{"gene":"GPR158","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2012,"finding":"GPR158 (and GPR179) physically interact with RGS7 complexes, recruit them to the plasma membrane, and augment their ability to regulate GPCR signaling; loss of GPR179 in a mouse model of night blindness prevented targeting of RGS to the postsynaptic compartment of bipolar neurons, establishing the functional role of this interaction in compartmentalizing G protein signaling.","method":"Co-immunoprecipitation, subcellular fractionation, mouse knockout model (night blindness), plasma membrane recruitment assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, mouse KO with defined cellular phenotype, replicated across two receptor family members with functional consequence","pmids":["22689652"],"is_preprint":false},{"year":2015,"finding":"GPR158 stabilizes RGS7 post-transcriptionally, maintains its membrane association in the brain, and allosterically enhances RGS7 GTPase-activating protein (GAP) activity through a conserved sequence in the proximal C terminus; the distal C terminus contains PDE-Eγ-like motifs that selectively recruit activated G proteins. Knockout of GPR158 in mice causes marked loss of RGS7 and its membrane association.","method":"GPR158 knockout mouse, in vitro GAP activity assays, C-terminal domain mapping/mutagenesis, pulldown assays, western blot","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro enzymatic assay with domain mutagenesis plus mouse KO with defined molecular phenotype, single lab but multiple orthogonal methods","pmids":["25792749"],"is_preprint":false},{"year":2017,"finding":"GPR158 is expressed in neurons of the CA3 region of the hippocampus and transduces osteocalcin (OCN) signaling to regulate hippocampal-dependent memory and anxiety-like behaviors, in part through inositol 1,4,5-trisphosphate (IP3) and BDNF pathways; genetic, electrophysiological, molecular, and behavioral assays established GPR158 as the neuronal receptor for OCN.","method":"Genetic (knockout mice), electrophysiology, behavioral assays (memory, anxiety), molecular signaling assays (IP3, BDNF measurement)","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (genetics, electrophysiology, behavioral readouts, molecular signaling) in a single focused study","pmids":["28851741"],"is_preprint":false},{"year":2018,"finding":"GPR158 is upregulated in the prefrontal cortex (PFC) by glucocorticoids in response to chronic stress; viral overexpression of GPR158 in the PFC induces depressive-like behaviors, while GPR158 ablation produces antidepressant-like phenotype and stress resiliency. GPR158 exerts these effects by modulating synaptic strength via AMPA receptor activity.","method":"Chronic stress mouse model, viral overexpression, GPR158 knockout, behavioral assays, glucocorticoid treatment, AMPA receptor activity measurements","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Moderate — bidirectional genetic manipulation (KO and OE) with defined behavioral and synaptic phenotypes, glucocorticoid-dependent mechanism established","pmids":["29419376"],"is_preprint":false},{"year":2018,"finding":"GPR158 acts as a postsynaptic binding partner for heparan sulfate proteoglycan glypican 4 (GPC4), which is enriched on hippocampal mossy fiber axons; GPR158-induced presynaptic differentiation requires cell-surface GPC4 and co-receptor LAR. Loss of GPR158 increases mossy fiber synapse density but disrupts bouton morphology, active zone and postsynaptic density ultrastructure, and reduces synaptic strength selectively at mossy fiber-CA3 synapses.","method":"Co-immunoprecipitation, pulldown assay, immunofluorescence, GPR158 knockout mouse, electron microscopy, electrophysiology","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal binding assays, mouse KO, ultrastructural and electrophysiological phenotyping, multiple orthogonal methods","pmids":["30290982"],"is_preprint":false},{"year":2018,"finding":"RbAp48/Rbbp4 controls expression of GPR158 and BDNF in the hippocampus; inhibition of RbAp48 inhibits OCN/GPR158-dependent cognition; disruption of OCN/GPR158 signaling downregulates RbAp48, and activation of OCN/GPR158 pathway increases RbAp48 expression in the aged dentate gyrus to rescue age-related memory loss, establishing a feedback loop between RbAp48 and GPR158.","method":"Hippocampal RbAp48 inhibition (mouse), GPR158 knockout, behavioral memory assays, western blot for protein expression","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function genetic manipulations with defined molecular and behavioral readouts, single lab","pmids":["30355501"],"is_preprint":false},{"year":2019,"finding":"GPR158 forms a physical complex with RGS7 that controls A-type potassium channel Kv4.2 subunit in layer 2/3 PFC pyramidal