Characterization of ciliary targeting sequence of rat melanin-concentrating hormone receptor 1
Characterization of ciliary targeting sequence of rat melanin-concentrating hormone receptor 1
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DOI：
10.1016/j.ygcen.2013.02.020
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发表时间：
2013-07-01
影响因子：
2.7
通讯作者：
Saito, Yumiko
中科院分区：
文献类型：
--
作者：
Nagata, Asami;Hamamoto, Akie;Saito, Yumiko
黑色素浓集激素（MCH）是MCHR 1和MCHR 2的天然肽配体，MCHR 1和MCHR 2属于G蛋白偶联受体（GPCR）超家族。MCH-MCHR 1系统参与啮齿动物的摄食、能量稳态和情绪处理的调节。最近，在小鼠中枢神经系统的神经元不动初级纤毛中发现了MCHR 1的表达。纤毛在许多类型的细胞中具有重要的化学感受功能，并且纤毛功能障碍与诸如多囊肾病、视网膜营养不良和肥胖症的纤毛病相关。睫状膜蛋白的靶向序列被认为是独特的。虽然这些序列已被预测在细胞质的第三环和/或GPCR的C-末端，鲜为人知的是MCHR 1的特性。因此，我们通过瞬时表达一系列MCHR 1突变体到纤毛hRPE 1细胞中，并评估这些突变对异源受体纤毛定位的影响，探索了MCHR 1靶向的分子机制。这种方法表明，在第三胞内环内的丙氨酸到甘氨酸突变（A242 G）诱导受体的纤毛定位显着减少，而不影响纤毛发生。相反，没有C-末端截断突变体有任何影响纤毛定位或纤毛长度。这项研究提供了一个潜在的纤毛缺陷和临床表现，如肥胖之间的分子联系。(C)2013 Elsevier Inc. All rights reserved.
Melanin-concentrating hormone (MCH) is the natural peptide ligand for MCHR1 and MCHR2, which belong to the G protein-coupled receptor (GPCR) superfamily. The MCH-MCHR1 system is involved in the regulation of feeding, energy homeostasis and emotional processing in rodents. Recently, MCHR1 expression was discovered in neuronal immotile primary cilia of the central nervous system in mice. The cilium has an important chemosensory function in many types of cell and ciliary dysfunction is associated with cliopathies such as polycystic kidney disease, retinal dystrophy, and obesity. The targeting sequence of ciliary membrane proteins is thought to be unique. Although these sequences have been predicted in the cytoplasmic third loop and/or C-terminus of GPCRs, little is known about the characteristics of MCHR1. We thus explored the molecular mechanisms of MCHR1 targeting by transiently expressing a series of MCHR1 mutants into ciliated hRPE1 cells and evaluated the effects of these mutations on the ciliary localization of the heterologous receptor. This approach demonstrated that an Ala-to-Gly mutation (A242G) within the third intracellular loop induced a significant reduction in ciliary localization of the receptor without affecting the ciliogenesis. In contrast, no C-terminal truncation mutant had any effect on ciliary localization or cilia length. This study provides a potential molecular link between defective cilia and clinical manifestations such as obesity. (C) 2013 Elsevier Inc. All rights reserved.