Involvement of Kir6.2-composing ATP-sensitive potassium channels in phencyclidine-induced negative symptoms of schizophrenia / Kir6.2构成的ATP敏感性钾通道在苯环己哌啶诱导的精神分裂症阴性症状中的作用

神经药理学报 ›› 2011, Vol. 1 ›› Issue (1): 31-38.

Involvement of Kir6.2-composing ATP-sensitive potassium channels in phencyclidine-induced negative symptoms of schizophrenia / Kir6.2构成的ATP敏感性钾通道在苯环己哌啶诱导的精神分裂症阴性症状中的作用

戴婷，陈中国，段磊，丁建花，范益，胡刚^*

南京医科大学药理学系，江苏省神经退行性疾病重点实验室，南京，210029

出版日期:2011-02-26 发布日期:2011-10-20
通讯作者: 胡刚，男，教授，博士，博士生导师；研究方向：神经药理学
基金资助:
国家自然科学基金重点项目（No.81030060）

Involvement of Kir6.2-composing ATP-sensitive potassium channels in phencyclidine-induced negative symptoms of schizophrenia

DAI Ting,CHEN Zhong-Guo，DUAN Lei，DING Jian-Hua，FAN Yi，HU Gang^*

Jiangsu Key Laboratory of Neurodegeneration，Department of Pharmacology，Nanjing Medical University，Nanjing，Jiangsu 210029，P. R. China

Online:2011-02-26 Published:2011-10-20
Contact: 胡刚，男，教授，博士，博士生导师；研究方向：神经药理学

摘要/Abstract

摘要： 目的：ATP敏感性钾（K-ATP）通道对多巴胺和谷氨酸能传导具有重要的调节作用，而多巴胺和谷氨酸能传导之间相互作用是精神分裂症病理机制的重要神经化学基础。因此，我们应用Kir6.2（主要表达在神经元的K-ATP亚基）敲除小鼠，通过苯环己哌啶诱导强迫游泳不动时间的延长，模拟精神分裂症的阴性症状，从而研究K-ATP通道在其中的作用。 方法：连续注射14天苯环己哌啶（10 mg•kg-1，i.p.）后，通过观察强迫游泳实验中小鼠不动时间的长短，评价Kir6.2敲除对精神分裂症阴性症状中抑郁样表现的影响；应用高效液相色谱联合电化学检测法观察纹状体多巴胺及其代谢产物、多巴胺更新率的改变；应用溴脱氧尿嘧啶核苷插入法观察海马齿状回颗粒下区神经干细胞增殖的改变；应用Western blot技术观察磷酸化Akt水平的变化。 结果：Kir6.2敲除取消了苯环己哌啶引起的强迫游泳不动时间的延长。不仅如此，Kir6.2敲除还抑制了苯环己哌啶诱导的纹状体多巴胺更新率的增加、海马齿状回颗粒下区神经干细胞增殖的减弱，以及磷酸化Akt水平升高。 结论：Kir6.2组成的K-ATP通道参与了苯环己哌啶诱导的精神分裂症阴性症状，阻断K-ATP通道有望成为治疗精神分裂症的新策略。

关键词: ATP敏感性钾通道, 苯环己哌啶, 多巴胺, 神经再生, 精神分裂症

Abstract: Objective: ATP-sensitive potassium (K-ATP) channels are crucial for dopaminergic and glutamatergic transmission，which has been demonstrated to be the important feature of pathophysiology in schizophrenia. We studied the effects of K-ATP channels on the phencyclidine (PCP)-induced changes in the forced swimming test (FST，an animal model of negative symptoms of schizophrenia)，using mice with knockout of the Kir6.2 (a pore-forming subunit of neuronal K-ATP channel). Methods:After repeated PCP (10 mg·kg^-1，i.p. daily for 14 days) administration，The FST were used to assess depression-related behaviors associated with negative symptoms. Striatal dopamine and dopamine turnover were measured by high pressure liquid chromatography with electrochemical detection. Cell proliferation in the subgranular zone (SGZ) was determined by bromodeoxyuridine immunohistochemistry. The expressions of total Akt and phosphorylation Akt were evaluated using Western blot. Results: After repeated PCP administration，the enhancement of immobility induced by the FST was attenuated in Kir6.2 knockout mice. Meanwhile，Kir6.2 knockout decreased striatal dopamine turnover，whereas wild-type mice exhibited an augmentation in response to PCP treatment. Furthermore，Kir6.2 knockout could prevent the inhibition of neural stem cell proliferation in the SGZ and suppressed the PCP-induced phosphorylation of Akt^Ser473. Conclusion: These results suggest a possible implication of Kir6.2-composing K-ATP channels dysfunction in the pathogenesis of negative symptoms associated with schizophrenia.

