{"gene":"GPR158","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":2012,"finding":"GPR158 recruits RGS7 complexes to the plasma membrane and augments their ability to regulate GPCR signaling; GPR158 physically interacts with the R7 group of RGS proteins (RGS7/RGS11) to control their subcellular localization and signaling activity.","method":"Co-immunoprecipitation, cell fractionation, mouse knockout model, retinal localization studies","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, KO model with defined cellular phenotype, replicated across labs","pmids":["22689652"],"is_preprint":false},{"year":2015,"finding":"GPR158 stabilizes RGS7 protein post-transcriptionally and anchors it to membranes in the brain; the C-terminus of GPR158 contains the RGS7-binding site and a conserved sequence that allosterically enhances RGS7 GTPase-activating protein (GAP) activity; the distal C-terminus selectively recruits activated G proteins via PDEγ-like motifs.","method":"GPR158 knockout mice (RGS7 protein levels assessed), domain mapping, in vitro GAP activity assay with C-terminal fragments, mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro enzymatic assay with mutagenesis plus KO model, multiple orthogonal methods","pmids":["25792749"],"is_preprint":false},{"year":2017,"finding":"GPR158 is expressed in CA3 hippocampal neurons and transduces osteocalcin (OCN) signaling to regulate hippocampal-dependent memory, in part through inositol 1,4,5-trisphosphate (IP3) and BDNF pathways.","method":"Genetic (Gpr158 knockout), electrophysiology, molecular (IP3/BDNF measurement), behavioral assays","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (genetics, electrophysiology, molecular signaling, behavior) in single study","pmids":["28851741"],"is_preprint":false},{"year":2018,"finding":"GPR158 expression in the prefrontal cortex is upregulated by glucocorticoids in response to chronic stress; GPR158 modulates synaptic strength via AMPA receptor activity; viral overexpression of GPR158 in PFC induces depressive-like behaviors while GPR158 ablation confers stress resilience.","method":"Viral overexpression, knockout mice, glucocorticoid treatment, synaptic transmission recordings (AMPA receptor activity)","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — KO and OE with defined cellular phenotype (AMPA receptor activity), multiple behavioral paradigms, glucocorticoid mechanism established","pmids":["29419376"],"is_preprint":false},{"year":2018,"finding":"GPR158 is a postsynaptic binding partner for heparan sulfate proteoglycan glypican 4 (GPC4) and co-receptor LAR; GPR158 is restricted to proximal CA3 apical dendrites receiving mossy fiber input; loss of GPR158 disrupts mossy fiber bouton morphology, active zone/PSD ultrastructure, and reduces synaptic strength specifically at mossy fiber-CA3 synapses.","method":"Co-immunoprecipitation (GPR158-GPC4 interaction), immunofluorescence localization, GPR158 knockout mice, electron microscopy, electrophysiology","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, KO with defined ultrastructural and electrophysiological phenotype, input-specificity confirmed","pmids":["30290982"],"is_preprint":false},{"year":2018,"finding":"RbAp48 controls expression of GPR158 in the hippocampus; disruption of OCN/GPR158 signaling leads to downregulation of RbAp48 protein; activation of the OCN/GPR158 pathway increases RbAp48 expression in the aged dentate gyrus, rescuing age-related memory loss.","method":"Hippocampal inhibition of RbAp48 (viral), GPR158 KO, behavioral memory assays, western blot for RbAp48/BDNF/GPR158","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 — KO with defined behavioral phenotype and molecular readout, single lab","pmids":["30355501"],"is_preprint":false},{"year":2019,"finding":"The GPR158-RGS7 complex in layer 2/3 PFC pyramidal neurons controls A-type potassium channel Kv4.2 function by suppressing cAMP-PKA-mediated phosphorylation; GPR158 physically associates with Kv4.2 channel; deletion of GPR158 or RGS7 enhances excitability of L2/3 PFC neurons and prevents stress-induced depression-like states.","method":"Co-immunoprecipitation (GPR158-Kv4.2), GPR158/RGS7 knockout, whole-cell patch-clamp, PKA phosphorylation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, KO with defined electrophysiological and behavioral phenotype, PKA mechanism established","pmids":["31311860"],"is_preprint":false},{"year":2019,"finding":"GPR158 deficiency in CA1 hippocampal neurons reduces dendritic complexity (length, branching, bifurcations) specifically in apical dendrites, increases intrinsic excitability as compensation, and impairs Schaffer collateral-mediated postsynaptic currents, resulting in spatial memory deficits.","method":"GPR158 knockout mice, Morris water maze, passive avoidance, whole-cell patch-clamp, neuronal morphology analysis (ex vivo and in vitro)","journal":"Frontiers in cellular neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 — KO with multiple orthogonal readouts (morphology, electrophysiology, behavior), single lab","pmids":["31749686"],"is_preprint":false},{"year":2013,"finding":"GPR158 localizes predominantly to the nucleus in trabecular meshwork cells via clathrin-mediated endocytosis from the plasma membrane; a bipartite nuclear localization signal (NLS) in the 8th helix is required for nuclear targeting; nuclear localization is required for GPR158-mediated cell