Identification of the regulating molecules for the melanin-concentrating hormone receptor 1 that is specifically involved in feeding and depression.

黑色素浓缩激素受体1 （melanin - concentrated hormone receptor 1, MCHR1）是一种在中枢神经系统中高度表达的G蛋白偶联受体（GPCR）。对基因工程动物和选择性拮抗剂的广泛研究表明，MCHR1在包括能量稳态和情绪处理在内的许多生理功能的调节中发挥重要作用。通过分析大鼠MCHR1的一系列位点突变对受体构象变化的影响，我们发现MCHR1的i2环上的DRY和8螺旋上的Phe318是受体动态的结构关键位点。我们进一步确定了三种RGS蛋白通过gtpase激活方式负向调节mchr1介导的信号传导。这些结果将有助于更好地理解MCHR1激活的复杂机制。

Melanin-concentrating hormone receptor 1 (MCHR1) is a G protein-coupled receptor (GPCR) that is highly expressed in the central nervous system. Extensive studies of genetically engineered animals and selective antagonists showed an important role of MCHR1 in the regulation of many physiological functions including energy homeostasis and emotional processing. By analyzing the effect of a series of site-directed mutations of rat MCHR1 on receptor conformational changes, we found that DRY in i2 loop and Phe318 in helix 8 of MCHR1 are the structurally critical site for receptor dynamics. We further identified three RGS proteins that negatively modulated MCHR1-mediated signaling by acting as GTPase-activating manner. These results will help to better understand the complex mechanism for MCHR1 activation.