The association of spinophilin with disks large-associated protein 3 (SAPAP3) is regulated by metabotropic glutamate receptor (mGluR) 5.,Molecular and Cellular Neuroscience

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The association of spinophilin with disks large-associated protein 3 (SAPAP3) is regulated by metabotropic glutamate receptor (mGluR) 5.
Molecular and Cellular Neuroscience ( IF 2.6 ) Pub Date : 2018-06-14 , DOI: 10.1016/j.mcn.2018.06.001
Cameron W Morris ₁ , Darryl S Watkins ₂ , Asma B Salek ₃ , Michael C Edler ₃ , Anthony J Baucum ₄

Affiliation

Spinophilin is the most abundant protein phosphatase 1 targeting protein in the postsynaptic density of dendritic spines. Spinophilin associates with myriad synaptic proteins to regulate normal synaptic communication; however, the full complement of spinophilin interacting proteins and mechanisms regulating spinophilin interactions are unclear. Here we validate an association between spinophilin and the scaffolding protein, disks large-associated protein 3 (SAP90/PSD-95 associated protein 3; SAPAP3). Loss of SAPAP3 leads to obsessive-compulsive disorder (OCD)-like behaviors due to alterations in metabotropic glutamate receptor (mGluR) signaling. Here we report that spinophilin associates with SAPAP3 in the brain and in a heterologous cell system. Moreover, we have found that expression or activation of group I mGluRs along with activation of the mGluR-dependent kinase, protein kinase C β, enhances this interaction. Functionally, global loss of spinophilin attenuates amphetamine-induced hyperlocomotion, a striatal behavior associated with dopamine dysregulation and OCD. Together, these data delineate a novel link between mGluR signaling, spinophilin, and SAPAP3 in striatal pathophysiology.

中文翻译：

亲旋蛋白与椎间盘大相关蛋白 3 (SAPAP3) 的关联受代谢型谷氨酸受体 (mGluR) 5 调节。

Spinophilin 是树突棘突触后密度中最丰富的蛋白磷酸酶 1 靶向蛋白。 Spinophilin 与无数突触蛋白结合以调节正常的突触通讯；然而，亲旋蛋白相互作用蛋白的完整补充和调节亲旋蛋白相互作用的机制尚不清楚。在这里，我们验证了亲旋蛋白和支架蛋白、圆盘大相关蛋白 3（SAP90/PSD-95 相关蛋白 3；SAPAP3）之间的关联。由于代谢型谷氨酸受体 (mGluR) 信号传导的改变，SAPAP3 的缺失会导致强迫症 (OCD) 样行为。在这里，我们报道了 Spinophilin 与大脑和异源细胞系统中的 SAPAP3 相关。此外，我们发现 I 组 mGluR 的表达或激活以及 mGluR 依赖性激酶（蛋白激酶 C β）的激活增强了这种相互作用。从功能上讲，亲旋蛋白的整体丧失会减弱安非他明引起的过度运动，这是一种与多巴胺失调和强迫症相关的纹状体行为。这些数据共同描绘了纹状体病理生理学中 mGluR 信号传导、spinophilin 和 SAPAP3 之间的新联系。

更新日期：2018-06-14

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