Orphan receptor GPR158 serves as a metabotropic glycine receptor: mGlyR

Abstract

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.

Structure of the photoreceptor synaptic assembly of the extracellular matrix protein pikachurin with the orphan receptor GPR179

“…This pocket is analogous to the ligand-binding pockets in the Cache domains of bacterial chemoreceptors (27), suggesting that GPR179 may also use it to detect small-molecule ligands. This pocket in GPR158 has been recently identified as a binding site for its ligand, glycine (28). However, the pocket in GPR179 appears to be distinct from that seen in GPR158, suggesting that its ligand is also likely different.…”

GPR158 in pyramidal neurons mediates social novelty behavior via modulating synaptic transmission in mice

“…Thus, GPR158 could modulate intracellular second messenger cAMP and cellular processes by regulating the generation and modifications of vesicle-related proteins through docking to RGS. Recently, glycine has been identified as a ligand for GPR158, and can inhibit the cAMP level by binding GPR158 to modulate cortical neuronal activity 54 . Besides, some studies have shown that the bone-derived hormone (which was not certified by peer review) is the author/funder.…”

A Bright Future? A Perspective on Class C GPCR Based Genetically Encoded Biosensors

“…Precise visualization of neurotransmitter dynamics in health and disease would contribute to a better understanding of the molecular interplay underlying the associated diseases. 52,53 For example, two notable ligands in this context could be γ-aminobutyric acid (GABA) and glycine, which have been shown to be involved in the pathophysiology of major depressive disorder (MDD) 45,54,55 For GABA, a bacterial periplasmic binding protein (PBP) based fluorescent biosensor (iGABASnFR) already exists. iGABASnFR was obtained by structure-guided mutagenesis and library screening of a PBP from Pseudomanas fluorescence, 56 based on the general design of the fluorescent glutamate biosensor iGluSnFR.…”

“…Glycine is an inhibitory neurotransmitter but can be excitatory in developing neurons. 45 In addition to ligandgated glycine channels, there is an orphan receptor, GPR158, which was identified as a metabotropic receptor for glycine. 45 Glycine appears to play a role in the pathophysiological changes observed in MDD.…”

“…45 In addition to ligandgated glycine channels, there is an orphan receptor, GPR158, which was identified as a metabotropic receptor for glycine. 45 Glycine appears to play a role in the pathophysiological changes observed in MDD. Plasma from patients with MDD contains decreased levels of glycine and increased levels of taurine.…”