2. Academic Validation
  3. Identification of MRAP protein family as broad-spectrum GPCR modulators

Identification of MRAP protein family as broad-spectrum GPCR modulators

  • Clin Transl Med. 2022 Nov;12(11):e1091. doi: 10.1002/ctm2.1091.
Meng Wang 1,  Xiaozhu Wang 1,  Bopei Jiang 2,  Yue Zhai 2,  Jihong Zheng 2,  Liu Yang 3,  Xiaolu Tai 2,  Yunpeng Li 2,  Shaliu Fu 2,  Jing Xu 2,  Xiaowei Lei 2,  Zhe Kuang 2,  Cong Zhang 1,  Xuanxuan Bai 2,  Mingyu Li 4,  Tao Zan 1,  Shen Qu 3,  Qingfeng Li 1,  Chao Zhang 1
Affiliations

Affiliations

  • 1 Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2 School of Life Sciences and Technology, Tongji University, Shanghai, China.
  • 3 Department of Endocrinology and Metabolism, National Metabolic Management Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
  • 4 Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China.
PMID: 36314066 DOI: 10.1002/ctm2.1091
Abstract

Background: The Melanocortin Receptor accessory proteins (MRAP1 and MRAP2) are well-known endocrine regulators for the trafficking and signalling of all five melanocortin receptors (MC1R-MC5R). The observation of MRAP2 on regulating several non-melanocortin G protein-coupled receptors (GPCRs) has been sporadically reported, whereas other endogenous GPCR partners of the MRAP protein family are largely unknown.

Methods: Here, we performed single-cell transcriptome analysis and drew a fine GPCR blueprint and MRAPs-associated network of two major endocrine organs, the hypothalamus and adrenal gland at single-cell resolution. We also integrated multiple bulk RNA-seq profiles and single-cell datasets of human and mouse tissues, and narrowed down a list of 48 GPCRs with strong endogenous co-expression correlation with MRAPs.

Results: 36 and 46 metabolic-related GPCRs were consequently identified as novel interacting partners of MRAP1 or MRAP2, respectively. MRAPs exhibited protein-protein interactions and varying pharmacological properties on the surface translocation, constitutive activities and ligand-stimulated downstream signalling of these GPCRs. Knockdown of MRAP2 expression by hypothalamic administration of adeno-associated virus (AAV) packed shRNA stimulated body weight gain in mouse model. Co-injection of corticotropinreleasing factor (CRF), the agonist of corticotropin releasing hormone receptor 1 (CRHR1), suppressed feeding behaviour in a MRAP2-dependent manner.

Conclusions: Collectively, our study has comprehensively elucidated the complex GPCR networks in two major endocrine organs and redefined the MRAP protein family as broad-spectrum GPCR modulators. MRAP proteins not only serve as a vital endocrine pivot on the regulation of global GPCR activities in vivo that could explain the composite physiological phenotypes of the MRAP2 null murine model but also provide us with new insights of the phenotyping investigation of GPCR-MRAP functional complexes.

Keywords

GPCR; MRAP1; MRAP2; bulk RNA-seq; energy homeostasis; single-cell RNA-seq.

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