neurons; GPR158 physically associates with Kv4.2 and promotes its function by suppressing inhibitory cAMP-PKA-mediated phosphorylation, thereby controlling neuronal excitability and stress-induced depressive-like behaviors.","method":"Co-immunoprecipitation (GPR158-Kv4.2 association), patch-clamp electrophysiology, GPR158/RGS7 knockout mice, chronic stress paradigm, cAMP-PKA assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP for physical association, mouse KO with defined electrophysiological and behavioral phenotypes, molecular mechanism (cAMP-PKA-Kv4.2) supported by multiple methods","pmids":["31311860"],"is_preprint":false},{"year":2019,"finding":"Gpr158 deficiency in mice impairs hippocampal CA1 dendritic architecture (reduced dendritic length, surface, branching in apical but not basal dendrites) and reduces Schaffer collateral-mediated postsynaptic currents while increasing intrinsic excitability of CA1 pyramidal neurons; these morphological deficits correlate with spatial memory impairments.","method":"Gpr158 knockout mouse, Morris water maze, passive avoidance test, patch-clamp electrophysiology, dendritic morphology analysis (ex vivo and in vitro)","journal":"Frontiers in cellular neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with defined morphological, electrophysiological and behavioral phenotypes, single lab","pmids":["31749686"],"is_preprint":false},{"year":2021,"finding":"Cryo-EM structures of human GPR158 alone and in complex with RGS7-Gβ5 reveal: (1) GPR158 forms a homodimer stabilized by a pair of phospholipids; (2) it possesses an extracellular Cache domain as an unusual ligand-binding domain; (3) the structural basis of GPR158 coupling to RGS7-Gβ5 is provided by interaction of the C terminus intracellular coiled-coil region with RGS7.","method":"Single-particle cryo-electron microscopy (cryo-EM), structural determination of apo and RGS7-Gβ5-bound states","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution cryo-EM structure of GPR158 alone and in complex, 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: GPR158 dimerizes through Per-Arnt-Sim (PAS)-fold extracellular and TM domains connected by an EGF-like linker; ICL2, ICL3, TM3, and first helix of the cytoplasmic coiled-coil provide a platform for the DHEX domain of one RGS7, while the second helix recruits another RGS7; the unique RGS7-binding site underlies selectivity of GPR158 for RGS7.","method":"Cryo-EM structural determination, domain analysis, structure-based selectivity analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — independent cryo-EM structure replicating and extending findings of PMID:34793198, multiple structural features defined","pmids":["34815401"],"is_preprint":false},{"year":2023,"finding":"GPR158 is a metabotropic glycine receptor (mGlyR): glycine and taurine directly bind to the extracellular Cache domain of GPR158; glycine binding inhibits the RGS7-Gβ5 signaling complex associated with the receptor and inhibits cAMP production; glycine (but not taurine) acts through GPR158 to regulate neuronal excitability in cortical neurons.","method":"Ligand binding assays (Cache domain), in vitro signaling assays (cAMP measurement), electrophysiology in cortical neurons, GPR158 knockout comparison","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct binding demonstrated, in vitro signaling assay, electrophysiology with KO controls; multiple orthogonal methods in one rigorous study","pmids":["36996198"],"is_preprint":false},{"year":2013,"finding":"In trabecular meshwork cells, glucocorticoid treatment increases GPR158 expression through transcriptional mechanisms; endogenous and overexpressed GPR158 localizes almost entirely to the nucleus via a bipartite nuclear localization signal (NLS) in the 8th helix; inhibition of clathrin-mediated endocytosis shifts GPR158 to the plasma membrane; NLS mutation abrogates GPR158-mediated enhancement of cell proliferation and cyclin D1 upregulation, demonstrating a functional requirement for nuclear localization.","method":"siRNA knockdown, transient overexpression, clathrin endocytosis inhibitors, NLS mutagenesis, subcellular fractionation/immunofluorescence, cell proliferation assays, western blot","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — NLS mutagenesis with functional consequence, endocytosis inhibitor experiments, multiple orthogonal methods; single lab","pmids":["23451275"],"is_preprint":false},{"year":2015,"finding":"GPR158 promotes prostate cancer cell proliferation independently of androgen receptor (AR) functionality, and this requires nuclear localization; GPR158 expression is stimulated by androgens and GPR158 stimulates AR expression (positive feedback); GPR158 promotes anchorage-independent colony formation and its nuclear