GluA1 Phosphorylation Contributes to Postsynaptic Amplification of Neuropathic Pain in the Insular Cortex
GluA1 Phosphorylation Contributes to Postsynaptic Amplification of Neuropathic Pain in the Insular Cortex
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GluA1 磷酸化有助于岛叶皮质神经病理性疼痛的突触后放大
DOI：
10.1523/jneurosci.1431-14.2014
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发表时间：
2014-10-01
影响因子：
5.3
通讯作者：
Zhuo, Min
中科院分区：
文献类型：
--
作者：
Qiu, Shuang;Zhang, Ming;Zhuo, Min
在生理学习或病理损伤后，在不同的脑区，包括脊髓、海马、杏仁核和皮质中观察到了海马能传递的长时程增强。岛叶皮层是在厌恶性学习和神经病理性疼痛中起重要作用的关键皮层区域。然而，很少有人知道是否兴奋性传递在岛皮质发生塑性变化后，周围神经损伤。在这里，我们发现，周围神经结扎引发的增强AMPA受体（AMPAR）介导的兴奋性突触传递的岛叶皮层。神经结扎后，AMPAR的突触GluA 1亚基增加，但GluA 2/3亚基没有增加。基因敲入小鼠缺乏Ser 845位点的磷酸化，但不是Ser 831位点的磷酸化，阻断了突触GluA 1亚基的增强，这表明蛋白激酶A（PKA）在Ser 845位点的GluA 1磷酸化对于神经损伤后的这种上调是至关重要的。此外，神经损伤后，A-激酶锚定蛋白79/150（AKAP 79/150）和PKA易位到突触。腺苷酸环化酶亚型1（AC 1）的基因缺失阻止了AKAP 79/150和PKA的易位，以及含突触GluA 1的AMPAR的上调。药理学抑制岛叶皮层中的钙渗透性AMPAR功能可减少神经损伤引起的行为敏感化。我们的研究结果表明，AMPAR的表达增强神经损伤后的岛叶皮层的通路涉及AC 1，AKAP 79/150，PKA，这种增强可能至少部分有助于行为敏化与其他皮质区域，如前扣带回和前额叶皮质。
Long-term potentiation of glutamatergic transmission has been observed after physiological learning or pathological injuries in different brain regions, including the spinal cord, hippocampus, amygdala, and cortices. The insular cortex is a key cortical region that plays important roles in aversive learning and neuropathic pain. However, little is known about whether excitatory transmission in the insular cortex undergoes plastic changes after peripheral nerve injury. Here, we found that peripheral nerve ligation triggered the enhancement of AMPA receptor (AMPAR)-mediated excitatory synaptic transmission in the insular cortex. The synaptic GluA1 subunit of AMPAR, but not the GluA2/3 subunit, was increased after nerve ligation. Genetic knock-in mice lacking phosphorylation of the Ser845 site, but not that of the Ser831 site, blocked the enhancement of the synaptic GluA1 subunit, indicating that GluA1 phosphorylation at the Ser845 site by protein kinase A (PKA) was critical for this upregulation after nerve injury. Furthermore, A-kinase anchoring protein 79/150 (AKAP79/150) and PKA were translocated to the synapses after nerve injury. Genetic deletion of adenylyl cyclase subtype 1 (AC1) prevented the translocation of AKAP79/150 and PKA, as well as the upregulation of synaptic GluA1-containing AMPARs. Pharmacological inhibition of calcium-permeable AMPAR function in the insular cortex reduced behavioral sensitization caused by nerve injury. Our results suggest that the expression of AMPARs is enhanced in the insular cortex after nerve injury by a pathway involving AC1, AKAP79/150, and PKA, and such enhancement may at least in part contribute to behavioral sensitization together with other cortical regions, such as the anterior cingulate and the prefrontal cortices.