Melanocortin 4 Receptor Becomes an ACTH Receptor by Coexpression of Melanocortin Receptor Accessory Protein 2
Melanocortin 4 Receptor Becomes an ACTH Receptor by Coexpression of Melanocortin Receptor Accessory Protein 2
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DOI：
10.1210/me.2013-1099
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发表时间：
2013-11-01
影响因子：
--
通讯作者：
Miguel Cerda-Reverter, Jose
中科院分区：
文献类型：
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作者：
Josep Agulleiro, Maria;Cortes, Raul;Miguel Cerda-Reverter, Jose
黑素皮质素2受体（MC2R）是唯一的典型ACTH受体。它的功能性表达需要一种辅助蛋白的存在，称为黑皮质素受体2辅助蛋白1（MRAP 1）。脊椎动物的基因组中有一个名为MRAP 2的paradox基因，它在斑马鱼中是重复的（MRAP 2a和MRAP 2b），尽管它的功能尚不清楚。在本文中，我们证明，MRAP 2a使MC4R，一个典型的MSH受体，被激活的ACTH与MC2R表现出类似的敏感性。这两种蛋白质在物理上相互作用，并在视前区的神经元中共表达，视前区是控制鱼类能量平衡和垂体分泌的关键区域。ACTH注射抑制野生型斑马鱼的食物摄入，但对缺乏功能性MC4R的鱼类没有抑制作用。MRAP 1和MRAP 2a都是神经调控的，这表明这些蛋白质是黑皮质素信号传导的反馈调节途径的底物。禁食对MRAP 2a的中枢表达没有影响，但刺激MRAP 2b的表达。这种蛋白质相互作用，并与MC4R共定位在结节下丘脑神经元，但对MC4R的药理学特征没有影响。然而，MRPA2b能够降低表达MC4R的细胞系中的基础报告基因活性。MRAP 2b在禁食期间降低MC4R的组成性活性，驱使动物朝向正能量平衡是合理的。我们的数据表明，MRAP 2控制MC4R的活性，为调节黑皮质素信号传导开辟了新的途径，并进一步为调节能量平衡和肥胖开辟了新的途径。
Melanocortin 2 receptor (MC2R) is the only canonical ACTH receptor. Its functional expression requires the presence of an accessory protein, known as melanocortin receptor 2 accessory protein 1 (MRAP1). The vertebrate genome exhibits a paralogue gene called MRAP2, which is duplicated in zebrafish (MRAP2a and MRAP2b), although its function remains unknown. In this paper, we demonstrate that MRAP2a enables MC4R, a canonical MSH receptor, to be activated by ACTH with a similar sensitivity to that exhibited by MC2R. Both proteins physically interact and are coexpressed in the neurons of the preoptic area, a key region in the control of the energy balance and hypophyseal secretion in fish. ACTH injections inhibit food intake in wild-type zebrafish but not in fish lacking functional MC4R. Both MRAP1 and MRAP2a are hormonally regulated, suggesting that these proteins are substrates for feed-back regulatory pathways of melanocortin signaling. Fasting has no effect on the central expression of MRAP2a but stimulates MRAP2b expression. This protein interacts and is colocalized with MC4R in the tuberal hypothalamic neurons but has no effect on the pharmacologic profile of MC4R. However, MRPA2b is able to decrease basal reporter activity in cell lines expressing MC4R. It is plausible that MRAP2b decreases the constitutive activity of the MC4R during fasting periods, driving the animal toward a positive energy balance. Our data indicate that MRAP2s control the activity of MC4R, opening up new pathways for the regulation of melanocortin signaling and, by extension, for the regulation of the energy balance and obesity.