Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA.
Sci Signal. 2022 May 10;15(733):eabh3066. doi: 10.1126/scisignal.abh3066.
Synapses connect discrete neurons into vast networks that send, receive, and encode diverse forms of information. Synaptic function and plasticity, the neuronal process of adapting to diverse and variable inputs, depend on the dynamic nature of synaptic molecular components, which is mediated in part by cell adhesion signaling pathways. Here, we found that the enzyme biliverdin reductase (BVR) physically links together key focal adhesion signaling molecules at the synapse. -null () mice exhibited substantial deficits in learning and memory on neurocognitive tests, and hippocampal slices in which BVR was postsynaptically depleted showed deficits in electrophysiological responses to stimuli. RNA sequencing, biochemistry, and pathway analyses suggested that these deficits were mediated through the loss of focal adhesion signaling at both the transcriptional and biochemical level in the hippocampus. Independently of its catalytic function, BVR acted as a bridge between the primary focal adhesion signaling kinases FAK and Pyk2 and the effector kinase Src. Without BVR, FAK and Pyk2 did not bind to and stimulate Src, which then did not phosphorylate the -methyl-d-aspartate (NMDA) receptor, a critical posttranslational modification for synaptic plasticity. Src itself is a molecular hub on which many signaling pathways converge to stimulate NMDAR-mediated neurotransmission, thus positioning BVR at a prominent intersection of synaptic signaling.
突触将离散的神经元连接成庞大的网络，这些网络可以发送、接收和编码各种形式的信息。突触功能和可塑性是神经元适应各种不同和可变输入的过程，依赖于突触分子成分的动态特性，而这部分是由细胞黏附信号通路介导的。在这里，我们发现酶胆绿素还原酶 (BVR) 将关键的焦点黏附信号分子在突触处物理连接在一起。-null () 小鼠在神经认知测试中表现出明显的学习和记忆缺陷，而在后突触中耗尽 BVR 的海马切片显示出对刺激的电生理反应缺陷。RNA 测序、生物化学和途径分析表明，这些缺陷是通过海马体转录和生化水平上焦点黏附信号的丧失介导的。BVR 独立于其催化功能，充当了主要焦点黏附信号激酶 FAK 和 Pyk2 与效应激酶 Src 之间的桥梁。没有 BVR，FAK 和 Pyk2 就不能与 Src 结合并刺激它，从而不能磷酸化 -甲基-d-天冬氨酸 (NMDA) 受体，这是突触可塑性的一个关键翻译后修饰。Src 本身就是一个分子枢纽，许多信号通路都汇聚在这个枢纽上，以刺激 NMDAR 介导的神经传递，因此 BVR 处于突触信号的突出交汇点。
