哈尔滨工业大学何元政等研究人员合作完成油酸作为GPR3内源配体的鉴定。这一研究成果于2024年1月29日在线发表在国际学术期刊《细胞研究》上。

研究人员结合结构方法（包括冷冻电镜）、质谱分析和功能研究，确定油酸（OA）是GPR3的内源配体。这项研究揭示了GPR3内的疏水通道，该通道将受体的细胞外侧与质膜中间连接起来，使脂肪酸能够轻易地与受体接合。功能研究表明，OA会触发下游G_s信号，而溶血磷脂则无法激活受体。此外，研究人员还发现，寒冷刺激会诱导小鼠分泌OA，进而激活棕色脂肪组织中的G_s/cAMP/PKA 信号。

值得注意的是，Gpr3基因敲除小鼠的棕色脂肪组织在冷刺激过程中对OA没有反应，这进一步证实了GPR3在这一过程中的重要性。最后，研究人员提出了一个“天生激活，寒冷增强”的GPR3激活模型。这项研究为了解冷刺激产热过程中的GPR3信号提供了一个起始框架。

据悉，尽管GPR3在神经系统和新陈代谢过程（如冷诱导产热）中发挥着关键作用，但其内源性配体仍然难以捉摸。

附：英文原文

Title: Identification of oleic acid as an endogenous ligand of GPR3 Corrections

Author: Xiong, Yangjie, Xu, Zhenmei, Li, Xinzhi, Wang, Yuqin, Zhao, Jing, Wang, Na, Duan, Yaning, Xia, Ruixue, Han, Zhengbin, Qian, Yu, Liang, Jiale, Zhang, Anqi, Guo, Changyou, Inoue, Asuka, Xia, Yu, Chen, Zheng, He, Yuanzheng

Issue&Volume: 2024-01-29

Abstract: Although GPR3 plays pivotal roles in both the nervous system and metabolic processes, such as cold-induced thermogenesis, its endogenous ligand remains elusive. Here, by combining structural approach (including cryo-electron microscopy), mass spectrometry analysis, and functional studies, we identify oleic acid (OA) as an endogenous ligand of GPR3. Our study reveals a hydrophobic tunnel within GPR3 that connects the extracellular side of the receptor to the middle of plasma membrane, enabling fatty acids to readily engage the receptor. Functional studies demonstrate that OA triggers downstream Gs signaling, whereas lysophospholipids fail to activate the receptor. Moreover, our research reveals that cold stimulation induces the secretion of OA in mice, subsequently activating Gs/cAMP/PKA signaling in brown adipose tissue. Notably, brown adipose tissues from Gpr3 knockout mice do not respond to OA during cold stimulation, reinforcing the significance of GPR3 in this process. Finally, we propose a “born to be activated and cold to enhance” model for GPR3 activation. Our study provides a starting framework for the understanding of GPR3 signaling in cold-stimulated thermogenesis.

DOI: 10.1038/s41422-024-00932-5

Source: https://www.nature.com/articles/s41422-024-00932-5