Molecular biology of adenosine triphosphate-sensitive potassium channels.
Molecular biology of adenosine triphosphate-sensitive potassium channels.
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DOI：
10.1210/edrv.20.2.0361
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发表时间：
1999-04
影响因子：
20.3
通讯作者：
L. Aguilar-Bryan;J. Bryan
中科院分区：
文献类型：
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作者：
L. Aguilar-Bryan;J. Bryan
KATP通道是基于ABC蛋白、磺酰脲受体和K+内向整流亚基的物理关联而新定义的一类钾通道。β细胞KATP通道由具有多个TMDs和两个NBFs的高亲和磺酰脲受体SUR1和弱内向整流器KIR6.2组成，其化学计量比例为1:1。通道孔由KIR6.2以四聚体排列形成；活性通道的总化学计量为（SUR1/KIR6.2）4。这两个亚单位形成了一个紧密结合的整体。KIR6.2可以在质膜中通过删除其c末端的内质网保留信号或通过高水平表达来压倒保留机制来表达。同质KIR6.2通道的单通道电导与SUR/KIR6.2通道相当，但它们在所有其他方面都不同，包括破裂行为、药理学性质、对ATP和ADP的敏感性以及向质膜的运输。与SUR的共表达式恢复正常的通道属性。研究发现，隐性形式的婴儿期持续性高胰岛素性低血糖症（PHHI）是由KATP通道亚基突变引起的，导致通道活性丧失，这一发现强调了KATP通道在葡萄糖代谢变化时调节胰岛素分泌中的关键作用。KATP通道设置β细胞的静息膜电位，它们的丢失导致结构性去极化，允许电压门控Ca2+通道自发打开，增加细胞质Ca2+水平，足以触发胰岛素的持续释放。实际上，KATP通道的丧失使β细胞的电活动与它们的代谢活动分离。PHHI突变对SUR1的功能和腺嘌呤核苷酸对KATP通道的调节提供了信息。结果表明，SUR1除了作为药物传感器外，在感知核苷酸变化方面也很重要，这表明它与其他ABC蛋白的序列相似。一个意想不到的发现是ATP的抑制作用似乎是通过位于KIR6.2上的一个位点，其对ATP的亲和力被SUR1修饰。在SUR1的第二个NBF中，PHHI突变G1479R形成活跃的KATP通道，对ATP有正常反应，但不能被MgADP激活。结果表明ATP强直性抑制KATP通道，但禁食β细胞中的ADP水平拮抗这种抑制作用。葡萄糖代谢过程中ADP水平降低导致KATP通道关闭。虽然KATP通道是用于治疗NIDDM的磺脲类药物的靶标，但现有数据表明，已确定的KATP通道突变在糖尿病中并不起主要作用。另一方面，了解KATP通道如何适应葡萄糖稳态的整体方案，有望深入了解糖尿病和其他葡萄糖代谢紊乱，同时了解这些通道的结构和调节为开发调节细胞电活动的新化合物提供了潜力。
KATP channels are a newly defined class of potassium channels based on the physical association of an ABC protein, the sulfonylurea receptor, and a K+ inward rectifier subunit. The beta-cell KATP channel is composed of SUR1, the high-affinity sulfonylurea receptor with multiple TMDs and two NBFs, and KIR6.2, a weak inward rectifier, in a 1:1 stoichiometry. The pore of the channel is formed by KIR6.2 in a tetrameric arrangement; the overall stoichiometry of active channels is (SUR1/KIR6.2)4. The two subunits form a tightly integrated whole. KIR6.2 can be expressed in the plasma membrane either by deletion of an ER retention signal at its C-terminal end or by high-level expression to overwhelm the retention mechanism. The single-channel conductance of the homomeric KIR6.2 channels is equivalent to SUR/KIR6.2 channels, but they differ in all other respects, including bursting behavior, pharmacological properties, sensitivity to ATP and ADP, and trafficking to the plasma membrane. Coexpression with SUR restores the normal channel properties. The key role KATP channel play in the regulation of insulin secretion in response to changes in glucose metabolism is underscored by the finding that a recessive form of persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is caused by mutations in KATP channel subunits that result in the loss of channel activity. KATP channels set the resting membrane potential of beta-cells, and their loss results in a constitutive depolarization that allows voltage-gated Ca2+ channels to open spontaneously, increasing the cytosolic Ca2+ levels enough to trigger continuous release of insulin. The loss of KATP channels, in effect, uncouples the electrical activity of beta-cells from their metabolic activity. PHHI mutations have been informative on the function of SUR1 and regulation of KATP channels by adenine nucleotides. The results indicate that SUR1 is important in sensing nucleotide changes, as implied by its sequence similarity to other ABC proteins, in addition to being the drug sensor. An unexpected finding is that the inhibitory action of ATP appears to be through a site located on KIR6.2, whose affinity for ATP is modified by SUR1. A PHHI mutation, G1479R, in the second NBF of SUR1 forms active KATP channels that respond normally to ATP, but fail to activate with MgADP. The result implies that ATP tonically inhibits KATP channels, but that the ADP level in a fasting beta-cell antagonizes this inhibition. Decreases in the ADP level as glucose is metabolized result in KATP channel closure. Although KATP channels are the target for sulfonylureas used in the treatment of NIDDM, the available data suggest that the identified KATP channel mutations do not play a major role in diabetes. Understanding how KATP channels fit into the overall scheme of glucose homeostasis, on the other hand, promises insight into diabetes and other disorders of glucose metabolism, while understanding the structure and regulation of these channels offers potential for development of novel compounds to regulate cellular electrical activity.