A conserved inhibitory and differential stimulatory action of nucleotides on KIR6.0/SUR complexes is essential for excitation-metabolism coupling by KATP channels
A conserved inhibitory and differential stimulatory action of nucleotides on KIR6.0/SUR complexes is essential for excitation-metabolism coupling by KATP channels
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DOI：
10.1074/jbc.m108763200
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发表时间：
2001-12-28
影响因子：
4.8
通讯作者：
Bryan, J
中科院分区：
文献类型：
--
作者：
Babenko, AP;Bryan, J
无处不在的腺嘌呤核苷酸门控K(IR)6.0(4)/SUR4通道将膜兴奋性与细胞代谢联系起来的机制存在争议。是否需要降低对抑制性ATP的敏感性，或者是否需要Mg-ADP/ATP依赖性的ATP酶，磺酰脲受体（SUR）对K-IR的刺激作用足以引起生理上显著的开放通道概率？为了评估核苷酸抑制与刺激的作用，我们比较了基于K(IR)6.1的K- ndp通道与基于K(IR)6.2的K- atp通道以及所有可能的K(IR)6.1/6.2杂种。虽然K-NDP通道被认为对抑制性ATP不敏感，并且需要mg -核苷酸二磷酸才能发挥活性，但我们证明，与K-ATP和杂交通道一样，它们的IC50（ATP）比[ATP]低100倍(i)。然而，K(IR)6.1比K(IR)6.2更有效地受到SUR的刺激，因此除了已知的mg -核苷酸与SUR同种异构体的差异相互作用外，还提供了一种差异核苷酸调节机制。天然细胞中鉴定的K-NDP、K-ATP和杂交通道的细胞内和自发活性是不同的；因此，它们相似的IC50（ATP）值表明，调节的“β”SUR亚基在耦合兴奋与代谢中起着卓越的作用，并对假设开放K(IR)s的ATP不敏感的模型的生理意义提出了质疑。
The mechanism by which ubiquitous adenine nucleotide-gated K(IR)6.0(4)/SUR4 channels link membrane excitability with cellular metabolism is controversial. Is a decreased sensitivity to inhibitory ATP required, or is the Mg-ADP/ATP-dependent stimulatory action of the ATPase, sulfonylurea receptor (SUR), on K-IR sufficient to elicit a physiologically significant open channel probability? To evaluate the roles of nucleotide inhibition versus stimulation, we compared K(IR)6.1-based K-NDP channels with K(IR)6.2-based K-ATP channels and all possible K(IR)6.1/6.2 hybrids. Although K-NDP channels are thought to be poorly sensitive to inhibitory ATP and to require Mg-nucleotide diphosphates for activity, we demonstrate that, like K-ATP, and hybrid channels, they are inhibited with an IC50(ATP) 100-fold lower than [ATP](i). K(IR)6.1 is, however, more efficiently stimulated by SUR than K(IR)6.2, thus providing a mechanism for differential nucleotide regulation, in addition to the known differential interactions of Mg-nucleotides with SUR isoforms. The on-cell and spontaneous activities of K-NDP, K-ATP, and hybrid channels identified in native cells, are different; thus, their similar IC50(ATP) values argue the regulatory "beta" SUR subunits play a preeminent role in coupling excitation to metabolism and pose questions about the physiologic significance of models, which assume the ATP insensitivity of open K(IR)s.