Persistent Inflammation-induced Up-regulation of Brain-derived Neurotrophic Factor (BDNF) Promotes Synaptic Delivery of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Receptor GluA1 Subunits in Descending Pain Modulatory Circuits*
Persistent Inflammation-induced Up-regulation of Brain-derived Neurotrophic Factor (BDNF) Promotes Synaptic Delivery of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Receptor GluA1 Subunits in Descending Pain Modulatory Circuits*
复制标题
DOI：
10.1074/jbc.m114.580381
复制
发表时间：
2014-06
期刊：
影响因子：
--
通讯作者：
Wenjuan Tao;Quan Chen;Wenjie Zhou;Yunping Wang;Lu Wang;Zhi Zhang
中科院分区：
文献类型：
--
作者：
Wenjuan Tao;Quan Chen;Wenjie Zhou;Yunping Wang;Lu Wang;Zhi Zhang
背景：在疼痛条件下，ampa型谷氨酸受体介导的突触传递在下行疼痛调节回路中增强。结果：持续炎症对BDNF的表观遗传调控可触发AMPA受体GluA1磷酸化。结论：疼痛条件下脑干GluA1的突触传递是由BDNF/TrKB激活启动的。意义：我们研究GluA1如何传递到突触，以了解下行疼痛调节回路中疼痛的分子机制。中枢疼痛调节系统中GluA1丝氨酸831位点AMPA受体磷酸化增强在炎症后疼痛促进下降中起关键作用，但其潜在机制尚不清楚。我们在此发现，在大鼠脑干中，在脑下行疼痛调节系统的关键中继中条大核中，由完全弗氏佐剂（CFA）诱导的持续性炎症性疼痛可以增强AMPA受体介导的兴奋性突触后电流和缺乏glua2的AMPA受体介导的纠正指数。Western blot分析显示Ser-831位点的GluA1磷酸化增加，而Ser-845位点没有。这伴随着突触GluA1亚基分布的增加。与此同时，在注射CFA后3天，bdnf基因启动子区域的组蛋白H3乙酰化水平显著降低，这是由ChIP检测显示的。这与BDNF mRNA水平和BDNF蛋白水平的增加有关。用TrkB-IgG在中缝大核中隔离内源性细胞外BDNF，在注射CFA后3天，AMPA受体介导的突触传递和Ser-831的GluA1磷酸化减少。在相同的条件下，阻断TrkB受体功能、磷脂酶C或PKC会破坏GluA1 Ser-831位点的磷酸化，并减少由缺乏glua2的AMPA受体介导的兴奋性突触后电流。综上所述，这些结果表明外周炎症对BDNF的表观遗传上调通过激活磷脂酶C-PKC信号级联诱导Ser-831位点的GluR1磷酸化，导致GluA1转运到疼痛调节神经元突触。
Background: AMPA-type glutamate receptor-mediated synaptic transmission is enhanced in descending pain modulatory circuits under pain conditions. Results: Epigenetic regulation of BDNF by persistent inflammation triggers AMPA receptor GluA1 phosphorylation. Conclusion: Synaptic delivery of GluA1 in the brain stem is initiated by BDNF/TrKB activation under pain conditions. Significance: We investigate how GluA1 is delivered to synapses to understand the molecular mechanisms underlying pain in descending pain modulatory circuits. The enhanced AMPA receptor phosphorylation at GluA1 serine 831 sites in the central pain-modulating system plays a pivotal role in descending pain facilitation after inflammation, but the underlying mechanisms remain unclear. We show here that, in the rat brain stem, in the nucleus raphe magnus, which is a critical relay in the descending pain-modulating system of the brain, persistent inflammatory pain induced by complete Freund adjuvant (CFA) can enhance AMPA receptor-mediated excitatory postsynaptic currents and the GluA2-lacking AMPA receptor-mediated rectification index. Western blot analysis showed an increase in GluA1 phosphorylation at Ser-831 but not at Ser-845. This was accompanied by an increase in distribution of the synaptic GluA1 subunit. In parallel, the level of histone H3 acetylation at bdnf gene promoter regions was reduced significantly 3 days after CFA injection, as indicated by ChIP assays. This was correlated with an increase in BDNF mRNA levels and BDNF protein levels. Sequestering endogenous extracellular BDNF with TrkB-IgG in the nucleus raphe magnus decreased AMPA receptor-mediated synaptic transmission and GluA1 phosphorylation at Ser-831 3 days after CFA injection. Under the same conditions, blockade of TrkB receptor functions, phospholipase C, or PKC impaired GluA1 phosphorylation at Ser-831 and decreased excitatory postsynaptic currents mediated by GluA2-lacking AMPA receptors. Taken together, these results suggest that epigenetic up-regulation of BDNF by peripheral inflammation induces GluR1 phosphorylation at Ser-831 sites through activation of the phospholipase C-PKC signaling cascade, leading to the trafficking of GluA1 to pain-modulating neuronal synapses.