GPR158

GPR158 is a class C orphan GPCR that functions as a metabotropic glycine receptor (mGlyR), organizing postsynaptic signaling complexes to regulate neuronal excitability, synaptic strength, and dendritic spine maturation across multiple brain regions. Glycine and taurine bind directly to its extracellular Cache domain, and ligand engagement inhibits an intracellular RGS7–Gβ5 complex that GPR158 scaffolds to suppress cAMP–PKA signaling and modulate potassium channel activity (Kv4.2, Kv7/KCNQ), thereby controlling neuronal firing rates in cortical, hippocampal, and nucleus accumbens circuits (PMID:36996198, PMID:31311860, PMID:38884814). Cryo-EM structures reveal a phospholipid-stabilized homodimer whose intracellular coiled-coil selectively recruits one or two RGS7–Gβ5 heterodimers, with the GPR158 C-terminus allosterically enhancing RGS7 GAP activity (PMID:34793198, PMID:34815401, PMID:25792749). GPR158 also serves as a postsynaptic organizer at mossy fiber–CA3 synapses through interaction with glypican 4/LAR, and restrains the constitutively active phospholipase PLCXD2 to control spine apparatus incorporation and dendritic spine maturation via a non-canonical GPCR-to-PLC pathway (PMID:30290982, PMID:40393451).

1. 2012 High

   Establishing GPR158 as a membrane scaffold for RGS7 signaling complexes resolved how R7-family RGS proteins achieve subcellular targeting in neurons, converting GPR158 from an orphan receptor to a functional signaling organizer.

   Evidence Co-immunoprecipitation, cell fractionation, and retinal localization in WT vs. Gpr158 KO mice

   PMID:22689652

   Open questions at the time

   • Identity of the endogenous ligand remained unknown
   • Mechanism by which GPR158 enhances RGS7 catalytic activity was not defined
   • Downstream physiological consequences in higher brain regions not established
2. 2013 Medium

   Discovery that GPR158 undergoes clathrin-mediated endocytosis to the nucleus, where it drives cell proliferation and cyclin D1 expression, revealed a non-canonical trafficking route for a GPCR with potential relevance to ocular and cancer biology.

   Evidence Immunofluorescence, NLS mutagenesis, siRNA knockdown, and overexpression in trabecular meshwork cells

   PMID:23451275

   Open questions at the time

   • Nuclear function mechanism beyond cyclin D1 upregulation unclear
   • Relevance of nuclear localization to neuronal signaling not tested
   • Single cell-type study without in vivo confirmation
3. 2015 High

   Domain mapping of the GPR158 C-terminus showed it contains both an RGS7-binding site that allosterically enhances GAP activity and PDE-γ-like motifs that recruit activated Gα subunits, explaining how GPR158 integrates G protein signal termination at the receptor level.

   Evidence GPR158 KO mice (RGS7 protein stability), in vitro GAP assays with C-terminal fragments, mutagenesis

   PMID:25792749

   Open questions at the time

   • Structural basis of allosteric GAP enhancement unknown
   • Whether GPR158 signals through canonical Gα coupling remained unclear
4. 2017 High

   Identification of GPR158 as a transducer of osteocalcin signaling in hippocampal neurons linked it to IP3/BDNF pathways and hippocampal-dependent memory, establishing its first in vivo cognitive function.

   Evidence Gpr158 KO mice with behavioral testing, electrophysiology, IP3 and BDNF measurements

   PMID:28851741

   Open questions at the time

   • Whether osteocalcin directly binds GPR158 was not demonstrated
   • Relationship between osteocalcin and later-identified glycine ligand unresolved
5. 2018 High

   Demonstrating that glucocorticoid-induced GPR158 upregulation in PFC modulates AMPA receptor-mediated synaptic strength and drives depressive-like behavior established GPR158 as a stress-responsive mediator of mood, while its interaction with GPC4/LAR at mossy fiber–CA3 synapses revealed a role as a postsynaptic organizer controlling synapse ultrastructure.