中图分类号:

R332

戴婷, 陈中国, 段磊, 丁建花, 范益, 胡刚. Involvement of Kir6.2-composing ATP-sensitive potassium channels in phencyclidine-induced negative symptoms of schizophrenia / Kir6.2构成的ATP敏感性钾通道在苯环己哌啶诱导的精神分裂症阴性症状中的作用[J]. 神经药理学报, 2011, 1(1): 31-38.

DAI Ting, CHEN Zhong-Guo, DUAN Lei, DING Jian-Hua, FAN Yi, HU Gang. Involvement of Kir6.2-composing ATP-sensitive potassium channels in phencyclidine-induced negative symptoms of schizophrenia[J]. ACTA NEUROPHARMACOLOGICA, 2011, 1(1): 31-38.

参考文献

1 Alejandro Akrouh，Halcomb S. Eliza，Colin G. Nichols，et al. Molecular biology of K(ATP) channels and implications for health and disease[J]. IUBMB Life，2009，61(10): 971-978

2 Leonid V. Zingman，Denice M. Hodgson，Alexey E. Alekseev，et al. Stress without distress: homeostatic role for K(ATP) channels[J]. Mol Psychiatry，2003，8(3): 253-254

3 SUN Xiu-Lan and HU Gang. ATP-sensitive potassium channels: a promising target for protecting neurovascular unit function in stroke[J]. Clin Exp Pharmacol Physiol，2010，37(2): 243-252

4 Christine Karschinb，Claudia Eckea，Frances M. Ashcroftc，et al. Overlapping distribution of K(ATP) channel-forming Kir6.2 subunit and the sulfonylurea receptor SUR1 in rodent brain[J]. FEBS Lett，1997，401(1): 59-64

5 Marat V. Avshalumov and Margaret E. Rice. Activation of ATP-sensitive K+ (K(ATP)) channels by H2O2 underlies glutamate-dependent inhibition of striatal dopamine release[J]. Proc Natl Acad Sci U S A，2003，100(20): 11729-11734

6 Birgit Liss，Olga Haeckel，Johannes Wildmann，et al. K-ATP channels promote the differential degeneration of dopaminergic midbrain neurons[J]. Nat Neurosci，2005，8(12): 1742-1751

7 Mangala M. Soundarapandian，Xiaofen Zhong，Lisheng Peng，et al. Role of K(ATP) channels in protection against neuronal excitatory insults[J]. J Neurochem，2007，103(5): 1721-1729

8 Tost Heike and Meyer-Lindenberg Andreas. Dopamine-glutamate interactions: a neural convergence mechanism of common schizophrenia risk variants[J]. Biol Psychiatry，2011，69(10): 912-913

9 Joanna C. Neill, Samuel Barnes, Samantha Cook，et al. Animal models of cognitive dysfunction and negative symptoms of schizophrenia: focus on NMDA receptor antagonism[J]. Pharmacol Ther，2010，128(3): 419-432

10 Akihiro Mouri，Yukihiro Noda，Akeshi Enomoto，et al. Phencyclidine animal models of schizophrenia: approaches from abnormality of glutamatergic neurotransmission and neurodevelopment[J]. Neurochem Int，2007，51(2-4): 173-184

11 Takashi Miki，Kazuaki Nagashima，Fumi Tashiro，et al. Defective insulin secretion and enhanced insulin action in KATP channel-deficient mice[J]. Proc Natl Acad Sci U S A，1998，95(18): 10402-10406

12 Judith A Siuciak，Sheryl A McCarthy，Douglas S Chapin，et al. Behavioral and neurochemical characterization of mice deficient in the phosphodiesterase-1B (PDE1B) enzyme[J]. Neuropharmacology，2007，53(1): 113-124