proliferation and upregulation of cyclin D1; GPR158 overexpression enhances tight junction proteins ZO-1 and occludin; glucocorticoid treatment increases GPR158 transcription.","method":"Immunofluorescence, clathrin inhibitors, NLS mutagenesis, siRNA knockdown, overexpression, cyclin D1/ZO-1/occludin western blot","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — mutagenesis with functional readout (cell proliferation), subcellular localization with direct mechanistic consequence, single lab","pmids":["23451275"],"is_preprint":false},{"year":2021,"finding":"Cryo-EM structure of human GPR158 reveals a homodimeric organization stabilized by a pair of phospholipids, an extracellular Cache domain as ligand-binding domain, and the structural basis of GPR158 coupling to RGS7-Gβ5 via its intracellular regions.","method":"Single-particle cryo-EM of GPR158 alone and bound to RGS7-Gβ5 complex","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structure with functional validation of RGS7-Gβ5 coupling, replicated in independent study (PMID:34815401)","pmids":["34793198"],"is_preprint":false},{"year":2021,"finding":"Cryo-EM structures of GPR158 alone and in complex with one or two RGS7-Gβ5 heterodimers reveal that GPR158 dimerizes through PAS-fold extracellular and transmembrane domains connected by an EGF-like linker; ICL2, ICL3, TM3, and first helix of cytoplasmic coiled-coil form the platform for one RGS7 DHEX domain; the second helix recruits another RGS7, explaining selectivity for RGS7.","method":"Cryo-EM structural determination of GPR158 alone and GPR158:RGS7-Gβ5 complexes","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structure independently confirming findings from PMID:34793198","pmids":["34815401"],"is_preprint":false},{"year":2023,"finding":"Glycine and taurine directly bind to the extracellular Cache domain of GPR158, identifying GPR158 as a metabotropic glycine receptor (mGlyR); glycine binding inhibits the intracellular RGS7-Gβ5 signaling complex associated with the receptor; glycine signals through mGlyR to inhibit cAMP production; glycine (but not taurine) acts through mGlyR to regulate neuronal excitability in cortical neurons.","method":"Ligand-binding assay (Cache domain), in vitro RGS7-Gβ5 activity assay, cAMP measurements, electrophysiology in cortical neurons, mutagenesis","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 — direct binding assay, in vitro enzymatic assay, cellular signaling readout, and electrophysiology, multiple orthogonal methods in one study","pmids":["36996198"],"is_preprint":false},{"year":2024,"finding":"Glycine-dependent activation of GPR158 in nucleus accumbens medium spiny neurons (MSNs) increases firing rate by reducing M-current amplitude (Kv7/KCNQ channels) via PKA and ERK signaling, increasing phosphorylation of ERK and Kv7.2 serine residues.","method":"Whole-cell patch-clamp, pharmacological PKA/ERK inhibition, western blot for phospho-ERK and phospho-Kv7.2, selective M-current pharmacology","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 — electrophysiology with pharmacological dissection and biochemical readout, single lab","pmids":["38884814"],"is_preprint":false},{"year":2025,"finding":"GPR158 forms a postsynaptic complex with the constitutively active phospholipase C family member PLCXD2; GPR158 restrains PLCXD2 activity to control spine apparatus (SA) abundance in dendritic spines; in the absence of GPR158, unrestrained PLCXD2 impedes SA incorporation and hampers dendritic spine maturation; extracellular HSPG binding modulates the GPR158-PLCXD2 interaction, providing spatiotemporal control; this represents a direct GPCR-to-PLC signaling pathway bypassing canonical G protein-mediated PLC regulation.","method":"Co-immunoprecipitation (GPR158-PLCXD2), in vivo sparse genetic manipulation (cortical neurons), electron microscopy, live imaging, HSPG binding assay","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 — Co-IP, in vivo genetic manipulation with defined ultrastructural and functional phenotype, multiple orthogonal methods","pmids":["40393451"],"is_preprint":false},{"year":2024,"finding":"GPR158 in mPFC pyramidal neurons modulates social novelty behavior; loss of GPR158 reduces excitatory synaptic transmission (fewer glutamate vesicles, reduced GluN2B expression and phosphorylation); the social novelty deficit is rescued by GPR158 re-expression or chemogenetic activation of GPR158-deficient pyramidal neurons.","method":"Conditional and constitutive Gpr158 KO mice, three-chamber social test, electrophysiology, western blot (GluN2B), chemogenetic rescue (DREADDs), viral re-expression","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 — KO with multiple rescue approaches and molecular readout, single lab","pmids":["39383040"],"is_preprint":false},{"year":2015,"finding":"GPR158 promotes prostate cancer cell proliferation independent of androgen receptor functionality, and this requires its nuclear localization; GPR158 expression is stimulated by androgens, and GPR158 stimulates AR expression in a positive feedback loop; GPR158 promotes anchorage-independent colony formation.","method":"siRNA knockdown, overexpression, NLS mutation, colony formation assay, androgen treatment","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2-3 — KO/OE with defined phenotype, NLS mutagenesis linking localization to function, single lab","pmids":["25693195"],"is_preprint":false},{"year":2019,"finding":"GPR158 