Gpr61, an orphan G protein-coupled receptor (GPCR) related to biogenic amine receptors, has drawn attention due to its association with phenotypes related to appetite, making it a potential druggable target for metabolism and body-weight disorders such as obesity and cachexia [1]. It couples to Gαs, shows constitutive activity, and is subject to post-translational modification like N-glycosylation [5,6,7]. Its N-terminal domain is essential for maintaining this constitutive activity [7].

A recent study reported a structural characterization of GPR61 in both active-like and inactive states, along with the discovery of a potent and selective small-molecule inverse agonist and its allosteric binding site and mode of action, which provides a framework for further functional studies [1]. Another study identified GPR61 as a gene with higher methylation levels in mothers and newborns, and its methylation in cord blood may be a potential target of prenatal exposure to air pollutants [2]. Additionally, GPR61 was among orphan GPCRs suggested to be involved in modulating emotional behaviors [3]. A study on weather and birth weight found significant associations among prenatal weather, GPR61 methylation, and birth weight, with maternal GPR61 methylation potentially modifying susceptibility and neonatal GPR61 methylation mediating the effects of relative humidity and daily temperature range on birth weight [4].

In summary, Gpr61 is an orphan GPCR with constitutive activity, potentially involved in appetite-related phenotypes, emotional behaviors, and the effects of prenatal environment on birth weight. The structural and ligand-related findings, along with methylation-associated discoveries, enhance our understanding of its functions. Further research on Gpr61 may provide insights into treating metabolism-related disorders and understanding the impacts of prenatal environment on offspring.

References:

1. Lees, Joshua A, Dias, João M, Rajamohan, Francis, Zhang, Yuan, Han, Seungil. 2023. An inverse agonist of orphan receptor GPR61 acts by a G protein-competitive allosteric mechanism. In Nature communications, 14, 5938. doi:10.1038/s41467-023-41646-3. https://pubmed.ncbi.nlm.nih.gov/37741852/

2. Feng, Feifei, Huang, Li, Zhou, Guoyu, Zhang, Yawei, Ba, Yue. 2020. GPR61 methylation in cord blood: a potential target of prenatal exposure to air pollutants. In International journal of environmental health research, 32, 463-472. doi:10.1080/09603123.2020.1773414. https://pubmed.ncbi.nlm.nih.gov/32478566/

3. Watkins, Lyndsay R, Orlandi, Cesare. 2020. Orphan G Protein Coupled Receptors in Affective Disorders. In Genes, 11, . doi:10.3390/genes11060694. https://pubmed.ncbi.nlm.nih.gov/32599826/

4. Li, Zhi Yuan, Gong, Yong Xiang, Yang, Meng, Ba, Yue, Zhou, Guo Yu. . Weather and Birth Weight: Different Roles of Maternal and Neonatal GPR61 Promoter Methylation. In Biomedical and environmental sciences : BES, 35, 181-193. doi:10.3967/bes2022.027. https://pubmed.ncbi.nlm.nih.gov/35317898/

5. Kozielewicz, Pawel, Grafton, Gillian, Sajkowska-Kozielewicz, Joanna J, Barnes, Nicholas M. 2019. Overexpression of Orphan Receptor GPR61 Increases cAMP Levels upon Forskolin Stimulation in HEK293 Cells: in vitro and in silico Validation of 5-(Nonyloxy)Tryptamine as a Low-Affinity Inverse Agonist. In Pharmacology, 104, 377-382. doi:10.1159/000501926. https://pubmed.ncbi.nlm.nih.gov/31352450/

6. Kozielewicz, Paweł, Alomar, Hatun, Yusof, Syaratul, Pall, Hardev, Barnes, Nicholas M. 2017. N-glycosylation and expression in human tissues of the orphan GPR61 receptor. In FEBS open bio, 7, 1982-1993. doi:10.1002/2211-5463.12339. https://pubmed.ncbi.nlm.nih.gov/29226084/

7. Toyooka, Masaru, Tujii, Takashi, Takeda, Shigeki. . The N-terminal domain of GPR61, an orphan G-protein-coupled receptor, is essential for its constitutive activity. In Journal of neuroscience research, 87, 1329-33. doi:10.1002/jnr.21955. https://pubmed.ncbi.nlm.nih.gov/19025769/