GPR135 is an orphan G protein-coupled receptor (GPCR) located on chromosome 14, meaning its endogenous ligand remains unidentified. Phylogenetic analysis suggests GPR135 may structurally resemble receptors for 11-cis-retinal 1. Functionally, GPR135 exhibits spontaneous, ligand-independent activity for β-arrestin recruitment, leading to receptor internalization into endosomal compartments 2. GPR135 does not bind melatonin but forms heteromeric complexes with the melatonin MT2 receptor, exhibiting reciprocal regulatory interactions that inhibit melatonin-induced β-arrestin2 recruitment to MT2 and decrease melatonin-stimulated cAMP signaling 2. These MT2/GPR135 heteromers represent novel pharmacological entities with functional properties distinct from individual receptors 3. GPR135 is expressed in central nervous system tissues 4. Disease relevance includes potential involvement in affective disorders based on GPCR dysfunction patterns 5, and emerging evidence suggests GPR135 dysregulation in azoospermia complicated with COVID-19 and asbestos-associated lung cancer, though mechanistic roles require clarification 67. The clinical significance of GPR135 as a therapeutic target remains undetermined pending ligand identification and functional characterization.