overexpression in trabecular meshwork cells enhances cAMP production in response to epinephrine; GPR158 deficiency in mice negates the intraocular pressure-lowering effect of epinephrine.","method":"GPR158 overexpression (cAMP assay), Gpr158 KO mice (intraocular pressure measurement with epinephrine)","journal":"Journal of ocular pharmacology and therapeutics","confidence":"Medium","confidence_rationale":"Tier 2-3 — KO with defined physiological phenotype plus cellular cAMP assay, single lab","pmids":["30855200"],"is_preprint":false}],"current_model":"GPR158 is a class C orphan GPCR that functions as a metabotropic glycine receptor (mGlyR), binding glycine and taurine via its extracellular Cache domain; it forms a homodimer (stabilized by phospholipids) that scaffolds an intracellular RGS7-Gβ5 signaling complex—whose GAP activity GPR158 allosterically enhances—to suppress cAMP production and regulate G protein signaling duration; postsynaptically, GPR158 organizes mossy fiber-CA3 synapses through interaction with glypican 4 (GPC4)/LAR and controls dendritic spine maturation by restraining a PLCXD2 phospholipase C via a non-canonical direct GPCR-to-PLC pathway; it additionally associates with Kv4.2 potassium channels to modulate neuronal excitability downstream of stress-induced glucocorticoid signaling in the prefrontal cortex, and transduces osteocalcin signals in hippocampal neurons through IP3 and BDNF to regulate memory and mood."},"narrative":{"teleology":[{"year":2012,"claim":"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","pmids":["22689652"],"confidence":"High","gaps":["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"]},{"year":2013,"claim":"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","pmids":["23451275"],"confidence":"Medium","gaps":["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"]},{"year":2015,"claim":"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","pmids":["25792749"],"confidence":"High","gaps":["Structural basis of allosteric GAP enhancement unknown","Whether GPR158 signals through canonical Gα coupling remained unclear"]},{"year":2017,"claim":"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","pmids":["28851741"],"confidence":"High","gaps":["Whether osteocalcin directly binds GPR158 was not demonstrated","Relationship between osteocalcin and later-identified glycine ligand unresolved"]},{"year":2018,"claim":"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","pmids":["29419376","30290982"],"confidence":"High","gaps":["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"]},{"year":2019,"claim":"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","pmids":["31311860"],"confidence":"High","gaps":["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"]},{"year":2021,"claim":"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","pmids":["34793198","34815401"],"confidence":"High","gaps":["No ligand was bound in any structure, leaving the activation mechanism unresolved","How phospholipid binding contributes to signaling vs. structural stability was unclear"]},{"year":2023,"claim":"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","pmids":["36996198"],"confidence":"High","gaps":["Structural basis of glycine-induced conformational change not captured","Whether taurine produces distinct downstream signaling from glycine in vivo was unexplored"]},{"year":2024,"claim":"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","pmids":["38884814"],"confidence":"Medium","gaps":["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"]},{"year":2025,"claim":"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","pmids":["40393451"],"confidence":"High","gaps":["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"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Low","gaps":["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"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,11,13]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[2,11,12]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,4,9,10]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[8,15]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,6,11,12]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[3,4,6,7,14]}],"complexes":["GPR158–RGS7–Gβ5","GPR158–PLCXD2"],"partners":["RGS7","GNB5","PLCXD2","GPC4","PTPRF","KCND2","RGS11"],"other_free_text":[]},"mechanistic_narrative":"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]."},"prefetch_data":{"uniprot":{"accession":"Q5T848","full_name":"Metabotropic glycine receptor","aliases":["G-protein coupled receptor 158"],"length_aa":1215,"mass_kda":135.5,"function":"Metabotropic receptor for glycine that controls synapse formation and function in the brain (PubMed:36996198). Acts as an atypical G-protein coupled receptor that recruits and regulates the RGS7-GNB5 complex instead of activating G proteins (PubMed:31189666, PubMed:36996198). In absence of glycine ligand, promotes the GTPase activator activity of RGS7, increasing the GTPase activity of G protein alpha subunits, thereby driving them into their inactive GDP-bound form (PubMed:36996198). Glycine-binding 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 (PubMed:36996198). Also able to bind taurine, a compound closely related to glycine, but with a two-fold lower affinity (PubMed:36996198). Glycine receptor-dependent regulation of cAMP controls key ion channels, kinases and neurotrophic