Gpr135, an orphan G protein-coupled receptor (GPCR), has its endogenous ligand yet to be clearly identified. GPCRs are key mediators of signal transduction, and Gpr135 may participate in multiple signaling pathways, such as those related to cAMP, inositol phosphate, and ß-arrestin, as it shows spontaneous ligand-independent activities on these pathways [2]. It has been phylogenetically classified among the melatonin receptor subfamily, though it does not bind melatonin [2].

Research has shown that Gpr135 gene expression is significantly decreased in cervical, breast, skin, prostate, and astrocytoma tissues compared to healthy human fibroblasts, suggesting its potential role in cancer development [1]. In diabetic Wistar rats, Gpr135 is expressed in various tissues like the brain, heart, kidney, etc., and its expression is modified due to diabetes. Functional studies using siRNA indicate that it may be coupled to Gi/o protein, potentially involved in cardiovascular complications associated with diabetes [3]. Additionally, Gpr135 has been identified as significantly hypermethylated in lung cancer, and it was also recognized as a significant hub gene in both azoospermia and COVID-19, suggesting its possible role in the common pathogenesis of these two conditions [4,5].

In summary, Gpr135 is an orphan GPCR with spontaneous signaling activities. Its altered expression in cancer and diabetes-related tissues, along with its hypermethylation in lung cancer and association with azoospermia and COVID-19, implies its importance in multiple disease conditions. The study of Gpr135, especially through gene-knockout or conditional-knockout mouse models (not directly mentioned in the references but crucial for in-vivo functional studies), could further elucidate its exact role in these diseases and related biological processes.