Spinophilin-Targeted Protein Phosphatase-1 Alleviated Inflammatory Pain by Negative Control of MEK/ERK Signaling in Spinal Cord Dorsal Horn of Rats
Spinophilin-Targeted Protein Phosphatase-1 Alleviated Inflammatory Pain by Negative Control of MEK/ERK Signaling in Spinal Cord Dorsal Horn of Rats
复制标题
Spinophilin 靶向蛋白磷酸酶 1 通过负控制大鼠脊髓背角 MEK/ERK 信号传导缓解炎症疼痛
DOI：
10.1523/jneurosci.2293-15.2015
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发表时间：
2015-10-14
影响因子：
5.3
通讯作者：
Yang, Xian
中科院分区：
文献类型：
--
作者：
Hu, Xiao-Dong;Liu, Yan-Ni;Yang, Xian
蛋白磷酸酶-1（PP 1）通过调节或靶向蛋白锚定在兴奋性突触上，控制突触后底物的磷酸化，调节神经传递和可塑性。在这里，我们发现，spinophilin，肌动蛋白结合蛋白的目标PP 1在突触后密度，作为细胞外信号调节激酶（ERK）信号成分的支架。通过C-末端PDZ结构域，spinophilin直接与ERK及其上游的丝裂原活化蛋白激酶激酶（MEK）相互作用。PP 1，由spinophilin招募，获得访问和去磷酸化这些激酶，发挥紧张性抑制ERK信号。通过干扰spinophilin/PP 1相互作用去除PP 1抑制允许在突触处限制MEK/ERK的激活，这反过来增强了由含有GluN 2B亚基的N-甲基-D-天冬氨酸亚型的谷氨酸受体特异性介导的突触传递。我们提供的证据表明，在疼痛相关的脊髓背角，spinophilin的支架功能在ERK依赖性和GluN 2B依赖性疼痛敏化的负调控中发挥了重要作用。表达野生型spinophilin对大鼠完全弗氏佐剂诱导的慢性炎性疼痛产生有效的镇痛作用。
Protein phosphatase-1 (PP1), anchored by regulatory or targeting proteins at excitatory glutamatergic synapses, controls the phosphorylation of postsynaptic substrates and regulates the neurotransmission and plasticity. Here, we found that spinophilin, an actin-binding protein that targets PP1 at postsynaptic density, served as a scaffold for extracellular signal-regulated kinase (ERK) signaling components. Through the C-terminal PDZ domain, spinophilin directly interacted with ERK and its upstream mitogen-activated protein kinase kinase (MEK). PP1, recruited by spinophilin, gained access to and dephosphorylated these kinases, exerting a tonic inhibition of ERK signaling. The removal of PP1 inhibition by disturbing spinophilin/PP1 interaction allowed a restricted activation of MEK/ERK at synapses, which in turn augmented the synaptic transmission specifically mediated by GluN2B subunit-containing N-methyl-D-aspartate subtype of glutamate receptors. We provided evidence that in pain-related spinal cord dorsal horn, the scaffolding function of spinophilin played an important role in the negative control of ERK-dependent and GluN2B-dependent pain sensitization. Expression of wild-type spinophilin produced an effective analgesic action against chronic inflammatory pain induced by complete Freund's adjuvant in rats.