factors involved in neuronal excitability and synaptic transmission (PubMed:36996198). Plays a pivotal role in regulating mood and cognition via its ability to regulate neuronal excitability in L2/L3 pyramidal neurons of the prefrontal cortex (By similarity). Also involved in spatial learning by regulating hippocampal CA1 neuronal excitability (By similarity). Acts as a synaptic organizer in the hippocampus, required for proper mossy fiber-CA3 neurocircuitry establishment, structure and function: induces presynaptic differentiation in contacting axons via its interaction with GPC4 (By similarity). In addition to glycine, 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 (By similarity)","subcellular_location":"Cell membrane; Postsynaptic cell membrane; Presynaptic cell membrane; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q5T848/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GPR158","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/GPR158","total_profiled":1310},"omim":[{"mim_id":"614573","title":"G PROTEIN-COUPLED RECEPTOR 158; GPR158","url":"https://www.omim.org/entry/614573"},{"mim_id":"614515","title":"G PROTEIN-COUPLED RECEPTOR 179; GPR179","url":"https://www.omim.org/entry/614515"},{"mim_id":"604551","title":"CHOLESTEROL 25-HYDROXYLASE; CH25H","url":"https://www.omim.org/entry/604551"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":10.1},{"tissue":"retina","ntpm":4.2}],"url":"https://www.proteinatlas.org/search/GPR158"},"hgnc":{"alias_symbol":["KIAA1136"],"prev_symbol":[]},"alphafold":{"accession":"Q5T848","domains":[{"cath_id":"-","chopping":"64-88_317-364_387-409","consensus_level":"medium","plddt":76.2344,"start":64,"end":409},{"cath_id":"3.30.450.20","chopping":"99-229_260-314","consensus_level":"medium","plddt":79.8753,"start":99,"end":314},{"cath_id":"1.20.1070.10","chopping":"416-514_522-672","consensus_level":"high","plddt":86.9759,"start":416,"end":672}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5T848","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5T848-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5T848-F1-predicted_aligned_error_v6.png","plddt_mean":58.03},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GPR158","jax_strain_url":"https://www.jax.org/strain/search?query=GPR158"},"sequence":{"accession":"Q5T848","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5T848.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5T848/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5T848"}},"corpus_meta":[{"pmid":"28851741","id":"PMC_28851741","title":"Gpr158 mediates osteocalcin's regulation of cognition.","date":"2017","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28851741","citation_count":238,"is_preprint":false},{"pmid":"22689652","id":"PMC_22689652","title":"GPR158/179 regulate G protein signaling by controlling localization and activity of the RGS7 complexes.","date":"2012","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/22689652","citation_count":88,"is_preprint":false},{"pmid":"29419376","id":"PMC_29419376","title":"Orphan receptor GPR158 controls stress-induced depression.","date":"2018","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/29419376","citation_count":67,"is_preprint":false},{"pmid":"30355501","id":"PMC_30355501","title":"RbAp48 Protein Is a Critical Component of GPR158/OCN Signaling and Ameliorates Age-Related Memory Loss.","date":"2018","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/30355501","citation_count":65,"is_preprint":false},{"pmid":"30290982","id":"PMC_30290982","title":"An Input-Specific Orphan Receptor GPR158-HSPG Interaction Organizes Hippocampal Mossy Fiber-CA3 Synapses.","date":"2018","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/30290982","citation_count":58,"is_preprint":false},{"pmid":"36996198","id":"PMC_36996198","title":"Orphan receptor GPR158 serves as a metabotropic glycine receptor: mGlyR.","date":"2023","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/36996198","citation_count":56,"is_preprint":false},{"pmid":"25792749","id":"PMC_25792749","title":"Orphan Receptor GPR158 Is an Allosteric Modulator of RGS7 Catalytic Activity with an Essential Role in Dictating Its Expression and Localization in the Brain.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25792749","citation_count":52,"is_preprint":false},{"pmid":"34793198","id":"PMC_34793198","title":"Cryo-EM structure of human GPR158 receptor coupled to the RGS7-Gβ5 signaling complex.","date":"2021","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/34793198","citation_count":49,"is_preprint":false},{"pmid":"23451275","id":"PMC_23451275","title":"GPR158, an orphan member of G protein-coupled receptor Family C: glucocorticoid-stimulated expression and novel nuclear role.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23451275","citation_count":42,"is_preprint":false},{"pmid":"34815401","id":"PMC_34815401","title":"Structure of the class C orphan GPCR GPR158 in complex with RGS7-Gβ5.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/34815401","citation_count":34,"is_preprint":false},{"pmid":"25693195","id":"PMC_25693195","title":"Expression and functional role of orphan receptor GPR158 in prostate cancer growth and progression.