A human glucagon-like peptide-1 receptor polymorphism results in reduced agonist responsiveness
A human glucagon-like peptide-1 receptor polymorphism results in reduced agonist responsiveness
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DOI：
10.1016/j.regpep.2005.05.001
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发表时间：
2005-08-15
影响因子：
--
通讯作者：
Kopin, AS
中科院分区：
文献类型：
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作者：
Beinborn, M;Worrall, CI;Kopin, AS
胰高血糖素样肽-1（GLP-1）及其受体在维持血糖稳态中起着重要的生理作用。GLP-1受体（GLP-1 R）多态性，其中苏氨酸149被甲硫氨酸残基取代，最近已在2型糖尿病患者中发现，但未在非糖尿病对照受试者中发现。我们在COS-7和HEK 293细胞中瞬时表达后，对重组GLP-1 R变体进行了功能评估。与野生型受体相比，变体GLP-1 R显示出（i）相似的表达水平，（ii）两种GLP-1 R完全激动剂GLP-1和毒蜥外泌肽-4的结合亲和力分别降低60倍和5倍，以及（iii）这些肽在触发cAMP介导的信号传导方面的效力显著降低（尽管效力保守）。与完全激动剂相比，主要GLP-1代谢产物/GLP-1 R部分激动剂GLP-1（9-36）酰胺的疗效基本上被T149 M取代所消除。通过亲水性分析，多态性定位于跨膜结构域1，表明该受体片段作为激动剂亲和力/功效的新决定因素。这些结果表明，GLP-1 R在人群中的天然序列变异性可导致实质性功能丧失。T149 M变异与2型糖尿病易感性增加之间的遗传联系仍有待建立。(c)2005 Elsevier B. V.保留所有权利。
Glucagon-like peptide-1 (GLP-1) and its cognate receptor play an important physiological rote in maintaining blood glucose homeostasis. A GLP-1 receptor (GLP-1R) polymorphism in which threonine 149 is substituted with a methionine residue has been recently identified in a patient with type 2 diabetes but was not found in non-diabetic control subjects. We have functionally assessed the recombinant GLP-1R variant after transient expression in COS-7 and HEK 293 cells. Compared to the wild type receptor, the variant GLP-1R showed (i) similar expression levels, (ii) 60-and 5-fold reduced binding affinities, respectively, for two GLP-1R full agonists, GLP-1 and exendin-4, and (iii) markedly decreased potencies of these peptides in triggering cAMP-mediated signaling (despite conserved efficacies). In contrast to full agonists, the efficacy of the primary GLP-1 metabolite/GLP-1R partial agonist, GLP-1 (9-36) amide, was essentially abolished by the T149M substitution. By hydropathy analysis, the polymorphism localizes to transmembrane domain 1, suggesting this receptor segment as a novel determinant of agonist affinity/efficacy. These findings reveal that naturally occurring sequence variability of the GLP-1R within the human population can result in substantial loss-of-function. A genetic link between the T149M variant and increased susceptibility to type 2 diabetes remains to be established. (c) 2005 Elsevier B.V. All rights reserved.