Jingliang Zhang1, Chenyu Zhang2, Xiaoling Chen1, Bingwei Wang2, Weining Ma3, Yang Yang4, Ruimao Zheng5,6,7,8, Zhuo Huang9,10,11. 1. State Key Laboratory of Natural and Biomimetic Drugs, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, China. 2. Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China. 3. Department of Neurology, Shengjing Hospital Affiliated to China Medical University, Shenyang, China. 4. Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University College of Pharmacy, West Lafayette, IN, USA. 5. Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China. rmzheng@pku.edu.cn. 6. Neuroscience Research Institute, Peking University, Beijing, China. rmzheng@pku.edu.cn. 7. Key Laboratory for Neuroscience, Ministry of Education, Beijing, China. rmzheng@pku.edu.cn. 8. Key Laboratory for Neuroscience of National Health Commission, Beijing, China. rmzheng@pku.edu.cn. 9. State Key Laboratory of Natural and Biomimetic Drugs, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, China. huangz@hsc.pku.edu.cn. 10. Key Laboratory for Neuroscience, Ministry of Education, Beijing, China. huangz@hsc.pku.edu.cn. 11. Key Laboratory for Neuroscience of National Health Commission, Beijing, China. huangz@hsc.pku.edu.cn.
Abstract
Temporal lobe epilepsy (TLE) is one of the most common and intractable neurological disorders in adults. Dysfunctional PKA signaling is causally linked to the TLE. However, the mechanism underlying PKA involves in epileptogenesis is still poorly understood. In the present study, we found the autophosphorylation level at serine 114 site (serine 112 site in mice) of PKA-RIIβ subunit was robustly decreased in the epileptic foci obtained from both surgical specimens of TLE patients and seizure model mice. The p-RIIβ level was negatively correlated with the activities of PKA. Notably, by using a P-site mutant that cannot be autophosphorylated and thus results in the released catalytic subunit to exert persistent phosphorylation, an increase in PKA activities through transduction with AAV-RIIβ-S112A in hippocampal DG granule cells decreased mIPSC frequency but not mEPSC, enhanced neuronal intrinsic excitability and seizure susceptibility. In contrast, a reduction of PKA activities by RIIβ knockout led to an increased mIPSC frequency, a reduction in neuronal excitability, and mice less prone to experimental seizure onset. Collectively, our data demonstrated that the autophosphorylation of RIIβ subunit plays a critical role in controlling neuronal and network excitabilities by regulating the activities of PKA, providing a potential therapeutic target for TLE.
Temporal lobe epilepsy (pan class="Disease">TLE) is one of the most common and intractable neurological disorders in adults. Dysfunctional PKA signaling is causally linked to the TLE. However, the mechanism underlying PKA involves in epileptogenesis is still poorly understood. In the present study, we found the autophosphorylation level at serine 114 site (serine 112 site in mice) of PKA-RIIβ subunit was robustly decreased in the epileptic foci obtained from both surgical specimens of TLEpatients and seizure model mice. The p-RIIβ level was negatively correlated with the activities of PKA. Notably, by using a P-site mutant that cannot be autophosphorylated and thus results in the released catalytic subunit to exert persistent phosphorylation, an increase in PKA activities through transduction with AAV-RIIβ-S112A in hippocampal DG granule cells decreased mIPSC frequency but not mEPSC, enhanced neuronal intrinsic excitability and seizure susceptibility. In contrast, a reduction of PKA activities by RIIβ knockout led to an increased mIPSC frequency, a reduction in neuronal excitability, and mice less prone to experimental seizure onset. Collectively, our data demonstrated that the autophosphorylation of RIIβ subunit plays a critical role in controlling neuronal and network excitabilities by regulating the activities of PKA, providing a potential therapeutic target for TLE.
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