Phospholipase C-linked receptors regulate the ATP-sensitive potassium channel by means of phosphatidylinositol 4,5-bisphosphate metabolism

作     者：Xie, LH Horie, M Takano, M 

作者机构：Kyoto Univ Grad Sch Med Dept Physiol & Biophys Kyoto 6068501 Japan Kyoto Univ Grad Sch Med Dept Cardiovasc Med Kyoto 6068501 Japan 

出 版 物：《PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA》 (美国国家科学院汇刊)

年 卷 期：1999年第96卷第26期

页      面：15292-15297页

核心收录：

学科分类：07[理学] 08[工学] 

主　　题：1-(5-异喹啉磺酰基)-2-甲基哌嗪/药理学 乙酰胆碱/代谢 腺苷三磷酸/药理学 剂量效应关系 药物 导电性 雌烯类/药理学 鸟苷二磷酸/类似物和衍生物 鸟苷二磷酸/药理学 磷脂酰肌醇4 5-二磷酸/代谢 钾通道/代谢 钾通道 内向整流 蛋白激酶C/代谢 吡咯烷酮类/药理学 受体 毒蕈碱M1 受体 毒蕈碱/代谢 硫代核苷酸类/药理学 C型磷脂酶类/代谢 

摘      要：In the COS7 cells transfected with cDNAs of the Kir6.2, SUR2A, and M-1 muscarinic receptors, we activated the ATP-sensitive potassium (K-ATP) channel with a K+ channel opener and recorded the whole-cell KATP current. The KATP current was reversibly inhibited by the stimulation of the M-1 receptor, which is linked to phospholipase C (PLC) by the G(q) protein. The receptor-mediated inhibition was observed even when protein kinase C (PKC) was inhibited by H-7 or by chelating intracellular Ca2+ with 10 mM 1,2-bis(2-aminophenoxy)ethane-N,N,N ,N -tetraacetate (BAPTA) included in the pipette solution. However, the receptor-mediated inhibition was blocked by U-73122, a PLC inhibitor. M-1-receptor stimulation failed to inhibit the K-ATP current activated by the injection of exogenous phosphatidylinositol 4,5-bisphosphate (PIP2) through the whole-cell patch pipette. The receptor-mediated inhibition became irreversible when the replenishment of PIP2 was blocked by wortmannin (an inhibitor of phosphatidylinositol kinases), or by including adenosine 5 -[beta,gamma-imido]triphosphate (AMPPNP, a nonhydrolyzable ATP analogue) in the pipette solution. In inside-out patch experiments, the ATP sensitivity of the K-ATP channel was significantly higher when the M-1 receptor in the patch membrane was stimulated by acetylcholine. The stimulatory effect of pinacidil was also attenuated under this condition. We postulate that stimulation of PLC-linked receptors inhibited the K-ATP channel by increasing the ATP sensitivity, not through PKC activation, but most probably through changing PIP2 levels.