Orphan receptor GPR158 serves as a metabotropic glycine receptor: mGlyR

Science. 2023 Mar 31;379(6639):1352-1358. doi: 10.1126/science.add7150. Epub 2023 Mar 30.


Glycine is a major neurotransmitter involved in several fundamental neuronal processes. The identity of the metabotropic receptor mediating slow neuromodulatory effects of glycine is unknown. We identified an orphan G protein-coupled receptor, GPR158, as a metabotropic glycine receptor (mGlyR). Glycine and a related modulator, taurine, directly bind to a Cache domain of GPR158, and this event inhibits the activity of the intracellular signaling complex regulator of G protein signaling 7-G protein β5 (RGS7-Gβ5), which is associated with the receptor. Glycine signals through mGlyR to inhibit production of the second messenger adenosine 3',5'-monophosphate. We further show that glycine, but not taurine, acts through mGlyR to regulate neuronal excitability in cortical neurons. These results identify a major neuromodulatory system involved in mediating metabotropic effects of glycine, with implications for understanding cognition and affective states.

MeSH terms

  • GTP-Binding Protein beta Subunits / metabolism
  • GTP-Binding Proteins / metabolism
  • Glycine* / metabolism
  • HEK293 Cells
  • Humans
  • Protein Domains
  • RGS Proteins / metabolism
  • Receptors, G-Protein-Coupled* / chemistry
  • Receptors, G-Protein-Coupled* / genetics
  • Receptors, G-Protein-Coupled* / metabolism
  • Receptors, Glycine* / chemistry
  • Receptors, Glycine* / genetics
  • Receptors, Glycine* / metabolism
  • Signal Transduction


  • Glycine
  • GTP-Binding Proteins
  • Receptors, G-Protein-Coupled
  • Receptors, Glycine
  • GPR158 protein, human
  • RGS7 protein, human
  • GNB5 protein, human
  • GTP-Binding Protein beta Subunits
  • RGS Proteins