ORIGINAL RESEARCH article

Front. Endocrinol.

Sec. Experimental Endocrinology

Volume 16 - 2025 | doi: 10.3389/fendo.2025.1593345

This article is part of the Research TopicFunction of hormones, their receptors and binding proteinsView all 4 articles

Pharmacological modulation of MRAP2 protein on murine melatonin receptor signaling

Provisionally accepted
Wenqi SongWenqi Song1Yanchuan LiYanchuan Li2Hongtao XuHongtao Xu3Yaqun ZhangYaqun Zhang4Liu LiuLiu Liu5Yihao LiYihao Li2Xinran WangXinran Wang6Yueming DuYueming Du7Jianjun LyuJianjun Lyu2*Lingjing JinLingjing Jin8*Chao ZhangChao Zhang3*Yuchen XiaoYuchen Xiao9*
  • 1Fundamental Research Center, Shanghai YangZhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), School of Life Sciences and Technology, Tongji University, Shanghai, China
  • 2Hubei Topgene Research Institute of Hubei Topgene Biotechnology Group Co., Ltd., East Lake High-Tech Development Zone, Wuhan 430205, P. R. China, Hubei, China
  • 3Department of Orthopedics and Precision Research Center for Refractory Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 200080, P.R.China, Shanghai, China
  • 4Department of Neuroscience, School of Basic Medical Science, Soochow University, Jiangsu Province, 215000, P.R.China, Jiangsu, China
  • 5Shanghai Yuhui Pharmaceutical Technology (Group) Co., Ltd., Shanghai 201203, P.R.China, Shanghai, China
  • 6The Hong Kong University of Science and Technology (HKUST), 6269#, Floor 6, Hong Kong Kowloon Clear Water Bay HKUST, Hong Kong, HongKong, China
  • 7Beijing No. 8 High School, Beijing, China
  • 8Fundamental Research Center, Shanghai Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), School of Medicine, Tongji University, Shanghai, 201619, P. R. China, Shanghai, China
  • 9Fundamental Research Center, Shanghai Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), School of Medicine, Tongji University, Tongji University, Shanghai, China

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MTNR1A and MTNR1B, crucial for regulating circadian rhythms and various physiological processes, have well-established biological significance. This study examines the role of MRAP2, a single transmembrane accessory protein, in modulating the pharmacological activity of melatonin receptors. We first examined the evolutionary profiles of melatonin receptors and MRAP2 by protein sequence alignment and synteny analysis. Bulk RNA-seq was then employed to analyze the expression distribution of these genes. Next, we performed co-immunoprecipitation and Bimolecular Fluorescence Complementation (BiFC) assays to investigate the interaction of MRAP2 with melatonin receptors. We also recruited the GloSensor luminescence assay to assess the impact of MRAP2 on the Gi signaling pathway of melatonin receptors, and conducted fixed-cell ELISA to evaluate MRAP2's effect on melatonin receptor membrane trafficking. Our results revealed that MTNR1A was most conserved in terms of evolution, while all of these genes showed adaptive changes in amphibians and zebrafish likely due to aquatic environment. MRAP2 was found to inhibit the constitutive activity of melatonin receptors and enhance their maximal agonist potency. Additionally, MRAP2 suppressed the membrane trafficking of MTNR1A, but promoted the surface trafficking of MTNR1B. Overall, these findings highlighted the complex regulatory role of MRAP2, and shed light on its diverse functions in GPCR biology and its potential implications in regulating physiological processes governed by melatonin signaling.

Keywords: MTNR1A, MTNR1B, MRAP2, Melatonin, Metabolism

Received: 13 Mar 2025; Accepted: 01 May 2025.

Copyright: © 2025 Song, Li, Xu, Zhang, Liu, Li, Wang, Du, Lyu, Jin, Zhang and Xiao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Jianjun Lyu, Hubei Topgene Research Institute of Hubei Topgene Biotechnology Group Co., Ltd., East Lake High-Tech Development Zone, Wuhan 430205, P. R. China, Hubei, China
Lingjing Jin, Fundamental Research Center, Shanghai Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), School of Medicine, Tongji University, Shanghai, 201619, P. R. China, Shanghai, China
Chao Zhang, Department of Orthopedics and Precision Research Center for Refractory Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 200080, P.R.China, Shanghai, China
Yuchen Xiao, Fundamental Research Center, Shanghai Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), School of Medicine, Tongji University, Tongji University, Shanghai, China

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