13 FAN Yi，KONG Hui，SHI Xue-Ru，et al. Hypersensitivity of aquaporin 4-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine and astrocytic modulation[J]. Neurobiol Aging，2008，29(8): 1226-1236

14 KONG Hui，SHA Lu-Lu，FAN Yi，et al. Requirement of AQP4 for Antidepressive Efficiency of Fluoxetine: Implication in Adult Hippocampal Neurogenesis[J]. Neuropsychopharmacology，2009，34(5): 1263-1276

15 Jean-Martin Beaulieu，Raul R. Gainetdinov，and Marc G. Caron. Akt/GSK3 signaling in the action of psychotropic drugs[J]. Annu Rev Pharmacol Toxicol，2009，49: 327-347

16 Josiane Budni，Vinícius M. Gadotti，Manuella P. Kaster，et al. Role of different types of potassium channels in the antidepressant-like effect of agmatine in the mouse forced swimming test[J]. Eur J Pharmacol，2007，575(1-3): 87-93

17 Katsuya Yamada，Juan Juan Ji，Hongjie Yuan，et al. Protective role of ATP-sensitive potassium channels in hypoxia-induced generalized seizure[J]. Science，2001，292(5521): 1543-1546

18 SHI Xue-Ru，CHANG Jing，DING Jian-Hua，et al. Kir6.2 knockout alters neurotransmitter release in mouse striatum: An in vivo microdialysis study[J]. Neurosci Lett，2008，439(3): 230-234

19 Kenji Maeda，Haruhiko Sugino，Tsuyoshi Hirose，et al. Clozapine prevents a decrease in neurogenesis in mice repeatedly treated with phencyclidine[J]. J Pharmacol Sci，2007，103(3): 299-308

[1]	禹文峰，李成朋，韩飞，官志忠. 硫辛酸抑制AIF 介导的非Caspase 凋亡通路对多巴胺能神经元的保护机制[J]. 神经药理学报, 2018, 8(2): 40-40.
[2]	孙争宇，李林. 精神分裂症认知障碍研究进展*[J]. 神经药理学报, 2017, 7(3): 60-60.
[3]	钟佳宏，汪海涛，徐江平. α - 突触核蛋白与帕金森病[J]. 神经药理学报, 2017, 7(2): 62-62.
[4]	郑益新，徐杰. FK506 和 FK1706 在体外对免疫抑制和促进神经轴突再生作用影响的对比研究[J]. 神经药理学报, 2016, 6(4): 13-18.
[5]	魏孟琳，田莉，王小琴，邹玉安，薛茜. 大鼠脑缺血预处理对缺血再灌注神经功能的影响[J]. 神经药理学报, 2016, 6(2): 7-13.
[6]	蒋湘云，尚超，李雷，孙树峥，李云峰，王恒林. 四氢孕酮：抑郁和焦虑障碍治疗的潜在新靶点[J]. 神经药理学报, 2016, 6(2): 26-30.
[7]	孙炎，宋爱霞，薛茜，邹玉安. 康脑液对脑缺血再灌注大鼠神经再生相关因子的影响[J]. 神经药理学报, 2015, 5(5): 7-14.
[8]	何娜，殷明，王泽剑. 成年海马神经再生与阿尔茨海默病关系的研究进展[J]. 神经药理学报, 2013, 3(6): 25-32.
[9]	郭琳, 镇学初. 抗精神分裂症药物的新靶点和新机制 [J]. 神经药理学报, 2013, 3(5): 2-12.
[10]	金灿, 张丹参, 陈乃宏. 成年海马神经元再生与抑郁症的机制研究进展[J]. 神经药理学报, 2013, 3(2): 58-64.
[11]	郑立卿 . 作用于GABAA受体的药物与神经可塑性[J]. 神经药理学报, 2012, 2(6): 40-48.
[12]	李东薇，窦德强. 人参防治帕金森病的研究进展[J]. 神经药理学报, 2011, 1(4): 55-64.

Involvement of Kir6.2-composing ATP-sensitive potassium channels in phencyclidine-induced negative symptoms of schizophrenia / Kir6.2构成的ATP敏感性钾通道在苯环己哌啶诱导的精神分裂症阴性症状中的作用

Involvement of Kir6.2-composing ATP-sensitive potassium channels in phencyclidine-induced negative symptoms of schizophrenia

PDF (PC)

可视化

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 12

编辑推荐

Metrics