Biliverdin reductase bridges focal adhesion kinase to Src to modulate synaptic signaling.
Biliverdin reductase bridges focal adhesion kinase to Src to modulate synaptic signaling.
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DOI：
10.1126/scisignal.abh3066
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发表时间：
2022-05-10
影响因子：
7.3
通讯作者：
Snyder, Solomon H.
中科院分区：
文献类型：
--
作者：
Vasavda, Chirag;Semenza, Evan R.;Liew, Jason;Kothari, Ruchita;Dhindsa, Ryan S.;Shanmukha, Shruthi;Lin, Anthony;Tokhunts, Robert;Ricco, Cristina;Snowman, Adele M.;Albacarys, Lauren;Pastore, Francesco;Ripoli, Cristian;Grassi, Claudio;Barone, Eugenio;Kornberg, Michael D.;Dong, Xinzhong;Paul, Bindu D.;Snyder, Solomon H.
突触将离散的神经元连接成巨大的网络，发送，接收和编码各种形式的信息。突触功能和可塑性神经元适应不同和可变输入的过程依赖于突触分子成分的动态性质，这部分是由细胞粘附信号通路介导的。在这里，我们发现胆绿素还原酶（BVR）在突触处将关键的粘着斑信号分子物理连接在一起。BVR-null（BVR-/-）小鼠在神经认知测试中表现出学习和记忆方面的严重缺陷，而BVR突触后耗竭的海马切片对刺激的电生理反应表现出缺陷。RNA测序，生物化学和途径分析表明，这些赤字介导的损失，在转录和生物化学水平的海马粘着斑信号。独立于其催化功能，BVR充当主要粘着斑信号传导激酶FAK和Pyk 2与效应激酶Src之间的桥梁。在没有BVR的情况下，FAK和Pyk 2不能结合并刺激Src，Src不能磷酸化N-甲基-D-天冬氨酸（NMDA）受体，这是突触可塑性的关键翻译后修饰。Src本身是一个分子枢纽，许多信号通路汇聚在其上以刺激NMDAR介导的神经传递，从而将BVR定位在突触信号传导的突出交叉点。
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. BVR-null (BVR−/−) 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 N-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.
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