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Modulation of neuronal ATP-sensitive K channels by adenosine and PKC.

腺苷和 PKC 对神经元 ATP 敏感 K 通道的调节。

基本信息

批准号：
15591651
负责人：
ANDOH Tomio
金额：
$ 2.37万
依托单位：
University of Yamanashi (2005)Yokohama City University (2003-2004)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15591651/
关键词：
ATP sensitive K channel neuron substantia nigra adenosine ischemia-reperfusion mitochondria oxygen radical 黒質ドーパミンニューロン protein kinase C フラビン蛋白

项目摘要

ATP-sensitive K (K_<ATP>) channels are widely expressed in cytoplasmic membranes of neurons and couple cell metabolism to excitability. They are considered to play important roles in controlling seizure activity during hypoxia and in neuroprotection against cell damage during hypoxia, ischemia and excitotoxicity by hyperpolarizing neurons and reducing excitability. It is known that adenosine augments opening of cardiac surface K_<ATP> by reducing sensitivity of these channels to ATP blockade. We investigated if similar modulation works in neuronal channels. Whole cell voltage-clamp recordings were made using rat midbrain slices to record the membrane current and conductance in principal neurons of substantia nigra pars compacta (SNc).When a pipette solution contained 1mM ATP and an external solution contained 25mM glucose, the membrane current at -60mV and cellular conductance remained stable for at least 15min. When slices were treated with (-)-N^6-2-phenylisopropyl adenosine (R-PIA), a selective agonist for A1 adenosine receptors, the outward current with the amplitude of 109.9±26.6pA developed slowly for 15 to 20min in the same condition and conductance increased to 229±50% of the baseline. These changes were strongly inhibited by 200μM tolbutamide, suggesting that opening of K_<ATP> channels mediated these changes. Pretreatment with 8-cyclopentyltheophylline (CPT), a selective A1 adenosine receptor antagonist, abolished the outward current and conductance increases. These results suggest that activation of A1 adenosine receptor promotes opening of K_<ATP> channels in principal neurons of SNc by removing blockade with ATP.

ATP敏感性K(K&lt；ATP&gt；)通道广泛表达于神经元的细胞膜上，并将细胞代谢与兴奋性联系起来。它们被认为通过超极化神经元和降低兴奋性，在控制缺氧时的癫痫发作活动和在缺氧、缺血和兴奋毒性时保护细胞损伤方面发挥重要作用。已知腺苷通过降低这些通道对三磷酸腺苷阻滞剂的敏感性来增加心脏表面的开放。我们调查了类似的调制是否在神经元通道中起作用。用大鼠中脑脑片作全细胞电压钳记录，记录黑质致密部(SNC)主神经元的膜电流和电导。在含1 mM三磷酸腺苷的吸管溶液和含25 mM葡萄糖的外液中，膜电流和细胞电导在-60 mV保持稳定至少15分钟。用腺苷A1受体选择性激动剂(-)-N-6-2-苯基异丙基腺苷(R-PIA)处理脑片，在相同条件下，外向电流的幅度为109.9±26.6pA，15~20min缓慢发展，电导增加至基线的229±50%。这些变化可被200μ的M-甲苯丁胺强烈抑制，提示钾通道的开放介导了这些变化。腺苷A1受体选择性拮抗剂8-环戊基茶碱(CPT)可阻断外向电流和电导增加。上述结果提示，激活A1腺苷受体可通过解除ATP的阻断作用，促进黑质主神经元K_1通道的开放。