Gpr50, a G protein-coupled receptor, is highly homologous to melatonin receptors. It is widely expressed in the pituitary, hypothalamus, cortex, midbrain, pons, amygdala, and several brainstem nuclei [3]. Gpr50 has been implicated in multiple biological processes, with its exact functions still being explored. It may be involved in pathways related to mitochondrial regulation, cell cycle control, and inflammatory and insulin signaling. Genetic models, such as gene knockout mouse models, can be valuable in further understanding its role.

In neurons, Gpr50 acts as a mitophagy receptor. Gpr50-deficient mice exhibit impaired social recognition, and Gpr50 deficiency leads to the accumulation of damaged mitochondria, disrupted oxidative phosphorylation (OXPHOS), insufficient ATP production, excessive ROS generation, and impaired neuronal development. Mutations in Gpr50 can attenuate its-mediated mitophagy [1].

In 3T3-L1 preadipocytes, Gpr50 deficiency increases inflammation and induces phosphorylation of AKT and insulin receptor substrate 1, while also suppressing PPAR-γ expression, suggesting it attenuates inflammatory levels and regulates insulin signaling in adipocytes [2].

In BRL-3A cells, overexpression of Gpr50 inhibits cell proliferation as it interacts with TβRI to activate the TGF-β signaling pathway and arrest the G1/S-phase cell cycle via the Smad3-p27/p21 pathway [4].

In conclusion, Gpr50 plays crucial roles in maintaining mitochondrial function in neurons, regulating inflammation and insulin signaling in adipocytes, and controlling cell proliferation in liver-related cells. Gene knockout mouse models have been instrumental in revealing these functions, providing insights into potential mechanisms underlying neuronal development, metabolic disorders, and liver-related pathologies.

References:

1. Liu, Ji-Chuan, Zhao, Xiu-Yun, Wu, Ming-Lei, Schachner, Melitta, Ma, Quan-Hong. 2024. GPR50 regulates neuronal development as a mitophagy receptor. In Cell death & disease, 15, 591. doi:10.1038/s41419-024-06978-y. https://pubmed.ncbi.nlm.nih.gov/39143050/

2. Yao, Zhenyu, Meng, Jun, Long, Jing, Zhang, Jian V, Ren, Pei-Gen. 2022. Orphan receptor GPR50 attenuates inflammation and insulin signaling in 3T3-L1 preadipocytes. In FEBS open bio, 13, 89-101. doi:10.1002/2211-5463.13516. https://pubmed.ncbi.nlm.nih.gov/36333974/

3. Khan, Muhammad Zahid, He, Ling, Zhuang, Xuxu. 2016. The emerging role of GPR50 receptor in brain. In Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 78, 121-128. doi:10.1016/j.biopha.2016.01.003. https://pubmed.ncbi.nlm.nih.gov/26898433/

4. Chang, Cuifang, Wang, Danlin, Xi, Lingling, Wang, Gaiping, Yu, Guoying. 2022. The orphan GPR50 receptor interacting with TβRI induces G1/S-phase cell cycle arrest via Smad3-p27/p21 in BRL-3A cells. In Biochemical pharmacology, 202, 115117. doi:10.1016/j.bcp.2022.115117. https://pubmed.ncbi.nlm.nih.gov/35671788/