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25693195","citation_count":31,"is_preprint":false},{"pmid":"29720725","id":"PMC_29720725","title":"Inhibition of GPR158 by microRNA-449a suppresses neural lineage of glioma stem/progenitor cells and correlates with higher glioma grades.","date":"2018","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/29720725","citation_count":27,"is_preprint":false},{"pmid":"31749686","id":"PMC_31749686","title":"Gpr158 Deficiency Impacts Hippocampal CA1 Neuronal Excitability, Dendritic Architecture, and Affects Spatial Learning.","date":"2019","source":"Frontiers in cellular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/31749686","citation_count":24,"is_preprint":false},{"pmid":"31311860","id":"PMC_31311860","title":"The signaling proteins GPR158 and RGS7 modulate excitability of L2/3 pyramidal neurons and control A-type potassium channel in the prelimbic cortex.","date":"2019","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31311860","citation_count":22,"is_preprint":false},{"pmid":"35347106","id":"PMC_35347106","title":"Bevacizumab attenuates osteosarcoma angiogenesis by suppressing MIAT encapsulated by serum-derived extracellular vesicles and facilitating miR-613-mediated GPR158 inhibition.","date":"2022","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/35347106","citation_count":16,"is_preprint":false},{"pmid":"36979415","id":"PMC_36979415","title":"Expression Mapping and Functional Analysis of Orphan G-Protein-Coupled Receptor GPR158 in the Adult Mouse Brain Using a GPR158 Transgenic Mouse.","date":"2023","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/36979415","citation_count":9,"is_preprint":false},{"pmid":"38884814","id":"PMC_38884814","title":"Glycine-induced activation of GPR158 increases the intrinsic excitability of medium spiny neurons in the nucleus accumbens.","date":"2024","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/38884814","citation_count":8,"is_preprint":false},{"pmid":"40337551","id":"PMC_40337551","title":"Osteocalcin and GPR158: linking bone and brain function.","date":"2025","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/40337551","citation_count":7,"is_preprint":false},{"pmid":"36467406","id":"PMC_36467406","title":"The emerging roles of GPR158 in the regulation of the endocrine system.","date":"2022","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/36467406","citation_count":7,"is_preprint":false},{"pmid":"30855200","id":"PMC_30855200","title":"GPR158 in the Visual System: Homeostatic Role in Regulation of Intraocular Pressure.","date":"2019","source":"Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/30855200","citation_count":6,"is_preprint":false},{"pmid":"36634900","id":"PMC_36634900","title":"Hyperglycemic microenvironment compromises the homeostasis of communication between the bone-brain axis by the epigenetic repression of the osteocalcin receptor, Gpr158 in the hippocampus.","date":"2023","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/36634900","citation_count":5,"is_preprint":false},{"pmid":"39383040","id":"PMC_39383040","title":"GPR158 in pyramidal neurons mediates social novelty behavior via modulating synaptic transmission in male mice.","date":"2024","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/39383040","citation_count":5,"is_preprint":false},{"pmid":"40393451","id":"PMC_40393451","title":"A postsynaptic GPR158-PLCXD2 complex controls spine apparatus abundance and dendritic spine maturation.","date":"2025","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/40393451","citation_count":3,"is_preprint":false},{"pmid":"36357076","id":"PMC_36357076","title":"The interaction, mechanism and function of GPR158-RGS7 cross-talk.","date":"2022","source":"Progress in molecular biology and translational science","url":"https://pubmed.ncbi.nlm.nih.gov/36357076","citation_count":3,"is_preprint":false},{"pmid":"37321907","id":"PMC_37321907","title":"Glycine: a long-sought novel ligand for GPR158.","date":"2023","source":"Trends in pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37321907","citation_count":2,"is_preprint":false},{"pmid":"40128223","id":"PMC_40128223","title":"Pharmacological and resting state fMRI reveal Osteocalcin's effects on mouse brain regions with high Gpr37 and Gpr158 expression.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/40128223","citation_count":2,"is_preprint":false},{"pmid":"39962827","id":"PMC_39962827","title":"Trilobatin, a Naturally Occurring GPR158 Ligand, Alleviates Depressive-like Behavior by Promoting Mitophagy.","date":"2025","source":"Journal of agricultural and food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/39962827","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.05.08.592949","title":"Cell-surface receptor-mediated regulation of synaptic organelle distribution controls dendritic spine maturation","date":"2024-05-08","source":"bioRxiv","url":"https://doi.org/10.1101/2024.05.08.592949","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.05.28.596141","title":"The correct temporal connectivity of the DG-CA3 circuits involved in declarative memory processes depends on Vangl2-dependent planar cell polarity signaling","date":"2024-06-01","source":"bioRxiv","url":"https://doi.org/10.1101/2024.05.28.596141","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14533,"output_tokens":4315,"usd":0.054162},"stage2":{"model":"claude-opus-4-6","input_tokens":7764,"output_tokens":3130,"usd":0.175605},"total_usd":0.229767,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"GPR158 recruits RGS7 complexes to the plasma membrane and augments their ability to regulate GPCR signaling; GPR158 physically interacts with the R7 group of RGS proteins (RGS7/RGS11) to control their subcellular localization and signaling activity.