title: GluA1 phosphorylation contributes to postsynaptic amplification of neuropathic pain in the insular cortex.
abstract: 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.
authors.affiliation: Department of Neurobiology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University School of Medicine, Hangzhou 310058, China, Center for Neuron and Disease, Frontier Institutes of Life Science and of Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China, Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada, M5S 1A8, and.
authors.forename: Shuang
authors.initials: S
authors.lastname: Qiu
authors.affiliation: Center for Neuron and Disease, Frontier Institutes of Life Science and of Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China, Institute of Neurosciences, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Institute of Neurosciences, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Center for Neuron and Disease, Frontier Institutes of Life Science and of Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Center for Neuron and Disease, Frontier Institutes of Life Science and of Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China, Institute of Neurosciences, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Center for Neuron and Disease, Frontier Institutes of Life Science and of Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Song
authors.affiliation: Center for Neuron and Disease, Frontier Institutes of Life Science and of Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China.
authors.forename: Minggao
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Department of Neuroscience and Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Huganir
authors.affiliation: Department of Neurobiology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Jianhong
authors.initials: J
authors.lastname: Luo
authors.affiliation: Center for Neuron and Disease, Frontier Institutes of Life Science and of Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China, Institute of Neurosciences, Fourth Military Medical University, Xi'an 710032, China, min.zhuo@utoronto.ca xubz@fmmu.edu.cn.
authors.forename: Hui
authors.initials: H
authors.lastname: Xu
authors.affiliation: Center for Neuron and Disease, Frontier Institutes of Life Science and of Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China, Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada, M5S 1A8, and min.zhuo@utoronto.ca xubz@fmmu.edu.cn.
authors.forename: Min
authors.initials: M
authors.lastname: Zhuo
mesh_terms: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009437:Neuralgia / Q000473:pathology* / Q000503:physiopathology; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D010852:Picrotoxin / Q000494:pharmacology; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D010852:Picrotoxin; D018091:Receptors, AMPA; D026941:Sodium Channel Blockers; D013779:Tetrodotoxin
keywords: GluA1; PKA; insular cortex; mouse; neuropathic pain; phosphorylation