GPR158
Description
The GPR158 (G protein-coupled receptor 158) is a protein-coding gene located on chromosome 10.
GPR158, also known as the metabotropic glycine receptor (mGlyR), is a protein encoded by the GPR158 gene. It is an orphan class C GPCR highly expressed in the brain, where it binds to RGS7, an inhibitor of Gi/o-coupled GPCR signaling, localizing it to the plasma membrane. It is also expressed at lower levels in other organs and shows an unusual subcellular localization pattern, being found at both the plasma membrane and in the nucleus. GPR158 in the medial prefrontal cortex (mPFC) regulates stress-induced depression in a mouse model of depression and is upregulated in post-mortem tissue samples from humans with major depressive disorder (MDD). The GPR158 gene is an androgen-regulated gene that stimulates cell proliferation in prostate cancer cell lines, and it is linked to neuroendocrine differentiation.
GPR158 acts as a metabotropic receptor for glycine, controlling synapse formation and function in the brain. It functions as an atypical G-protein coupled receptor, recruiting and regulating the RGS7-GNB5 complex instead of activating G proteins. In the absence of glycine, it promotes the GTPase activator activity of RGS7, increasing the GTPase activity of G protein alpha subunits, driving them into their inactive GDP-bound form. When glycine binds, it changes the conformation of the intracellular surface, inhibiting the GTPase activator activity of the RGS7-GNB5 complex, promoting G protein alpha subunits into their active GTP-bound form and regulating cAMP levels. It also binds taurine, a compound closely related to glycine, but with a two-fold lower affinity. Glycine receptor-dependent regulation of cAMP controls key ion channels, kinases and neurotrophic factors involved in neuronal excitability and synaptic transmission. GPR158 plays a pivotal role in regulating mood and cognition by regulating neuronal excitability in L2/L3 pyramidal neurons of the prefrontal cortex. It is also involved in spatial learning by regulating hippocampal CA1 neuronal excitability. It acts as a synaptic organizer in the hippocampus, required for proper mossy fiber-CA3 neurocircuitry establishment, structure and function: it induces presynaptic differentiation in contacting axons via its interaction with GPC4. In addition to glycine, GPR158 may also act as a receptor for osteocalcin (BGLAP) hormone: osteocalcin-binding initiates a signaling response that prevents neuronal apoptosis in the hippocampus and regulates the synthesis of neurotransmitters.
GPR158 is also known as mGlyR.