localization co-localizes with elevated AR in the Pten knockout mouse prostate tumor model.","method":"siRNA knockdown, overexpression, nuclear localization analysis (immunofluorescence), anchorage-independent colony assay, conditional Pten KO mouse model, AR/androgen treatment","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — loss/gain-of-function with defined cellular phenotypes, nuclear localization established, in vivo mouse model; single lab","pmids":["25693195"],"is_preprint":false},{"year":2019,"finding":"GPR158 overexpression enhances cAMP production in response to epinephrine in trabecular meshwork cells; Gpr158 knockout mice show altered intraocular pressure response to epinephrine (pressure-lowering effect negated), identifying GPR158 as a homeostatic regulator of intraocular pressure via cAMP signaling.","method":"GPR158 overexpression, Gpr158 knockout mouse, cAMP measurement, intraocular pressure measurement, epinephrine challenge","journal":"Journal of ocular pharmacology and therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with defined physiological phenotype, cAMP signaling mechanism, single lab","pmids":["30855200"],"is_preprint":false},{"year":2024,"finding":"Glycine-dependent activation of GPR158 in nucleus accumbens medium spiny neurons (MSNs) increases firing rate, reduces M-current (Kv7/KCNQ channels) amplitude, and this effect requires PKA and ERK signaling; GPR158 activation increases ERK phosphorylation and Kv7.2 serine phosphorylation, establishing a GPR158/PKA/ERK/Kv7.2 signaling pathway controlling MSN excitability.","method":"Whole-cell patch-clamp recordings, pharmacological inhibitors of PKA and ERK, phosphorylation assays (ERK, Kv7.2), Kv7 channel blockers (occlusion experiments)","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — electrophysiology with pharmacological dissection and phosphorylation assays, occlusion experiments; single lab","pmids":["38884814"],"is_preprint":false},{"year":2024,"finding":"GPR158 in pyramidal neurons of the medial PFC controls social novelty behavior; loss of GPR158 reduces excitatory synaptic transmission, glutamate vesicle abundance, and expression/phosphorylation of GluN2B in the mPFC; reintroduction of GPR158 in the mPFC or chemogenetic activation of GPR158-ablated pyramidal neurons rescues the social novelty deficit.","method":"Constitutive and conditional Gpr158 knockout, viral GPR158 re-expression, DREADD chemogenetics, behavioral assays, western blot (GluN2B expression/phosphorylation), electron microscopy (glutamate vesicles)","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional genetic manipulation with defined behavioral and molecular phenotypes, rescue experiments; single lab","pmids":["39383040"],"is_preprint":false},{"year":2025,"finding":"GPR158 forms a postsynaptic complex with PLCXD2 (a constitutively active PLC family member) that controls spine apparatus (SA) abundance in dendritic spines; in the absence of GPR158, unrestrained PLCXD2 activity impedes SA incorporation and hampers structural and functional dendritic spine maturation; extracellular HSPG binding modulates the GPR158-PLCXD2 interaction, providing spatiotemporal control; this establishes a direct GPCR-like receptor-to-PLC signaling pathway bypassing canonical G protein-mediated PLC regulation.","method":"Sparse genetic manipulation of mouse cortical neurons in vivo, co-immunoprecipitation (GPR158-PLCXD2), electron microscopy (spine apparatus), electrophysiology, HSPG binding assays","journal":"Developmental cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of complex, in vivo genetic manipulation with ultrastructural and functional phenotypes; novel mechanism, single lab","pmids":["40393451"],"is_preprint":false},{"year":2025,"finding":"Trilobatin directly binds to GPR158 and decreases its protein expression level; GPR158 deficiency promotes mitophagy and attenuates depressive-like behaviors; trilobatin's antidepressant effect was strengthened in GPR158-deficient mice, supporting GPR158 as its direct target.","method":"Direct binding assay (trilobatin-GPR158), GPR158 knockout mouse, CUMS chronic stress model, mitophagy assays, autophagy-associated protein expression, behavioral assays","journal":"Journal of agricultural and food chemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — direct binding assay reported but limited mechanistic detail in abstract; single lab, single compound study","pmids":["39962827"],"is_preprint":false}],"current_model":"GPR158 is a class C orphan GPCR that forms a homodimer (stabilized by phospholipids) with an extracellular Cache domain that directly binds glycine and taurine (acting as a metabotropic glycine receptor, mGlyR), and an intracellular C terminus that physically recruits and allosterically potentiates the RGS7-Gβ5 GAP complex to suppress Gαi/o signaling and cAMP production; at synapses, GPR158 interacts with heparan sulfate proteoglycans (GPC4) to organize mossy fiber-CA3 synapse architecture, associates with Kv4.2 to suppress cAMP-PKA-mediated phosphorylation and control neuronal excitability, forms a complex with PLCXD2 to regulate spine apparatus abundance, and is regulated by glucocorticoids to modulate stress-induced depression in the prefrontal cortex."