A mutation in the TMD0-L0 region of sulfonylurea receptor-1 (L225P) causes permanent neonatal diabetes mellitus (PNDM)
A mutation in the TMD0-L0 region of sulfonylurea receptor-1 (L225P) causes permanent neonatal diabetes mellitus (PNDM)
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DOI：
10.2337/db06-1746
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发表时间：
2007-05-01
期刊：
影响因子：
7.7
通讯作者：
Nichols, Colin G.
中科院分区：
文献类型：
--
作者：
Masia, Ricard;De Leon, Diva D.;Nichols, Colin G.
目的：我们试图研究一名磺脲受体（SUR）1 LO区杂合新生L225P突变患者永久性新生儿糖尿病（PNDM）的分子机制，SUR 1是胰腺atp敏感K+通道（K- atp通道）的调节亚基。研究设计和方法-通过膜片钳实验和完整细胞的宏观rb通量实验，评估L225P对转染COS细胞中重组KAT通道特性的影响。结果：完整细胞中含有l225p的KAT通道明显比野生型通道更活跃。在切除的膜斑块中，L225P增加了通道对刺激性Mg核苷酸的敏感性，而不改变内在门控或在没有Mg2+的情况下ATP对通道的抑制。在核苷酸结合折叠处阻止核苷酸水解的SUR1突变消除了L225P的影响。L225P没有改变磺脲类药物对通道的抑制作用，与此一致的是，患者对口服磺脲类药物治疗有反应。结论：L225P通过特异性地增加通道的mg -核苷酸刺激，从而导致K-ATP通道过度活跃和PNDM，这与最近报道的SUR1中机制相似的PNDM引起突变一致。突变不影响磺脲类药物的敏感性，患者可以成功地用磺脲类药物治疗。
OBJECTIVE - We sought to examine the molecular mechanisms underlying permanenent neonatal diabetes mellitus (PNDM) in a patient with a heterozygous de novo L225P mutation in the LO region of the sulfonylurea receptor (SUR)1, the regulatory subunit of the pancreatic ATP-sensitive K+ channel (K-ATP channel).RESEARCH DESIGN AND METHODS - The effects of L225P on the properties of recombinant KAT, channels in transfected COS cells were assessed by patch-clamp experiments on excised membrane patches and by macroscopic Rb-flux experiments in intact cells.RESULTS - L225P-containing KAT, channels were significantly more active in the intact cell than in wild-type channels. In excised membrane patches, L225P increased channel sensitivity to stimulatory Mg nucleotides without altering intrinsic gating or channel inhibition by ATP in the absence of Mg2+. The effects of L225P were abolished by SUR1 mutations that prevent nucleotide hydrolysis at the nucleotide binding folds. L225P did not alter channel inhibition by sulfonylurea drugs, and, consistent with this, the patient responded to treatment with oral sulfonylureas.CONCLUSIONS - L225P underlies K-ATP channel overactivity and PNDM by specifically increasing Mg-nucleotide stimulation of the channel, consistent with recent reports of mechanistically similar PNDM-causing mutations in SUR1. The mutation does not affect sulfonylurea sensitivity, and the patient is successfully treated with sulfonylureas.