G-protein-independent coupling of MC4R to Kir7.1 in hypothalamic neurons.
G-protein-independent coupling of MC4R to Kir7.1 in hypothalamic neurons.
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DOI：
10.1038/nature14051
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发表时间：
2015-04-02
期刊：
影响因子：
64.8
通讯作者：
Cone RD
中科院分区：
文献类型：
--
作者：
Ghamari-Langroudi M;Digby GJ;Sebag JA;Millhauser GL;Palomino R;Matthews R;Gillyard T;Panaro BL;Tough IR;Cox HM;Denton JS;Cone RD
下丘脑弓状神经细胞分泌的厌食性α-MSH和嗜食性刺激性相关蛋白在调节能量平衡中起着重要作用。这两种多肽都与黑素皮质素-4受体高度结合，现有数据表明α-msh是一种激动剂，将该受体偶联到G-αS信号通路上，而银杏叶提取物竞争性地结合以阻断α-msh的结合，并阻断该受体类似配体的氨基末端结构域所介导的构造活性。在这里，我们证明了α-MSH和AgRP对下丘脑室旁核神经元放电活动的调节不依赖于G-αS信号，而是通过配体诱导的偶联到关闭内向整流钾通道Kir7.1来实现的。此外，AgRP是一种偏向激动剂，通过与MC4R结合和开放Kir7.1来超极化神经元，而不依赖于它对α-MSH结合的抑制。因此，Kir7.1信号似乎是黑素皮质素介导的下丘脑室旁核内能量平衡调节的中心。MC4R与Kir7.1的偶联可能解释了黑素皮质素信号控制能量稳态的不寻常方面，包括MC4R的基因剂量效应，以及AgRP对食物摄入量的持续影响。
The regulated release of anorexigenic α-MSH and orexigenic Agouti-related protein (AgRP) from discrete hypothalamic arcuate neurons onto common target sites in the CNS plays a fundamental role in the regulation of energy homeostasis. Both peptides bind with high affinity to the melanocortin-4 receptor (MC4R); existing data showα-MSH is an agonist that couples the receptor to the Gαs signaling pathway, while AgRP binds competitively to block α-MSH binding, and block the constitutive activity mediated by the ligand-mimetic amino terminal domain of the receptor. Here, we show that regulation of firing activity of hypothalamic PVN neurons by α-MSH and AgRP can be mediated independently of Gαs signaling by ligand-induced coupling of MC4R to closure of inwardly rectifying potassium channel, Kir7.1. Further, AgRP is a biased agonist that hyperpolarizes neurons by binding to MC4R and opening Kir7.1, independently of its inhibition of α-MSH binding. Consequently, Kir7.1 signaling appears central to melanocortin-mediated regulation of energy homeostasis within the PVN. Coupling of MC4R to Kir7.1 may explain unusual aspects of the control of energy homeostasis by melanocortin signaling, including the gene dosage effect of MC4R, and the sustained effects of AgRP on food intake.
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影响因子：
4.3
作者：
Hida T;Wakamatsu K;Sviderskaya EV;Donkin AJ;Montoliu L;Lynn Lamoreux M;Yu B;Millhauser GL;Ito S;Barsh GS;Jimbow K;Bennett DC
通讯作者：
Bennett DC
影响因子：
5.5
作者：
Smith, Mark A.;Hisadome, Kazunari;Ashford, Michael L. J.
通讯作者：
Ashford, Michael L. J.
DOI：
10.1073/pnas.1016785108
发表时间：
2011-01-04
影响因子：
11.1
作者：
Ghamari-Langroudi, Masoud;Srisai, Dollada;Cone, Roger D.
通讯作者：
Cone, Roger D.
影响因子：
2.5
作者：
KIMMEL, CB;BALLARD, WW;SCHILLING, TF
通讯作者：
SCHILLING, TF
影响因子：
4.8
作者：
Doronin, SV;Potapova, IA;Cohen, IS
通讯作者：
Cohen, IS