Rho-Rho-Kinase Regulates Ras-ERK Signaling Through SynGAP1 for Dendritic Spine Morphology
Rho-Rho-Kinase Regulates Ras-ERK Signaling Through SynGAP1 for Dendritic Spine Morphology
复制标题
Rho-Rho-激酶通过 SynGAP1 调节 Ras-ERK 信号传导以实现树突棘形态
DOI：
10.1007/s11064-022-03623-y
复制
发表时间：
2022
影响因子：
4.4
通讯作者：
Kaibuchi K.
中科院分区：
文献类型：
--
作者：
Wu M;Funahashi Y;Takano T;Hossen E;Ahammad RU;Tsuboi D;Amano M;Yamada K;Kaibuchi K.
树突棘的结构可塑性在NMDA诱导的长时程增强（LTP）中起着关键作用。小GTP酶RhoA和Ras被认为是脊柱形态和增大的关键调节因子。然而，RhoA和Ras之间的相互作用的监管基础NMDA诱导的脊柱扩大在很大程度上是未知的。在这项研究中，我们发现Rho-kinase/ROCK，RhoA的一种效应物，在Ser 842磷酸化SynGAP 1（一种突触Ras-GTP酶激活蛋白），并增加其与14-3-3-ERK的相互作用，从而激活HeLa细胞重建系统中的Ras-ERK信号。我们还发现，通过甘氨酸刺激NMDA受体诱导LTP刺激SynGAP 1磷酸化，Ras-ERK激活，脊髓扩大和SynGAP 1从脊髓中的纹状体神经元的离域，这些影响被阻止Rho激酶抑制。Rho激酶介导的SynGAP 1磷酸化似乎通过与14-3-3 β形成复合物来增加其与PSD 95的解离，PSD 95是位于突触后密度的突触后支架蛋白。这些结果表明，Rho激酶磷酸化SynGAP 1在Ser 842，从而激活NMDA诱导的树突棘形态学变化的Ras-ERK途径。
The structural plasticity of dendritic spines plays a critical role in NMDA-induced long-term potentiation (LTP) in the brain. The small GTPases RhoA and Ras are considered key regulators of spine morphology and enlargement. However, the regulatory interaction between RhoA and Ras underlying NMDA-induced spine enlargement is largely unknown. In this study, we found that Rho-kinase/ROCK, an effector of RhoA, phosphorylated SynGAP1 (a synaptic Ras-GTPase activating protein) at Ser842 and increased its interaction with 14-3-3ζ, thereby activating Ras-ERK signaling in a reconstitution system in HeLa cells. We also found that the stimulation of NMDA receptor by glycine treatment for LTP induction stimulated SynGAP1 phosphorylation, Ras-ERK activation, spine enlargement and SynGAP1 delocalization from the spines in striatal neurons, and these effects were prevented by Rho-kinase inhibition. Rho-kinase-mediated phosphorylation of SynGAP1 appeared to increase its dissociation from PSD95, a postsynaptic scaffolding protein located at postsynaptic density, by forming a complex with 14-3-3ζ. These results suggest that Rho-kinase phosphorylates SynGAP1 at Ser842, thereby activating the Ras-ERK pathway for NMDA-induced morphological changes in dendritic spines.