后一直密不可分。然而，就像许多婚姻一样，婚姻也有起有落。基于CaMKII独特的生化特性，在与LTP进行任何生理连锁之前，CaMKII被认为是一种记忆分子。然而，正如这里回顾的那样，CaMKII与突触生理和行为之间令人信服的联系花了几十年的时间。新技术在这一旅程中至关重要，包括体外脑切片、小鼠遗传学、单细胞分子遗传学、药物试剂、蛋白质结构和双光子显微镜，这一令人兴奋的挑战吸引了新的研究人员。这篇评论追踪了这段旅程，并评估了这段婚姻40年来的状况。集体文献促使我们提出了一个相对简单的突触记忆模型，涉及以下步骤来驱动这一过程：1)通过N-甲基-d-天冬氨酸(NMDA)受体进入钙离子激活CaMKII。2)CaMKII经历自动磷酸化，导致NMDA受体亚单位GluN2B的结构性、非钙依赖性活性和结合位点的暴露。3)激活的CaMKII移位到突触后密度(PSD)，并与GluN2B的胞浆C-尾结合。4)CaMKII-GluN2B复合体引发PSD的结构重排，可能涉及液-液分离。5)这种重排涉及PSD-95支架蛋白、α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic酸受体(AMPAR)及其跨膜AMPAR调节蛋白(TARP)辅助亚基，导致作为突触增强基础的PSD中AMPAR的积聚。6)CaMKII-GluN2B复合体的稳定性维持了修饰后PSD的稳定性。7)在CaMKII蛋白周转时，CaMKII通过亚单位交换或全酶间磷酸化来维持突触增强。还有许多其他重要的蛋白质参与突触脊椎的扩大或调节驱动和维持增强的步骤。在这篇综述中，我们对每个步骤背后的数据进行了批判性的讨论。很明显，其中一些步骤的根基比其他步骤更牢固，我们就如何加强或根据新数据取代支持这些步骤的证据提出建议。尽管这是一段漫长的旅程，但对学习和记忆进行详细的细胞和分子理解的前景近在咫尺。
Ca2+/calmodulin-dependent protein kinase II (CaMKII) and long-term potentiation (LTP) were discovered within a decade of each other and have been inextricably intertwined ever since. However, like many marriages, it has had its up and downs. Based on the unique biochemical properties of CaMKII, it was proposed as a memory molecule before any physiological linkage was made to LTP. However, as reviewed here, the convincing linkage of CaMKII to synaptic physiology and behavior took many decades. New technologies were critical in this journey, including in vitro brain slices, mouse genetics, single-cell molecular genetics, pharmacological reagents, protein structure, and two-photon microscopy, as were new investigators attracted by the exciting challenge. This review tracks this journey and assesses the state of this marriage 40 years on. The collective literature impels us to propose a relatively simple model for synaptic memory involving the following steps that drive the process: 1) Ca2+ entry through N-methyl-d-aspartate (NMDA) receptors activates CaMKII. 2) CaMKII undergoes autophosphorylation resulting in constitutive, Ca2+-independent activity and exposure of a binding site for the NMDA receptor subunit GluN2B. 3) Active CaMKII translocates to the postsynaptic density (PSD) and binds to the cytoplasmic C-tail of GluN2B. 4) The CaMKII-GluN2B complex initiates a structural rearrangement of the PSD that may involve liquid-liquid phase separation. 5) This rearrangement involves the PSD-95 scaffolding protein, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), and their transmembrane AMPAR-regulatory protein (TARP) auxiliary subunits, resulting in an accumulation of AMPARs in the PSD that underlies synaptic potentiation. 6) The stability of the modified PSD is maintained by the stability of the CaMKII-GluN2B complex. 7) By a process of subunit exchange or interholoenzyme phosphorylation CaMKII maintains synaptic potentiation in the face of CaMKII protein turnover. There are many other important proteins that participate in enlargement of the synaptic spine or modulation of the steps that drive and maintain the potentiation. In this review we critically discuss the data underlying each of the steps. As will become clear, some of these steps are more firmly grounded than others, and we provide suggestions as to how the evidence supporting these steps can be strengthened or, based on the new data, be replaced. Although the journey has been a long one, the prospect of having a detailed cellular and molecular understanding of learning and memory is at hand.
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