Coassembly of different sulfonylurea receptor subtypes extends the phenotypic diversity of ATP-sensitive potassium (KATP) channels.
Coassembly of different sulfonylurea receptor subtypes extends the phenotypic diversity of ATP-sensitive potassium (KATP) channels.
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不同磺酰脲受体亚型的结合延长了ATP敏感钾（KATP）通道的表型多样性。
DOI：
10.1124/mol.108.048355
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发表时间：
2008-11
影响因子：
3.6
通讯作者：
Chan, Kim W.
中科院分区：
文献类型：
--
作者：
Wheeler, Adam;Wang, Chuan;Yang, Ke;Fang, Kun;Davis, Kevin;Styer, Amanda M.;Mirshahi, Uyenlinh;Moreau, Christophe;Revilloud, Jean;Vivaudou, Michel;Liu, Shunhe;Mirshahi, Tooraj;Chan, Kim W.
KATP通道是钾通道开放剂（KCO;例如二氮嗪和吡那地尔）的代谢传感器和靶标。它们包括四个磺酰脲受体（SUR）和四个钾通道亚基（Kir 6），在调节胰岛素分泌中至关重要。不同的SUR亚型（SUR 1、SUR 2A、SUR 2B）在很大程度上决定了KATP通道的代谢敏感性和药理学特征。含SUR 1通道对代谢抑制和二氮嗪高度敏感，而含SUR 2通道对吡那地尔敏感。一般认为，SUR 1和SUR 2在通道共组装中是不相容的。我们使用三重串联T1和T2，每个串联包含一个SUR（SUR 1或SUR 2A）和两个Kir6.2Δ26（最后26个残基缺失），以检查不同SUR的共组装。当T1或T2在非洲爪蟾卵母细胞中表达时，小的全细胞电流被代谢抑制（由叠氮化物诱导）加上KCO（T1为二氮嗪，T2为吡那地尔）激活。当与任何SUR亚型共表达时，激活电流增加2至13倍，表明不同的SUR可以共组装。与此一致，异聚体SUR 1 + SUR 2A通道对叠氮化物、二氮嗪、吡那地尔敏感，其单通道爆发持续时间是T1通道的2倍。此外，SUR 2A与SUR 1共沉淀。使用全细胞记录和免疫染色，也可以检测到异聚体通道时，T1和SUR 2A在哺乳动物细胞中共表达。最后，SUR 1 + SUR 2A通道对叠氮化物的响应被发现是同聚体通道的中间体。因此，不同的SUR亚型可以共组装成具有不同代谢敏感性和药理学特征的KATP通道。
KATP channels are metabolic sensors and targets of potassium channel openers (KCO; e.g. diazoxide and pinacidil). They comprise four sulfonylurea receptors (SUR) and four potassium channel subunits (Kir6) and are critical in regulating insulin secretion. Different SUR subtypes (SUR1, SUR2A, SUR2B) largely determine the metabolic sensitivities and the pharmacologoical profiles of KATP channels. SUR1-but not SUR2-containing channels are highly sensitive to metabolic inhibition and diazoxide while SUR2-channels are sensitive to pinacidil. It is generally believed that SUR1 and SUR2 are incompatible in channel coassembly. We used triple tandems, T1 and T2, each containing one SUR (SUR1 or SUR2A) and two Kir6.2Δ26 (last 26 residues are deleted) to examine the coassembly of different SUR. When T1 or T2 was expressed in Xenopus oocytes, small whole-cell currents were activated by metabolic inhibition (induced by azide) plus a KCO (diazoxide for T1, pinacidil for T2). When coexpressed with any SUR subtype, the activated-currents were increased 2 to 13-fold, indicating that different SUR can coassemble. Consistent with this, heteromeric SUR1+SUR2A channels were sensitive to azide, diazoxide, pinacidil and their single-channel burst duration was 2-fold longer than that of the T1 channels. Furthermore, SUR2A was coprecipitated with SUR1. Using whole-cell recording and immunostaining, heteromeric channels could also be detected when T1 and SUR2A were coexpressed in mammalian cells. Finally, the response of the SUR1+SUR2A channels to azide was found to be intermediate to those of the homomeric channels. Therefore, different SUR subtypes can coassemble into KATP channels with distinct metabolic sensitivities and pharmacological profiles.
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影响因子：
20.1
作者：
Baron, A;van Bever, L;Baertschi, AJ
通讯作者：
Baertschi, AJ
影响因子：
4.8
作者：
Giblin, JP;Cui, Y;Tinker, A
通讯作者：
Tinker, A
影响因子：
7.3
作者：
Shindo, T;Yamada, M;Kurachi, Y
通讯作者：
Kurachi, Y
影响因子：
4.8
作者：
Babenko, AP;Bryan, J
通讯作者：
Bryan, J
影响因子：
4.8
作者：
Babenko, AP;Bryan, J
通讯作者：
Bryan, J