\",\n      \"method\": \"Co-immunoprecipitation, cell fractionation, mouse knockout model, retinal localization studies\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, KO model with defined cellular phenotype, replicated across labs\",\n      \"pmids\": [\"22689652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"GPR158 stabilizes RGS7 protein post-transcriptionally and anchors it to membranes in the brain; the C-terminus of GPR158 contains the RGS7-binding site and a conserved sequence that allosterically enhances RGS7 GTPase-activating protein (GAP) activity; the distal C-terminus selectively recruits activated G proteins via PDEγ-like motifs.\",\n      \"method\": \"GPR158 knockout mice (RGS7 protein levels assessed), domain mapping, in vitro GAP activity assay with C-terminal fragments, mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro enzymatic assay with mutagenesis plus KO model, multiple orthogonal methods\",\n      \"pmids\": [\"25792749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"GPR158 is expressed in CA3 hippocampal neurons and transduces osteocalcin (OCN) signaling to regulate hippocampal-dependent memory, in part through inositol 1,4,5-trisphosphate (IP3) and BDNF pathways.\",\n      \"method\": \"Genetic (Gpr158 knockout), electrophysiology, molecular (IP3/BDNF measurement), behavioral assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (genetics, electrophysiology, molecular signaling, behavior) in single study\",\n      \"pmids\": [\"28851741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"GPR158 expression in the prefrontal cortex is upregulated by glucocorticoids in response to chronic stress; GPR158 modulates synaptic strength via AMPA receptor activity; viral overexpression of GPR158 in PFC induces depressive-like behaviors while GPR158 ablation confers stress resilience.\",\n      \"method\": \"Viral overexpression, knockout mice, glucocorticoid treatment, synaptic transmission recordings (AMPA receptor activity)\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO and OE with defined cellular phenotype (AMPA receptor activity), multiple behavioral paradigms, glucocorticoid mechanism established\",\n      \"pmids\": [\"29419376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"GPR158 is a postsynaptic binding partner for heparan sulfate proteoglycan glypican 4 (GPC4) and co-receptor LAR; GPR158 is restricted to proximal CA3 apical dendrites receiving mossy fiber input; loss of GPR158 disrupts mossy fiber bouton morphology, active zone/PSD ultrastructure, and reduces synaptic strength specifically at mossy fiber-CA3 synapses.\",\n      \"method\": \"Co-immunoprecipitation (GPR158-GPC4 interaction), immunofluorescence localization, GPR158 knockout mice, electron microscopy, electrophysiology\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, KO with defined ultrastructural and electrophysiological phenotype, input-specificity confirmed\",\n      \"pmids\": [\"30290982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RbAp48 controls expression of GPR158 in the hippocampus; disruption of OCN/GPR158 signaling leads to downregulation of RbAp48 protein; activation of the OCN/GPR158 pathway increases RbAp48 expression in the aged dentate gyrus, rescuing age-related memory loss.\",\n      \"method\": \"Hippocampal inhibition of RbAp48 (viral), GPR158 KO, behavioral memory assays, western blot for RbAp48/BDNF/GPR158\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO with defined behavioral phenotype and molecular readout, single lab\",\n      \"pmids\": [\"30355501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The GPR158-RGS7 complex in layer 2/3 PFC pyramidal neurons controls A-type potassium channel Kv4.2 function by suppressing cAMP-PKA-mediated phosphorylation; GPR158 physically associates with Kv4.2 channel; deletion of GPR158 or RGS7 enhances excitability of L2/3 PFC neurons and prevents stress-induced depression-like states.\",\n      \"method\": \"Co-immunoprecipitation (GPR158-Kv4.2), GPR158/RGS7 knockout, whole-cell patch-clamp, PKA phosphorylation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, KO with defined electrophysiological and behavioral phenotype, PKA mechanism established\",\n      \"pmids\": [\"31311860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"GPR158 deficiency in CA1 hippocampal neurons reduces dendritic complexity (length, branching, bifurcations) specifically in apical dendrites, increases intrinsic excitability as compensation, and impairs Schaffer collateral-mediated postsynaptic currents, resulting in spatial memory deficits.\",\n      \"method\": \"GPR158 knockout mice, Morris water maze, passive avoidance, whole-cell patch-clamp, neuronal morphology analysis (ex vivo and in vitro)\",\n      \"journal\": \"Frontiers in cellular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO with multiple orthogonal readouts (morphology, electrophysiology, behavior), single lab\",\n      \"pmids\": [\"31749686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"GPR158 localizes predominantly to the nucleus in trabecular meshwork cells via clathrin-mediated endocytosis from the plasma membrane; a bipartite nuclear localization signal (NLS) in the 8th helix is required for nuclear targeting; nuclear localization is required for GPR158-mediated cell proliferation and upregulation of cyclin D1; GPR158 overexpression enhances tight junction proteins ZO-1 and occludin; glucocorticoid treatment increases GPR158 transcription.