Agouti-related protein segments outside of the receptor binding core are required for enhanced short- and long-term feeding stimulation.
Agouti-related protein segments outside of the receptor binding core are required for enhanced short- and long-term feeding stimulation.
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DOI：
10.1021/cb2003412
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发表时间：
2012-02-17
影响因子：
4
通讯作者：
Millhauser, Glenn L.
中科院分区：
文献类型：
--
作者：
Madonna, Michael E.;Schurdak, Jennifer;Yang, Ying-kui;Benoit, Stephen;Millhauser, Glenn L.
agouti相关蛋白（AgRP）通过减少下丘脑黑素皮质素受体（mcr） 3和4的信号传导，在能量平衡中发挥核心作用，从而刺激摄食和减少能量消耗。成熟的AgRP（83-132）是由蛋白内分解过程产生的，它包含一个中心区域，作为抑制剂胱氨酸结（ICK）折叠，由二硫键网络稳定；该结构域具有高亲和力McR结合和逆激动作用的分子特征。ICK结构域外有两个多肽片段，一个n端延伸和一个c端环，它们都是完全保守的，但功能未知。在这里，我们通过开发一组改良的agrp，通过脑室内注射给大鼠，研究了这些非ick片段的生理作用。对食物消耗的分析表明，碱性（带正电的）残留物对于有效的短期和长期AgRP刺激喂养是必不可少的。此外，我们证明了蛋白质电荷密度与24小时食物摄入量之间的近似线性关系。接下来，我们开发了正电荷增加的人工AgRP（83-132）类似物，发现这些物种的效力比野生型强得多。单剂量的一种名为AgRP- 4k的蛋白质，可以在一周多的时间内增强喂养，体重增加几乎是AgRP的两倍（83-132）。这些研究提出了开发强致氧物种的新策略，并可能为开发治疗诸如恶病质等消耗疾病的治疗方法提供线索。
The Agouti-Related Protein (AgRP) plays a central role in energy balance by reducing signaling through the hypothalamic melanocortin receptors (McRs) 3 and 4, in turn stimulating feeding and decreasing energy expenditure. Mature AgRP(83-132), produced by endoproteolytic processing, contains a central region that folds as an inhibitor cystine knot (ICK) stabilized by a network of disulfide bonds; this domain alone carries the molecular features for high affinity McR binding and inverse agonism. Outside of the ICK domain are two polypeptide segments – an N-terminal extension and a C-terminal loop – both completely conserved but of unknown function. Here we examine the physiological roles of these non-ICK segments by developing a panel of modified AgRPs that were administered to rats through intracerebroventricular (ICV) injection. Analysis of food consumption demonstrates that basic (positively charged) residues are essential for potent short and long term AgRP stimulated feeding. Moreover, we demonstrate an approximate linear relationship between protein charge density and 24 hr food intake. Next, we developed artificial AgRP(83-132) analogs with increased positive charge and found that these species were substantially more potent than wild type. A single dose of one protein, designated AgRP-4K, results in enhanced feeding for well over a week and weight gain that is nearly double that of AgRP(83-132). These studies suggest new strategies for the development of potent orexigenic species, and may serve as leads for the development of therapeutics for treating wasting conditions such as cachexia.
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影响因子：
--
作者：
Jackson, Pilgrim J.;Douglas, Nick R.;Millhauser, Glenn L.
通讯作者：
Millhauser, Glenn L.
DOI：
10.1152/ajpregu.2000.279.1.r47
发表时间：
2000-07-01
影响因子：
2.8
作者：
Hagan, MM;Rushing, PA;Seeley, RJ
通讯作者：
Seeley, RJ
影响因子：
30.8
作者：
He, L;Gunn, TM;Barsh, GS
通讯作者：
Barsh, GS
DOI：
10.1111/j.1749-6632.2003.tb03163.x
发表时间：
2003-01-01
期刊：
MELANOCORTIN SYSTEM
影响因子：
--
作者：
Reizes, O;Benoit, SC;Seeley, RJ
通讯作者：
Seeley, RJ
影响因子：
5.6
作者：
Patel MP;Cribb Fabersunne CS;Yang YK;Kaelin CB;Barsh GS;Millhauser GL
通讯作者：
Millhauser GL