Gpr158, an orphan G protein-coupled receptor, 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 complex, which is associated with the receptor, and then inhibits the production of the second messenger adenosine 3',5'-monophosphate [1]. Gpr158 is highly expressed in the central nervous system and is involved in regulating emotions, memory, and cognitive functions, as well as in endocrine regulation [2,3]. Genetic models, such as transgenic and knockout mice, have been crucial for studying its functions.

Constitutive and cell-/tissue-specific knockouts of Gpr158 in pyramidal neurons or the medial prefrontal cortex of male mice result in impaired novelty preference, along with a decline in excitatory synaptic transmission in the mPFC [4]. In Gpr158-deficient mice, short-term protection against age-related intraocular pressure increase was observed, but this effect was reversed over time, and the pressure-lowering effect of epinephrine was negated [5]. RNA-seq analysis of Gpr158-/-mice cerebral cortex showed that Gpr158 and its interacting proteins are involved in the chloride channel complex and synaptic vesicle membrane composition [6].

In conclusion, Gpr158 plays essential roles in multiple biological processes. Through gene knockout mouse models, its functions in social novelty behavior, intraocular pressure regulation, and synaptic vesicle function have been revealed. These findings contribute to understanding diseases related to cognitive and social impairments, as well as ocular hypertension [4,5,6].

References:

1. Laboute, Thibaut, Zucca, Stefano, Holcomb, Matthew, Forli, Stefano, Martemyanov, Kirill A. 2023. Orphan receptor GPR158 serves as a metabotropic glycine receptor: mGlyR. In Science (New York, N.Y.), 379, 1352-1358. doi:10.1126/science.add7150. https://pubmed.ncbi.nlm.nih.gov/36996198/

2. Darira, Shradha V, Sutton, Laurie P. 2022. The interaction, mechanism and function of GPR158-RGS7 cross-talk. In Progress in molecular biology and translational science, 193, 167-176. doi:10.1016/bs.pmbts.2022.06.007. https://pubmed.ncbi.nlm.nih.gov/36357076/

3. Lin, Jinju, Li, Qin, Lei, Xiaohua, Zhao, Huashan. 2022. The emerging roles of GPR158 in the regulation of the endocrine system. In Frontiers in cell and developmental biology, 10, 1034348. doi:10.3389/fcell.2022.1034348. https://pubmed.ncbi.nlm.nih.gov/36467406/

4. Wei, Shoupeng, Jiang, Jian, Wang, Dilong, Li, Huiliang, Li, Ningning. 2024. GPR158 in pyramidal neurons mediates social novelty behavior via modulating synaptic transmission in male mice. In Cell reports, 43, 114796. doi:10.1016/j.celrep.2024.114796. https://pubmed.ncbi.nlm.nih.gov/39383040/

5. Itakura, Tatsuo, Webster, Andrew, Chintala, Shravan K, Martemyanov, Kirill A, Fini, M Elizabeth. 2019. GPR158 in the Visual System: Homeostatic Role in Regulation of Intraocular Pressure. In Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics, 35, 203-215. doi:10.1089/jop.2018.0135. https://pubmed.ncbi.nlm.nih.gov/30855200/

6. Chang, Jinlong, Song, Ze, Wei, Shoupeng, Chi, Xinjin, Li, Ningning. 2023. Expression Mapping and Functional Analysis of Orphan G-Protein-Coupled Receptor GPR158 in the Adult Mouse Brain Using a GPR158 Transgenic Mouse. In Biomolecules, 13, . doi:10.3390/biom13030479. https://pubmed.ncbi.nlm.nih.gov/36979415/