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

ATP敏感性钾<ATP>通道广泛表达于神经元细胞膜上，将细胞代谢与兴奋性耦合起来。它们被认为在控制缺氧期间的癫痫发作活动以及在缺氧、缺血和兴奋性毒性期间通过超极化神经元和降低兴奋性对细胞损伤的神经保护中起重要作用。已知腺苷<ATP>通过降低这些通道对ATP阻断的敏感性来增加心脏表面K_2的开放。我们研究了类似的调制是否在神经元通道中起作用。用大鼠中脑脑片全细胞电压钳技术记录黑质背侧部（substantianigraparsacrutta，SNc）主要神经元的膜电流和电导，当移液器溶液中含有1 mMATP，外液中含有25 mM葡萄糖时，膜电流在-60mV，细胞电导至少在15 min内保持稳定。用腺苷A1受体激动剂（-）-N^6-2-苯基异丙基腺苷（R-PIA）处理脑片，在相同条件下，15 ~ 20 min内缓慢产生幅度为109.9±26.6pA的外向电流，电导增加到基线的229±50%。200μM甲苯磺丁脲可强烈抑制上述变化，提示钾通道开放<ATP>介导了上述变化。预处理8-环戊基茶碱（CPT），一种选择性的A1腺苷受体拮抗剂，取消外向电流和电导的增加。结果提示，激活A1腺苷受体可<ATP>通过解除ATP的阻断而促进SNc主要神经元K通道的开放。

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.