From Structural Resolution to Functional Elucidation: Research Progress of GPR158 as a Target for Antidepressant Drug...

G Protein-Coupled Receptors (GPCRs) are the most widely used drug targets in neuropsychiatric disorders. GPR158, an orphan class C GPCR, is highly enriched in the central nervous system and has emerged as a critical regulator of stress-related depression. However, its precise mechanisms in depression remain incompletely understood. This review aims to establish a systematic framework spanning the molecular structure to physiological function, highlighting the role of GPR158 in the onset and progression of depression. We summarize the expression pattern, unique structural features, novel ligands, and downstream signaling pathways of GPR158, with a focused discussion on its multiple regulatory mechanisms in depression, including Cyclic Adeno-sine Monophosphate (cAMP) signaling, neuronal excitability, Brain-derived Neurotrophic Factor (BDNF) translation, glutamatergic transmission, and mitophagy. Abnormally upregulated GPR158 in the prefrontal cortex and hippocampus promotes depressive-like behaviours, whereas knockout or inhibition of GPR158 exerts antidepressant-like effects. These findings not only reveal the potential regulatory function of GPR158 in the pathological process of depression but also provide a solid theoretical basis for the development of antidepressant drugs targeting GPCRs, facilitating the subsequent development of more accurate and efficient antidepressant candidate drugs.