Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan.
Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan; Graduate School of Integrated Arts and Sciences, Hiroshima University, Hiroshima, 739-8521, Japan.
Biochem Biophys Res Commun. 2024 May 28;710:149917. doi: 10.1016/j.bbrc.2024.149917. Epub 2024 Apr 7.
Melanin-concentrating hormone (MCH) receptor 1 (MCHR1), a G protein-coupled receptor, is poised for interaction with its ligands on the plasma membrane. Analyses of MCHR1 knockout mice suggest that this receptor could be a therapeutic target for the treatment of appetite disorders, glucose metabolism, psychiatric disorders, and inflammation. Binding of MCH to MCHR1 initiates calcium signaling, which is subsequently attenuated through receptor internalization. However, the ultimate destiny of the receptor post-internalization remains unexplored. In this study, we report the extracellular secretion of MCHR1 via exosomes. The recruitment of MCHR1 to exosomes occurs subsequent to its internalization, which is induced by stimulation with the ligand MCH. Although a highly glycosylated form of MCHR1, potentially representing a mature form, is selectively recruited to exosomes, the MCHR1 transferred into other cells does not exhibit functionality. The truncation of MCHR1 at the C-terminus not only impairs its response to MCH but also hinders its recruitment to exosomes. These findings imply that functional MCHR1 could be secreted extracellularly via exosomes, a process that may represent a mechanism for the termination of intracellular MCHR1 signaling.
黑皮质素浓缩激素 (MCH) 受体 1 (MCHR1) 是一种 G 蛋白偶联受体，它在细胞膜上与配体结合。对 MCHR1 敲除小鼠的分析表明，该受体可能是治疗食欲紊乱、葡萄糖代谢、精神疾病和炎症的靶点。MCH 与 MCHR1 的结合启动了钙信号转导，随后通过受体内化而减弱。然而，内化后受体的最终命运仍未被探索。在这项研究中，我们报告了 MCHR1 通过外泌体的细胞外分泌。MCHR1 被募集到外泌体中，这发生在其被配体 MCH 诱导内化之后。尽管 MCHR1 的一种高度糖基化形式（可能代表成熟形式）被选择性地募集到外泌体中，但转移到其他细胞中的 MCHR1 没有功能。MCHR1 在 C 末端的截断不仅损害了它对 MCH 的反应，也阻碍了它被募集到外泌体中。这些发现表明，功能性 MCHR1 可以通过外泌体被分泌到细胞外，这一过程可能代表了细胞内 MCHR1 信号终止的一种机制。
