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离子通道生物学功能与作用机制 -- 以酸敏感离子通道为例

离子通道生物学功能与作用机制 -- 以酸敏感离子通道为例. 徐天乐 2011.9. 上海交通大学 基础医学院. The brain is the body’s most complex organ. 《Times》2010. -10 12 neuronal cells and 10 15 synapses-. New Clues About What Makes the Human Brain Special Researchers who've examined preserved samples of cerebral cortex from humans and

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离子通道生物学功能与作用机制 -- 以酸敏感离子通道为例

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  1. 离子通道生物学功能与作用机制 -- 以酸敏感离子通道为例 徐天乐2011.9 上海交通大学 基础医学院

  2. The brain is the body’s most complex organ 《Times》2010

  3. -1012 neuronal cells and 1015 synapses-

  4. New Clues About What Makes the Human Brain SpecialResearchers who've examined preserved samples of cerebral cortex from humans and several species of ape report that in a particular region of the prefrontal cortex, neurons have more space between them in the human brain than in the brains of apes, allowing more room for connections between neurons.

  5. Neural connectivity and plasticity Anan Li et al, Science, 2010

  6. Neurons transmit electric and chemical signals http://www.bris.ac.uk/synaptic/basics/

  7. Linking Ab, Tau pathology to network dysfunction From 《Times》2010

  8. Ion channels are signaling proteins

  9. 离子通道研究历史性的贡献 －－ 获得三次诺贝尔奖 ③ 2003 ② 1991 ① 1963 • ①动作电位的离子机制－神经信号的物质基础 • ② 发明膜片钳技术－从单通道记录到突触传递 • ③ 晶体结构解析－从可视化到蛋白质动态行为

  10. 离子通道与神经科学 • 膜兴奋性 • 突触传递 • 思维记忆 • 感觉运动 • 疾病靶点 • 药理靶点

  11. 离子通道与药物安全 心脏 精子 • CatSper channel • hERG channel

  12. 离子通道多样性 ASIC NMDAR GABA(A)R/GlyR (+) (-) P2X AMPAR nAChR

  13. Acid-sensing ion channel: An ideal model Structure Dynamics Conductance pH 6.3 2 nA 10 s 1980’s- 1990’s 2007/9 2009 Nature papers, from E. Gouaux group PLoS Biology, from H. Jiang & T.L. Xu groups. Many papers, from O. Krishtal group (DRG) N. Akaike group (Central). 1997 Gene cloning: A Nature paper from M. Lazdunski group

  14. 1. J Biol Chem, 2004 2. Neuron, 2005 3. J Neurosci, 2007 与疾病的关系 What we have accomplished… 4. PLoS Biol, 2009 5. Cell Res, 2009 6. Neuron, 2010 7. J Neurosci, 2011 发现新配体, 揭示新机制 同源建模 分子对接 定点突变 功能分析 功能研究 药物发现 非质子配体结构域的分子构造 8. J Biol Chem, 2011 9. J Biol Chem, 2011 非质子门控 新机制 小分子配体类似物 合成与初步筛选 发现生理性 天然配体

  15. Ion channel research: paradigm shift 生物物理/药理 生理学/行为学 行为药理 疾病机理 结构与功能 遗传/化学 (化学生物学) 结构/计算 (蛋白质科学) 新药先导 化合物

  16. Strategies for ion channel research Translational research Basic research • Drug discovery • Chemical physiology • Genetic physiology • Structural physiology • Structure-function • Behavioral physiology • Cell physiology • Channelopathy • Chronic pain • Stroke and AD • Schizophrenia • Anxiety and depression • Cell injury and repair • Non-neuronal tissues

  17. 研究内容之一 • Pathophysilogical roles of endogenous activation of ASICs • Mechanisms underlying endogenous activation of ASICs • Implications in therapeutic intervention

  18. 离子通道与神经环路 (Nature, 465: 26, 2010)

  19. 神经环路：兴奋 vs抑制？

  20. 研究内容之二 • GABAergic and glycinergic neural circuits • Inhibition, network oscillations and cognition • Disinhibition in neuropsychiatric disorders • GABA(A)R and GlyR drug development

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