{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T19:23:14Z","timestamp":1775589794755,"version":"3.50.1"},"reference-count":57,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2022,10,31]],"date-time":"2022-10-31T00:00:00Z","timestamp":1667174400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp; Translational Med"],"published-print":{"date-parts":[[2022,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>The melanocortin receptor accessory proteins (MRAP1 and MRAP2) are well\u2010known endocrine regulators for the trafficking and signalling of all five melanocortin receptors (MC1R\u2013MC5R). The observation of MRAP2 on regulating several non\u2010melanocortin G protein\u2010coupled receptors (GPCRs) has been sporadically reported, whereas other endogenous GPCR partners of the MRAP protein family are largely unknown.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Here, we performed single\u2010cell transcriptome analysis and drew a fine GPCR blueprint and MRAPs\u2010associated network of two major endocrine organs, the hypothalamus and adrenal gland at single\u2010cell resolution. We also integrated multiple bulk RNA\u2010seq profiles and single\u2010cell datasets of human and mouse tissues, and narrowed down a list of 48 GPCRs with strong endogenous co\u2010expression correlation with MRAPs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>36 and 46 metabolic\u2010related GPCRs were consequently identified as novel interacting partners of MRAP1 or MRAP2, respectively. MRAPs exhibited protein\u2013protein interactions and varying pharmacological properties on the surface translocation, constitutive activities and ligand\u2010stimulated downstream signalling of these GPCRs. Knockdown of MRAP2 expression by hypothalamic administration of adeno\u2010associated virus (AAV)\u00a0packed shRNA stimulated body weight gain in mouse model. Co\u2010injection of corticotropinreleasing factor (CRF), the agonist of corticotropin releasing hormone receptor 1 (CRHR1), suppressed feeding behaviour in a MRAP2\u2010dependent manner.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Collectively, our study has comprehensively elucidated the complex GPCR networks in two major endocrine organs and redefined the MRAP protein family as broad\u2010spectrum 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\u2013MRAP functional complexes.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.1091","type":"journal-article","created":{"date-parts":[[2022,10,31]],"date-time":"2022-10-31T08:14:55Z","timestamp":1667204095000},"source":"Crossref","is-referenced-by-count":22,"title":["Identification of MRAP protein family as broad\u2010spectrum GPCR modulators"],"prefix":"10.1002","volume":"12","author":[{"given":"Meng","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Plastic and Reconstructive Surgery Shanghai Ninth People's Hospital Shanghai Jiao Tong University School of Medicine  Shanghai 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