},"narrative":{"mechanistic_narrative":"GPR158 is a class C orphan GPCR that functions as a synaptic organizing receptor and a master regulator of inhibitory G protein signaling in the brain [PMID:22689652, PMID:28851741]. Its intracellular C terminus stabilizes the RGS7-Gβ5 GAP complex post-transcriptionally, maintains its membrane association, and allosterically enhances RGS7 GAP activity, thereby suppressing Gαi/o signaling and cAMP production [PMID:25792749]. Cryo-EM structures show GPR158 assembles as a phospholipid-stabilized homodimer with an extracellular Cache/PAS-fold domain and a cytoplasmic coiled-coil that provides a selective docking platform recruiting one or two RGS7-Gβ5 heterodimers [PMID:34793198, PMID:34815401]. The extracellular Cache domain directly binds glycine and taurine, defining GPR158 as a metabotropic glycine receptor (mGlyR) whose glycine binding inhibits the associated RGS7-Gβ5 complex and cAMP production to regulate cortical neuronal excitability [PMID:36996198]. Downstream, GPR158 controls neuronal excitability by associating with the Kv4.2 channel and suppressing inhibitory cAMP-PKA-mediated phosphorylation [PMID:31311860], and a glycine/GPR158/PKA/ERK/Kv7.2 pathway tunes firing of nucleus accumbens medium spiny neurons [PMID:38884814]. At synapses, GPR158 acts as a postsynaptic partner for the heparan sulfate proteoglycan glypican-4 (GPC4) together with the co-receptor LAR to organize mossy fiber-CA3 synapse architecture and presynaptic differentiation [PMID:30290982], and forms a complex with the constitutively active PLCXD2 to restrain PLC activity and control spine apparatus abundance and dendritic spine maturation [PMID:40393451]. GPR158 transduces osteocalcin signaling in CA3 neurons to regulate memory and anxiety via IP3 and BDNF [PMID:28851741], and is upregulated by glucocorticoids in the prefrontal cortex where it drives stress-induced depressive-like behavior through effects on AMPA receptor-mediated synaptic strength [PMID:29419376]. Beyond its neuronal roles, GPR158 has also been reported to localize to the nucleus via a bipartite NLS and promote cell proliferation in non-neuronal cells [PMID:23451275].","teleology":[{"year":2012,"claim":"Established that GPR158 is a binding partner that recruits RGS7 complexes to the membrane and compartmentalizes G protein signaling, answering what cellular function this orphan receptor serves.","evidence":"Reciprocal Co-IP, subcellular fractionation, and a GPR179 night-blindness mouse KO with defined postsynaptic targeting phenotype","pmids":["22689652"],"confidence":"High","gaps":["Did not define the structural basis or the C-terminal element mediating RGS recruitment","Endogenous ligand and signaling output unknown"]},{"year":2015,"claim":"Mapped the C-terminal determinants by which GPR158 stabilizes RGS7, maintains its membrane association, and allosterically enhances its GAP activity, defining the molecular mechanism of signaling regulation.","evidence":"GPR158 KO mouse, in vitro GAP assays, and C-terminal domain mapping/mutagenesis","pmids":["25792749"],"confidence":"High","gaps":["Atomic structure of the GPR158-RGS7 interface not resolved","Upstream activating signal still unknown"]},{"year":2017,"claim":"Identified GPR158 as a neuronal receptor for osteocalcin in CA3, linking a peripheral hormone to hippocampal memory and anxiety circuits.","evidence":"KO mice, electrophysiology, behavioral assays, and IP3/BDNF molecular readouts","pmids":["28851741"],"confidence":"High","gaps":["Direct osteocalcin binding to GPR158 not biochemically demonstrated","Relationship between OCN signaling and RGS7 GAP activity unclear"]},{"year":2018,"claim":"Showed GPR158 is a glucocorticoid-induced driver of stress-induced depression in the PFC acting through synaptic AMPA receptor strength, establishing a behavioral pathophysiological role.","evidence":"Chronic stress model with bidirectional viral overexpression and KO, plus AMPA receptor activity measurements","pmids":["29419376"],"confidence":"High","gaps":["Molecular link between GPR158/RGS7 signaling and AMPA receptor regulation not fully defined","Ligand driving GPR158 activity in stress unknown"]},{"year":2018,"claim":"Defined GPR158 as a postsynaptic GPC4 binding partner that organizes mossy fiber-CA3 synapse