PKA Ca 基因DNA去甲基化调控岛叶AMPA受体GluA1亚单位磷酸化参与疼痛慢性化的机制研究

The insular cortex plays an important role in the generation, analysis and integration of pain sensation. Our preliminary data showed that the excitatory synaptic transmission mediated by AMPA receptors was increased and the expression of synaptic GluA1 subunit of AMPA receptors was upregulated in the insular cortex in the persistent chronic pain. It is inicated that the enhanced excitatory synaptic transmission in the insular cortex may play a key role in the persistence of chronic pain, but its upstream regulatory mechanisms are still unknown. Taken together with our data that the promoter regions of candidate genes, such as PKA catalytic subunit alpha subunit, were hypomethylated in the insular cortex during the persistence of chronic pain. It is speculated that the enhanced excitatory synaptic transmission and membrane trafficking of GluA1 subunits may be modulated by the DNA demethylation of candidate genes, for example, PKA catalytic subunit alpha gene, in the insular cortex in the chronicity of pain. In the ligation of the common peroneal nerve of mice, with the combination of electrophysiological, molecular biological and behavioral methods, the plastic changes of the excitatory synaptic transmission and synaptic plasticity will be further investigated in the insular cortex in the chronicity of pain. The modulatory mechanism of the phosphorylation of AMPA receptor GluA1 subunit through the DNA demethylation of PKA catalytic subunit alpha gene may be explored. The new role and modulatory mechanisms of the enhanced excitatory synaptic transmission will be elucidated in the insular cortex in the chronicity of pain. The proposed study may lay an important theoretical and experimental basis for illuminating cortical mechanisms of the chronicity of pain.

岛叶在痛觉信息产生、分析和整合中发挥重要作用。课题组前期预实验发现慢性痛维持过程中岛叶AMPA 受体介导的兴奋性突触传递增强，突触部位膜上AMPA受体GluA1亚单位表达增加。提示岛叶兴奋性突触传递增强在慢性痛维持过程中发挥重要作用，但其调控机制不明。结合课题组预实验结果，在慢性痛维持阶段，筛选到岛叶差异低甲基化表达候选基因PKA Ca等。我们推测PKA Ca等基因DNA去甲基化调控AMPA受体GluA1亚单位磷酸化水平，促进岛叶兴奋性突触传递和GluA1亚单位膜转运，参与疼痛慢性化。本项目拟通过腓总神经结扎小鼠模型，结合电生理学、分子生物学和行为学等手段深入研究在疼痛慢性化中岛叶兴奋性突触传递和突触可塑性的改变，揭示调控GluA1亚单位磷酸化水平的PKA Ca等基因DNA去甲基化机制，发现岛叶兴奋性突触传递增强在疼痛慢性化中新作用和新调控机制，为阐明疼痛慢性化的皮层机制提供重要理论和实验依据。

岛叶在痛觉信息产生、分析和整合中发挥重要作用。课题组前期预实验发现慢性痛维持过程中岛叶AMPA 受体介导的兴奋性突触传递增强，突触部位膜上AMPA受体GluA1亚单位表达增加。提示岛叶兴奋性突触传递增强在慢性痛维持过程中发挥重要作用，但其调控机制不明。结合课题组预实验结果，在慢性痛维持阶段，筛选到岛叶差异低甲基化表达候选基因PKA Ca。我们推测PKA Ca基因DNA去甲基化调控AMPA受体GluA1亚单位磷酸化水平，促进岛叶兴奋性突触传递和GluA1亚单位膜转运，参与疼痛慢性化。本项目通过腓总神经结扎小鼠模型，结合电生理学、分子生物学和行为学等手段深入研究在疼痛慢性化中岛叶兴奋性突触传递和突触可塑性的改变，研究主要发现在疼痛慢性化中岛叶兴奋性和抑制性突触传递发生可塑性变化，AMPA受体GluA1亚单位磷酸化的调节机制。揭示调控GluA1亚单位磷酸化水平的信号分子机制，发现岛叶兴奋性突触传递增强在疼痛慢性化中新作用和新调控机制，为阐明疼痛慢性化的皮层机制提供重要理论和实验依据。..揭示调控GluA1亚单位磷酸化水平的PKA Ca基因DNA去甲基化机制，发现岛叶兴奋性突触传递增强在疼痛慢性化中新作用和新调控机制，为阐明疼痛慢性化的皮层机制提供重要理论和实验依据。