Spinophilin negatively controlled the function of transient receptor potential vanilloid 1 in dorsal root ganglia neurons of mice
Spinophilin negatively controlled the function of transient receptor potential vanilloid 1 in dorsal root ganglia neurons of mice
复制标题
Spinophilin负向控制小鼠背根神经节神经元瞬时受体电位香草酸1的功能
DOI：
10.1016/j.ejphar.2019.172700
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发表时间：
2019
影响因子：
5
通讯作者：
Hu Xiao Dong
中科院分区：
文献类型：
--
作者：
Guo Zhen;Li Hu Ling;Cao Zheng;Suo Zhan Wei;Yang Xian;Hu Xiao Dong
蛋白磷酸酶-1 (PP1) 广泛分布于神经系统中，催化多种底物的去磷酸化。 PP1 介导的去磷酸化的特异性和功效取决于将 PP1 锚定到底物附近的支架蛋白。 Spinophilin 是支架蛋白之一，能够引导 PP1 进入突触后密度并调节突触传递和可塑性。在这里，我们发现脊髓蛋白在背根神经节（DRG）神经元中富集，并参与伤害感受信号处理的修改。干扰 DRG 神经元中的亲旋蛋白/PP1 相互作用导致小鼠对热和机械刺激的敏感性增强。瞬时受体电位香草酸 1 (TRPV1) 被确定为亲旋蛋白修饰的重要靶点。我们的数据表明，亲旋蛋白与 TRPV1 发生物理相互作用，并促进 TRPV1 Ser502 处的 PP1 去磷酸化。亲旋蛋白/PP1 复合物的破坏增强了 Ser502 磷酸化并增强了质膜上 TRPV1 的表达。福尔马林诱导的外周炎症扰乱了亲旋蛋白/PP1 相互作用，从而消除了 PP1 介导的抑制并导致 TRPV1 磷酸化显着增加。 DRG 神经元中野生型亲旋蛋白的病毒表达抑制 TRPV1 磷酸化并减轻福尔马林诱导的炎症疼痛。这些数据表明，spinophilin/PP1 复合物负向控制 DRG 神经元中的 TRPV1 功能。
Protein phosphatase-1 (PP1) is ubiquitously distributed in the nervous system and catalyzes the dephosphorylation of numerous substrates. The specificity and efficacy of PP1-mediated dephosphorylation depend on scaffolding proteins that anchor PP1 to the close vicinity of substrates. Spinophilin is one of the scaffolding proteins which are able to direct PP1 into postsynaptic density and regulate the synaptic transmission and plasticity. Here we found that spinophilin was enriched in dorsal root ganglia (DRG) neurons and engaged in the modification of nociceptive signaling processing. Disturbing spinophilin/PP1 interaction in DRG neurons led to the enhanced sensitivity of mice to heat and mechanical stimuli. The transient receptor potential vanilloid 1 (TRPV1) was identified as an important target for spinophilin modification. Our data showed that spinophilin physically interacted with TRPV1 and facilitated PP1 dephosphorylation of TRPV1 at Ser502. Disruption of spinophilin/PP1 complex enhanced Ser502 phosphorylation and boosted TRPV1 expression on plasma membrane. Peripheral inflammation induced by formalin disturbed spinophilin/PP1 interaction, which removed PP1-mediated inhibition and caused a marked increase of TRPV1 phosphorylation. Viral expression of wild-type spinophilin in DRG neurons repressed TRPV1 phosphorylation and alleviated formalin-induced inflammatory pain. These data suggested that spinophilin/PP1 complex negatively controlled TRPV1 function in DRG neurons.