architecture, identifying a trans-synaptic adhesion function distinct from G protein signaling.","evidence":"Reciprocal binding assays, KO mouse, electron microscopy, and electrophysiology","pmids":["30290982"],"confidence":"High","gaps":["How HSPG binding couples to intracellular signaling not resolved at this stage","Generalizability beyond mossy fiber-CA3 synapses unknown"]},{"year":2018,"claim":"Connected GPR158 to a transcriptional feedback loop with RbAp48/Rbbp4 governing memory, implicating it in age-related cognitive decline.","evidence":"Hippocampal RbAp48 inhibition, GPR158 KO, and behavioral memory assays with protein expression analysis","pmids":["30355501"],"confidence":"Medium","gaps":["Mechanism linking GPR158 signaling to RbAp48 transcription not defined","Single lab; feedback loop not independently confirmed"]},{"year":2019,"claim":"Demonstrated GPR158 physically associates with Kv4.2 and promotes its function by suppressing cAMP-PKA phosphorylation, defining an effector channel mechanism controlling excitability and depression.","evidence":"Co-IP, patch-clamp electrophysiology, GPR158/RGS7 KO mice, and cAMP-PKA assays","pmids":["31311860"],"confidence":"High","gaps":["Whether GPR158-Kv4.2 association is direct or scaffolded not established","Stoichiometry with the RGS7 complex unknown"]},{"year":2019,"claim":"Showed GPR158 deficiency impairs CA1 dendritic architecture and Schaffer collateral synaptic transmission, broadening its structural role beyond mossy fiber synapses.","evidence":"KO mouse with dendritic morphology analysis, electrophysiology, and spatial memory tests","pmids":["31749686"],"confidence":"Medium","gaps":["Molecular pathway driving dendritic morphology not defined","Single lab"]},{"year":2021,"claim":"Resolved cryo-EM structures of GPR158 alone and bound to RGS7-Gβ5, revealing a phospholipid-stabilized homodimer, an extracellular Cache/PAS-fold ligand-binding domain, and the coiled-coil platform underlying selective RGS7 recruitment.","evidence":"Single-particle cryo-EM of apo and RGS7-Gβ5-bound states, independently in two studies","pmids":["34793198","34815401"],"confidence":"High","gaps":["Endogenous ligand for the Cache domain not identified in these structures","Activation/conformational coupling between ligand site and RGS complex unresolved"]},{"year":2023,"claim":"Identified glycine and taurine as direct Cache-domain ligands, establishing GPR158 as a metabotropic glycine receptor that inhibits RGS7-Gβ5 signaling and cAMP to control cortical excitability.","evidence":"Cache-domain binding assays, in vitro cAMP signaling, and cortical neuron electrophysiology with KO controls","pmids":["36996198"],"confidence":"High","gaps":["Physiological glycine concentration ranges relevant in vivo not fully mapped","Distinct roles of taurine versus glycine downstream incompletely defined"]},{"year":2024,"claim":"Extended ligand-driven GPR158 signaling to a PKA/ERK/Kv7.2 (M-current) pathway in nucleus accumbens MSNs, linking glycine sensing to a second channel effector.","evidence":"Patch-clamp, PKA/ERK pharmacology, phosphorylation assays, and Kv7 occlusion experiments","pmids":["38884814"],"confidence":"Medium","gaps":["Direct versus indirect Kv7.2 regulation not resolved","Single lab"]},{"year":2024,"claim":"Showed mPFC GPR158 controls social novelty behavior through excitatory transmission and GluN2B regulation, with rescue establishing causality.","evidence":"Constitutive/conditional KO, viral re-expression, DREADD chemogenetics, western blot, and electron microscopy","pmids":["39383040"],"confidence":"Medium","gaps":["Mechanistic link from GPR158 signaling to GluN2B phosphorylation not defined","Single lab"]},{"year":2025,"claim":"Defined a GPR158-PLCXD2 postsynaptic complex that restrains constitutive PLC activity to control spine apparatus abundance and spine maturation, revealing a non-canonical receptor-to-PLC pathway gated by HSPG binding.","evidence":"In vivo sparse genetic manipulation, Co-IP, electron microscopy, electrophysiology, and HSPG binding assays","pmids":["40393451"],"confidence":"Medium","gaps":["How HSPG binding mechanistically modulates the GPR158-PLCXD2 interaction not fully resolved","Single lab; PLCXD2 activity regulation by GPR158 not biochemically reconstituted"]},{"year":2025,"claim":"Reported the natural compound trilobatin as a direct GPR158 binder that lowers its expression and links GPR158 to mitophagy and depression, suggesting a pharmacological handle.","evidence":"Direct binding assay, GPR158 KO, CUMS stress model, and mitophagy/autophagy protein readouts","pmids":["39962827"],"confidence":"Low","gaps":["Binding site and mechanism of expression reduction not defined","Single compound, single lab; mitophagy link not independently confirmed"]},{"year":null,"claim":"How