GPR158 is an orphan G protein-coupled receptor that functions as a metabotropic glycine receptor (mGlyR) in the brain 1. Unlike typical GPCRs, GPR158 acts through an atypical mechanism by recruiting and regulating the RGS7-GNB5 complex rather than directly activating G proteins 1. In the absence of glycine, GPR158 promotes RGS7's GTPase activator activity, keeping G protein alpha subunits in their inactive GDP-bound state 1. Glycine binding to GPR158's extracellular Cache domain inhibits RGS7-GNB5 activity, allowing G protein activation and regulating cAMP levels 1. Structurally, GPR158 forms homodimers stabilized by phospholipids and couples to the RGS7-Gβ5 signaling complex 2. GPR158 is critical for synaptic function and neuronal excitability, particularly in pyramidal neurons of the prefrontal cortex where it regulates social novelty behavior 3. The receptor also controls spine apparatus abundance and dendritic spine maturation through interaction with PLCXD2 4. GPR158 has clinical relevance in depression, with studies showing it can be targeted by compounds like trilobatin to alleviate depressive-like behaviors through mitophagy promotion 5. Additionally, GPR158 has been associated with diabetic kidney disease in genome-wide association studies 6.