Gpr3, a G protein-coupled receptor, is constitutively active and belongs to the class A rhodopsin-type GPCR family. It can constitutively activate the Gαs protein without a ligand, elevating the basal intracellular cAMP level. Gpr3 is involved in multiple biological processes, including adipose thermogenesis, macrophage-mediated metabolism, neuronal development, and ovarian function [1,2,3,4].

In adipose tissue, lipolysis drives Gpr3 transcription, leading to energy expenditure and counteracting metabolic diseases in mice, suggesting its potential as a target for obesity-related therapies [1]. In Kupffer cells, Gpr3 activation stimulates glycolysis, protecting mice from obesity and fatty liver disease [2]. In neurons, Gpr3 knockout in mouse hippocampal neurons delays neuronal polarity formation, and in retinal ganglion cells, Gpr3 knockout makes them vulnerable to neural death during aging and affects axonal regeneration after optic nerve crush [5,6]. In POI patients, rare variants in Gpr3 have been identified, indicating its potential role in this disease [4].

In conclusion, Gpr3 plays essential roles in adipose thermogenesis, metabolism, neuronal development, and ovarian function. Gene knockout mouse models have significantly contributed to understanding its functions in diseases such as obesity, fatty liver disease, and POI, providing potential targets for therapeutic intervention.

References:

1. Sveidahl Johansen, Olivia, Ma, Tao, Hansen, Jakob Bondo, Mandrup, Susanne, Gerhart-Hines, Zachary. 2021. Lipolysis drives expression of the constitutively active receptor GPR3 to induce adipose thermogenesis. In Cell, 184, 3502-3518.e33. doi:10.1016/j.cell.2021.04.037. https://pubmed.ncbi.nlm.nih.gov/34048700/

2. Dong, Ting, Hu, Guangan, Fan, Zhongqi, Lv, Guoyue, Chen, Jianzhu. 2024. Activation of GPR3-β-arrestin2-PKM2 pathway in Kupffer cells stimulates glycolysis and inhibits obesity and liver pathogenesis. In Nature communications, 15, 807. doi:10.1038/s41467-024-45167-5. https://pubmed.ncbi.nlm.nih.gov/38280848/

3. Laun, Alyssa S, Shrader, Sarah H, Brown, Kevin J, Song, Zhao-Hui. 2018. GPR3, GPR6, and GPR12 as novel molecular targets: their biological functions and interaction with cannabidiol. In Acta pharmacologica Sinica, 40, 300-308. doi:10.1038/s41401-018-0031-9. https://pubmed.ncbi.nlm.nih.gov/29941868/

4. Ren, Shuting, Zhang, Feng, Shang, Lingyue, Zhang, Xiaojin, Wu, Yanhua. 2023. Rare variants in GPR3 in POI patients: a case series with review of literature. In Journal of ovarian research, 16, 210. doi:10.1186/s13048-023-01282-3. https://pubmed.ncbi.nlm.nih.gov/37919810/

5. Tanaka, Shigeru, Shimada, Naoto, Shiraki, Hiroko, Hide, Izumi, Sakai, Norio. 2021. GPR3 accelerates neurite outgrowth and neuronal polarity formation via PI3 kinase-mediating signaling pathway in cultured primary neurons. In Molecular and cellular neurosciences, 118, 103691. doi:10.1016/j.mcn.2021.103691. https://pubmed.ncbi.nlm.nih.gov/34871769/

6. Masuda, Shun, Tanaka, Shigeru, Shiraki, Hiroko, Kiuchi, Yoshiaki, Sakai, Norio. 2022. GPR3 expression in retinal ganglion cells contributes to neuron survival and accelerates axonal regeneration after optic nerve crush in mice. In Neurobiology of disease, 172, 105811. doi:10.1016/j.nbd.2022.105811. https://pubmed.ncbi.nlm.nih.gov/35809764/