ZD0947, a novel and potent ATP-sensitive K+ channel opener, on smooth muscle-type ATP-sensitive K+ channels.
ZD0947, a novel and potent ATP-sensitive K+ channel opener, on smooth muscle-type ATP-sensitive K+ channels.
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ZD0947 是一种新型有效的 ATP 敏感 K 通道开放剂，作用于平滑肌型 ATP 敏感 K 通道。
DOI：
10.1016/j.ejphar.2016.09.038
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发表时间：
2016
影响因子：
5
通讯作者：
Teramoto N
中科院分区：
文献类型：
--
作者：
Mori K;Yamashita Y;Teramoto N
用细胞贴壁记录技术研究了新型ATP敏感性钾通道(KATP通道)开放剂ZD0947对重组KATP通道活动的影响。通过内向整流-6家族K+通道亚基(Kir6.x：Kir6.1和Kir6.2)与3种不同类型的磺脲受体(SUR.x：SUR1，SUR2A和SUR2B)的共表达，研究KATP通道在HEK 293细胞中的作用。ZD0947(100µM)以浓度依赖的方式激活SUR2B/Kir6.2通道，但仅引起HEK 293细胞表达的SUR1/Kir6.2通道和SUR2A/Kir6.2通道的微弱激活。ZD0947可逆地抑制二氮嗪引起的SUR1/Kir6.2通道活动和匹那地尔引起的SUR2A/Kir6.2通道活动。然而，ZD0947不影响100nM吡那地尔完全激活的SUR2B/Kir6.2通道。ZD0947对HEK293细胞表达的Kir6.2ΔC26通道(Kir6.2的截短亚型)或其突变通道(Kir6.2ΔC26C166A)的活性几乎没有抑制作用。ZD0947还可诱导HEK 293细胞表达的SUR2B/Kir6.1通道的活性，且呈浓度依赖性。因此，ZD0947是一种相对有效的SUR2B/Kir6.1和SUR2B/Kir6.2的平滑肌型KATP通道激动剂，但对胰腺型KATP通道(即SUR1/Kir6.2)和心脏型KATP通道(即SUR2A/Kir6.2)有部分拮抗作用。这些结果表明，根据SUR.x亚型的不同，药物对KATP通道的活性既有激动剂作用，也有拮抗剂作用。
The effects of ZD0947, a novel ATP-sensitive K+channel (KATPchannel) opener, on the activity of reconstituted KATPchannels were investigated using cell-attached recordings. KATPchannels were studied in HEK 293 cells by co-expression of inwardly rectifying-6 family K+channel subunits (Kir6.x: Kir6.1 and Kir6.2) with 3 different types of sulphonylurea receptors (SUR.x: SUR1, SUR2A and SUR2B). ZD0947 (100 µM) activated SUR2B/Kir6.2 channels in a concentration-dependent manner, but caused only weak activation of SUR1/Kir6.2 channels and SUR2A/Kir6.2 channels expressed in HEK 293 cells. ZD0947 reversibly suppressed diazoxide-elicited SUR1/Kir6.2 channels activity and pinacidil-elicited SUR2A/Kir6.2 channel activity. However, ZD0947 did not affect SUR2B/Kir6.2 channels fully activated by 100 µM pinacidil. ZD0947 had little inhibitory effects on the activity of Kir6.2ΔC26 channels (a truncated isoform of Kir6.2) or its mutant channels (i.e. Kir6.2ΔC26C166A) expressed in HEK 293 cells. ZD0947 also elicited activity in SUR2B/Kir6.1 channels expressed in HEK 293 cells, in a concentration-dependent manner. Therefore, ZD0947 is a relatively effective activator of smooth muscle-type KATPchannels (SUR2B/Kir6.1 and SUR2B/Kir6.2) but is a partial antagonist of pancreatic-type KATPchannels (i.e. SUR1/Kir6.2) and cardiac-type KATPchannels (i.e. SUR2A/Kir6.2). These results suggest that a pharmacological agent can possess either agonist or antagonist actions on the activity of KATPchannels, depending on the subtype of SUR.x.