   Evidence Viral OE/KO in PFC with electrophysiology and behavioral assays; Co-IP of GPR158–GPC4, electron microscopy and electrophysiology at MF–CA3 synapses in KO mice

   PMID:29419376 PMID:30290982

   Open questions at the time

   • How GPR158 coordinates GPC4-dependent transsynaptic signaling with intracellular RGS7 signaling was unresolved
   • Causal link between GPR158 and specific AMPA receptor subunit regulation not defined
6. 2019 High

   The discovery that GPR158–RGS7 physically associates with Kv4.2 and suppresses cAMP–PKA-mediated phosphorylation of the channel provided a concrete effector mechanism: GPR158 controls A-type potassium currents and hence PFC pyramidal neuron excitability, explaining the stress-resilience phenotype of GPR158 KO mice.

   Evidence Co-IP of GPR158–Kv4.2, GPR158/RGS7 KO with patch-clamp and PKA phosphorylation assays

   PMID:31311860

   Open questions at the time

   • Whether GPR158 directly binds Kv4.2 or requires RGS7 as an intermediary was not resolved
   • Ligand dependence of the Kv4.2 regulatory mechanism was unknown
7. 2021 High

   Cryo-EM structures of GPR158 alone and in complex with RGS7–Gβ5 revealed the atomic architecture of a phospholipid-stabilized homodimer with a Cache extracellular domain, EGF-like linker, and a cytoplasmic coiled-coil platform that selectively docks one or two RGS7–Gβ5 heterodimers through ICL2/ICL3/TM3 contacts, providing the structural framework for understanding ligand-induced signaling.

   Evidence Single-particle cryo-EM, independently confirmed by two groups

   PMID:34793198 PMID:34815401

   Open questions at the time

   • No ligand was bound in any structure, leaving the activation mechanism unresolved
   • How phospholipid binding contributes to signaling vs. structural stability was unclear
8. 2023 High

   Identification of glycine and taurine as direct Cache domain ligands deorphanized GPR158 as a metabotropic glycine receptor (mGlyR), showing that glycine binding inhibits the RGS7–Gβ5 complex, suppresses cAMP production, and regulates cortical neuron excitability — unifying the structural and signaling frameworks.

   Evidence Direct ligand-binding assay on Cache domain, in vitro RGS7–Gβ5 activity assay, cAMP measurements, cortical neuron electrophysiology, mutagenesis

   PMID:36996198

   Open questions at the time

   • Structural basis of glycine-induced conformational change not captured
   • Whether taurine produces distinct downstream signaling from glycine in vivo was unexplored
9. 2024 Medium

   Extension to nucleus accumbens MSNs showed that glycine-activated GPR158 increases firing by reducing M-current (Kv7/KCNQ) through PKA and ERK signaling, broadening the effector repertoire beyond Kv4.2 and establishing circuit-specific downstream outcomes.

   Evidence Whole-cell patch-clamp, pharmacological PKA/ERK inhibition, phospho-ERK and phospho-Kv7.2 western blots

   PMID:38884814

   Open questions at the time

   • Single lab; independent replication in NAc needed
   • How GPR158 couples to both cAMP suppression (via RGS7) and PKA/ERK activation in the same neuron type was not reconciled
10. 2025 High

    Discovery that GPR158 directly restrains the constitutively active phospholipase PLCXD2 to control spine apparatus incorporation and dendritic spine maturation established a non-canonical GPCR-to-PLC pathway independent of G protein–mediated PLC activation, with HSPG binding providing spatiotemporal regulation.

    Evidence Co-IP of GPR158–PLCXD2, in vivo sparse genetic manipulation in cortical neurons, electron microscopy, live imaging, HSPG binding assay

    PMID:40393451

    Open questions at the time

    • Whether glycine modulates the GPR158–PLCXD2 interaction is unknown
    • Structural basis of PLCXD2 restraint by GPR158 is unresolved
    • Relationship between PLCXD2-mediated spine maturation and RGS7-dependent cAMP signaling not addressed

• A ligand-bound structure of GPR158 capturing the conformational change induced by glycine or taurine, and a unified model explaining how GPR158 coordinates its multiple effector pathways (RGS7–Gβ5 GAP activity, Kv4.2/Kv7 modulation, PLCXD2 restraint) in a cell-type-specific manner, remain to be established.
• No ligand-bound cryo-EM structure exists
• Whether osteocalcin is a bona fide GPR158 ligand or acts indirectly is unresolved
• Mechanism reconciling cAMP suppression with PKA/ERK activation across neuron types is unknown