Gpr135 is an orphan G protein-coupled receptor (GPCR), which means its endogenous ligand is unknown. GPCRs are key mediators of signal transduction, and Gpr135 may be involved in multiple signaling pathways, potentially related to cAMP, inositol phosphate, and β-arrestin pathways based on its classification among the melatonin receptor subfamily [2]. It has significance in various biological contexts and diseases, with its expression being detected in multiple tissues [3,4].

In different cancers, Gpr135 receptor gene expression is significantly decreased in cervical, breast, skin, prostate, and astrocytoma tissues compared with healthy human fibroblasts, suggesting its potential role in cancer development [1]. In diabetic Wistar rats, Gpr135 is expressed in tissues like the brain, heart, kidney, etc., and its expression is modified due to diabetes. Functionally, responses to isoproterenol increase in diabetic rats administered with siRNA targeting Gpr135, indicating it may be coupled to Gi/o protein and participate in cardiovascular complications associated with diabetes [3].

In summary, Gpr135 is an orphan GPCR with potential importance in cancer and diabetes-related cardiovascular complications. Its decreased expression in cancerous tissues and altered expression and function in diabetic rats provide insights into its role in these disease conditions. Further research on Gpr135, perhaps through gene-knockout or conditional-knockout mouse models in the future, could deepen our understanding of its biological functions and its implications for disease mechanisms [1,3].

References:

1. Gutiérrez-Ruiz, Juan René, Villafaña, Santiago, Ruiz-Hernández, Armando, Hong, Enrique, Romero-Nava, Rodrigo. 2022. Expression profiles of GPR21, GPR39, GPR135, and GPR153 orphan receptors in different cancers. In Nucleosides, nucleotides & nucleic acids, 41, 123-136. doi:10.1080/15257770.2021.2002892. https://pubmed.ncbi.nlm.nih.gov/35021931/

2. Oishi, Atsuro, Karamitri, Angeliki, Gerbier, Romain, Ahmad, Raise, Jockers, Ralf. 2017. Orphan GPR61, GPR62 and GPR135 receptors and the melatonin MT2 receptor reciprocally modulate their signaling functions. In Scientific reports, 7, 8990. doi:10.1038/s41598-017-08996-7. https://pubmed.ncbi.nlm.nih.gov/28827538/

3. Ruiz-Hernández, Armando, Romero-Nava, Rodrigo, Huang, Fengyang, Hong, Enrique, Villafaña, Santiago. . Altered function and expression of the orphan GPR135 at the cardiovascular level in diabetic Wistar rats. In Journal of receptor and signal transduction research, 38, 484-491. doi:10.1080/10799893.2019.1597116. https://pubmed.ncbi.nlm.nih.gov/31038027/

4. Vanti, William B, Nguyen, Tuan, Cheng, Regina, George, Susan R, O'Dowd, Brian F. . Novel human G-protein-coupled receptors. In Biochemical and biophysical research communications, 305, 67-71. doi:. https://pubmed.ncbi.nlm.nih.gov/12732197/