\",\n      \"method\": \"Immunofluorescence, clathrin inhibitors, NLS mutagenesis, siRNA knockdown, overexpression, cyclin D1/ZO-1/occludin western blot\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mutagenesis with functional readout (cell proliferation), subcellular localization with direct mechanistic consequence, single lab\",\n      \"pmids\": [\"23451275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cryo-EM structure of human GPR158 reveals a homodimeric organization stabilized by a pair of phospholipids, an extracellular Cache domain as ligand-binding domain, and the structural basis of GPR158 coupling to RGS7-Gβ5 via its intracellular regions.\",\n      \"method\": \"Single-particle cryo-EM of GPR158 alone and bound to RGS7-Gβ5 complex\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structure with functional validation of RGS7-Gβ5 coupling, replicated in independent study (PMID:34815401)\",\n      \"pmids\": [\"34793198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cryo-EM structures of GPR158 alone and in complex with one or two RGS7-Gβ5 heterodimers reveal that GPR158 dimerizes through PAS-fold extracellular and transmembrane domains connected by an EGF-like linker; ICL2, ICL3, TM3, and first helix of cytoplasmic coiled-coil form the platform for one RGS7 DHEX domain; the second helix recruits another RGS7, explaining selectivity for RGS7.\",\n      \"method\": \"Cryo-EM structural determination of GPR158 alone and GPR158:RGS7-Gβ5 complexes\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structure independently confirming findings from PMID:34793198\",\n      \"pmids\": [\"34815401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Glycine and taurine directly bind to the extracellular Cache domain of GPR158, identifying GPR158 as a metabotropic glycine receptor (mGlyR); glycine binding inhibits the intracellular RGS7-Gβ5 signaling complex associated with the receptor; glycine signals through mGlyR to inhibit cAMP production; glycine (but not taurine) acts through mGlyR to regulate neuronal excitability in cortical neurons.\",\n      \"method\": \"Ligand-binding assay (Cache domain), in vitro RGS7-Gβ5 activity assay, cAMP measurements, electrophysiology in cortical neurons, mutagenesis\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct binding assay, in vitro enzymatic assay, cellular signaling readout, and electrophysiology, multiple orthogonal methods in one study\",\n      \"pmids\": [\"36996198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Glycine-dependent activation of GPR158 in nucleus accumbens medium spiny neurons (MSNs) increases firing rate by reducing M-current amplitude (Kv7/KCNQ channels) via PKA and ERK signaling, increasing phosphorylation of ERK and Kv7.2 serine residues.\",\n      \"method\": \"Whole-cell patch-clamp, pharmacological PKA/ERK inhibition, western blot for phospho-ERK and phospho-Kv7.2, selective M-current pharmacology\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — electrophysiology with pharmacological dissection and biochemical readout, single lab\",\n      \"pmids\": [\"38884814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GPR158 forms a postsynaptic complex with the constitutively active phospholipase C family member PLCXD2; GPR158 restrains PLCXD2 activity to control spine apparatus (SA) abundance in dendritic spines; in the absence of GPR158, unrestrained PLCXD2 impedes SA incorporation and hampers dendritic spine maturation; extracellular HSPG binding modulates the GPR158-PLCXD2 interaction, providing spatiotemporal control; this represents a direct GPCR-to-PLC signaling pathway bypassing canonical G protein-mediated PLC regulation.\",\n      \"method\": \"Co-immunoprecipitation (GPR158-PLCXD2), in vivo sparse genetic manipulation (cortical neurons), electron microscopy, live imaging, HSPG binding assay\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, in vivo genetic manipulation with defined ultrastructural and functional phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"40393451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GPR158 in mPFC pyramidal neurons modulates social novelty behavior; loss of GPR158 reduces excitatory synaptic transmission (fewer glutamate vesicles, reduced GluN2B expression and phosphorylation); the social novelty deficit is rescued by GPR158 re-expression or chemogenetic activation of GPR158-deficient pyramidal neurons.\",\n      \"method\": \"Conditional and constitutive Gpr158 KO mice, three-chamber social test, electrophysiology, western blot (GluN2B), chemogenetic rescue (DREADDs), viral re-expression\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO with multiple rescue approaches and molecular readout, single lab\",\n      \"pmids\": [\"39383040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"GPR158 promotes prostate cancer cell proliferation independent of androgen receptor functionality, and this requires its nuclear localization; GPR158 expression is stimulated by androgens, and GPR158 stimulates AR expression in a positive feedback loop; GPR158 promotes anchorage-independent colony formation.