Gpr158, an orphan G protein-coupled receptor (GPCR), is a member of class C GPCRs. It has been identified as a metabotropic glycine receptor (mGlyR) [1]. Glycine binds to its Cache domain, inhibiting the activity of RGS7-Gβ5, a regulator of the intracellular signaling complex, and suppressing the production of the second messenger adenosine 3',5'-monophosphate [1]. Gpr158 is highly expressed in the central nervous system (CNS) and is involved in regulating emotions, memory, and cognitive functions [2]. It also plays a role in the endocrine system, as it forms a stable dimer with RGS7, and the RGS7-Gβ5 complex is implicated in endocrine functions [2].

Constitutive and cell-/tissue-specific knockouts of Gpr158 in pyramidal neurons or the medial prefrontal cortex (mPFC) of male mice result in impaired novelty preference, with a decline in excitatory synaptic transmission in the mPFC [3]. Gpr158 deficiency in knockout mice also leads to deficits in spatial memory acquisition and retrieval in the Morris water maze, and in the acquisition of extinction memory in the passive avoidance test, along with disruptions in hippocampal CA1 neuronal dendritic architecture and physiology [5]. In addition, Gpr158-deficient mice show short-term protection against age-related intraocular pressure increase, but this is reversed over time, and the pressure-lowering effect of epinephrine is negated [4].

In conclusion, Gpr158 plays essential roles in multiple biological processes. Through gene knockout mouse models, its importance in social behavior, cognitive functions, and the regulation of intraocular pressure has been revealed. These findings enhance our understanding of Gpr158-related biological functions and its potential as a therapeutic target for related diseases such as social disorders and ocular hypertension.