Integrating Molecular Signaling, Systems Biology, and Neurodegenerative Disease Mechanisms linking GPR158 Receptor as an Emerging Therapeutic Target

GPR158 is an orphan Class C G protein-coupled receptor (GPCR) that communicates through a unique Cache-domain that attracts RGS7–Gβ5 regulatory complex to the plasma membrane instead of having the traditional Venus flytrap ligand-binding domain typical of its family. Through this non-canonical pathway, GPR158 is able to control Kv4.2 channel-dependent neuronal excitability, alter cAMP-PKA activity, and enhance RGS7-mediated regulation of Gαi/o signaling. GPR158, which is primarily expressed in excitatory neurons of the cortex, hippocampus, and hypothalamus, controls synaptic architecture, dendritic spine maturation, and cognitive function. It is also the receptor for the bone-derived hormone osteocalcin, which connects peripheral skeletal signaling to primary cilium-dependent autophagy, hippocampal memory, and energy metabolism. Recently discovered ligands like glycine, taurine, and trilobatin suggest antidepressant and neuroprotective uses, chronic stress and glucocorticoid exposure upregulate GPR158 in the medial prefrontal cortex, mechanistically linking prolonged stress to phenotypes resembling depression and anxiety. In addition to roles in neuroendocrine-driven prostate cancer and glioblastoma, GPR158 dysregulation is linked to neurodegenerative pathology, including amyloid-β and BACE1 dynamics in Alzheimer's disease, α-synuclein sequestration in Parkinson's disease, and cortical resistance patterns in frontotemporal dementia. There are currently no clinically authorized treatments that specifically target GPR158, despite its wide physiological importance. In order to establish GPR158 as convergent regulatory node connecting neuroendocrine, neuropsychiatric, and neurodegenerative disease processes, this review integrates the most recent structural, signaling, and functional evidence. It identifies cryo-EM structural pharmacology, single-cell transcriptomics, and AI-guided ligand discovery as crucial next steps toward converting GPR158 into a practical target for diagnosis and treatment.