\",\n      \"method\": \"siRNA knockdown, overexpression, NLS mutation, colony formation assay, androgen treatment\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — KO/OE with defined phenotype, NLS mutagenesis linking localization to function, single lab\",\n      \"pmids\": [\"25693195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"GPR158 overexpression in trabecular meshwork cells enhances cAMP production in response to epinephrine; GPR158 deficiency in mice negates the intraocular pressure-lowering effect of epinephrine.\",\n      \"method\": \"GPR158 overexpression (cAMP assay), Gpr158 KO mice (intraocular pressure measurement with epinephrine)\",\n      \"journal\": \"Journal of ocular pharmacology and therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — KO with defined physiological phenotype plus cellular cAMP assay, single lab\",\n      \"pmids\": [\"30855200\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GPR158 is a class C orphan GPCR that functions as a metabotropic glycine receptor (mGlyR), binding glycine and taurine via its extracellular Cache domain; it forms a homodimer (stabilized by phospholipids) that scaffolds an intracellular RGS7-Gβ5 signaling complex—whose GAP activity GPR158 allosterically enhances—to suppress cAMP production and regulate G protein signaling duration; postsynaptically, GPR158 organizes mossy fiber-CA3 synapses through interaction with glypican 4 (GPC4)/LAR and controls dendritic spine maturation by restraining a PLCXD2 phospholipase C via a non-canonical direct GPCR-to-PLC pathway; it additionally associates with Kv4.2 potassium channels to modulate neuronal excitability downstream of stress-induced glucocorticoid signaling in the prefrontal cortex, and transduces osteocalcin signals in hippocampal neurons through IP3 and BDNF to regulate memory and mood.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"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].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-immunoprecipitation, cell fractionation, and retinal localization in WT vs. Gpr158 KO mice\",\n      \"pmids\": [\"22689652\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"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.\",\n      \"evidence\": \"Immunofluorescence, NLS mutagenesis, siRNA knockdown, and overexpression in trabecular meshwork cells\",\n      \"pmids\": [\"23451275\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"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.\",\n      \"evidence\": \"GPR158 KO mice (RGS7 protein stability), in vitro GAP assays with C-terminal fragments, mutagenesis\",\n      \"pmids\": [\"25792749\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of allosteric GAP enhancement unknown\", \"Whether GPR158 signals through canonical Gα coupling remained unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"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.\",\n      \"evidence\": \"Gpr158 KO mice with behavioral testing, electrophysiology, IP3 and BDNF measurements\",\n      \"pmids\": [\"28851741\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether osteocalcin directly binds GPR158 was not demonstrated\", \"Relationship between osteocalcin and later-identified glycine ligand unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"29419376\", \"30290982\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP of GPR158–Kv4.2, GPR158/RGS7 KO with patch-clamp and PKA phosphorylation assays\",\n      \"pmids\": [\"31311860\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"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.\",\n      \"evidence\": \"Single-particle cryo-EM, independently confirmed by two groups\",\n      \"pmids\": [\"34793198\", \"34815401\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No ligand was bound in any structure, leaving the activation mechanism unresolved\", \"How phospholipid binding contributes to signaling vs. structural stability was unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"evidence\": \"Direct ligand-binding assay on Cache domain, in vitro RGS7–Gβ5 activity assay, cAMP measurements, cortical neuron electrophysiology, mutagenesis\",\n      \"pmids\": [\"36996198\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of glycine-induced conformational change not captured\", \"Whether taurine produces distinct downstream signaling from glycine in vivo was unexplored\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"evidence\": \"Whole-cell patch-clamp, pharmacological PKA/ERK inhibition, phospho-ERK and phospho-Kv7.2 western blots\",\n      \"pmids\": [\"38884814\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP of GPR158–PLCXD2, in vivo sparse genetic manipulation in cortical neurons, electron microscopy, live imaging, HSPG binding assay\",\n      \"pmids\": [\"40393451\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 11, 13]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [2, 11, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 4, 9, 10]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [8, 15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 6, 11, 12]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [3, 4, 6, 7, 14]}\n    ],\n    \"complexes\": [\n      \"GPR158–RGS7–Gβ5\",\n      \"GPR158–PLCXD2\"\n    ],\n    \"partners\": [\n      \"RGS7\",\n      \"GNB5\",\n      \"PLCXD2\",\n      \"GPC4\",\n      \"PTPRF\",\n      \"KCND2\",\n      \"RGS11\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}