ligand binding at the extracellular Cache domain is conformationally transmitted across the dimer to switch the intracellular RGS7-Gβ5 GAP activity, and how this integrates with the adhesion (GPC4) and PLCXD2 effector arms, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure capturing a ligand-bound active state coupled to RGS7","Integration of glycine sensing, trans-synaptic adhesion, and PLC signaling into one mechanistic model is incomplete"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[10,2]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,8,9]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,6]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,8]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[11,12]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,10]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[6,10,14]}],"complexes":["GPR158-RGS7-Gβ5 complex","GPR158 homodimer","GPR158-PLCXD2 complex"],"partners":["RGS7","GNB5","GPC4","KCND2","PLCXD2","LAR"],"other_free_text":[]}},"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":240,"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":"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":58,"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":"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":43,"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":35,"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":17,"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":"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":8,"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":8,"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":"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":6,"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":4,"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":"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":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":"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":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14231,"output_tokens":4968,"usd":0.058606,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13250,"output_tokens":4649,"usd":0.091237,"stage2_stop_reason":"end_turn"},"total_usd":0.149843,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"GPR158 (and GPR179) physically interact with RGS7 complexes, recruit them to the plasma membrane, and augment their ability to regulate GPCR signaling; loss of GPR179 in a mouse model of night blindness prevented targeting of RGS to the postsynaptic compartment of bipolar neurons, establishing the functional role of this interaction in compartmentalizing G protein signaling.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, mouse knockout model (night blindness), plasma membrane recruitment assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, mouse KO with defined cellular phenotype, replicated across two receptor family members with functional consequence\",\n      \"pmids\": [\"22689652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"GPR158 stabilizes RGS7 post-transcriptionally, maintains its membrane association in the brain, and allosterically enhances RGS7 GTPase-activating protein (GAP) activity through a conserved sequence in the proximal C terminus; the distal C terminus contains PDE-Eγ-like motifs that selectively recruit activated G proteins. Knockout of GPR158 in mice causes marked loss of RGS7 and its membrane association.\",\n      \"method\": \"GPR158 knockout mouse, in vitro GAP activity assays, C-terminal domain mapping/mutagenesis, pulldown assays, western blot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro enzymatic assay with domain mutagenesis plus mouse KO with defined molecular phenotype, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"25792749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"GPR158 is expressed in neurons of the CA3 region of the hippocampus and transduces osteocalcin (OCN) signaling to regulate hippocampal-dependent memory and anxiety-like behaviors, in part through inositol 1,4,5-trisphosphate (IP3) and BDNF pathways; genetic, electrophysiological, molecular, and behavioral assays established GPR158 as the neuronal receptor for OCN.\",\n      \"method\": \"Genetic (knockout mice), electrophysiology, behavioral assays (memory, anxiety), molecular signaling assays (IP3, BDNF measurement)\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (genetics, electrophysiology, behavioral readouts, molecular signaling) in a single focused study\",\n      \"pmids\": [\"28851741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"GPR158 is upregulated in the prefrontal cortex (PFC) by glucocorticoids in response to chronic stress; viral overexpression of GPR158 in the PFC induces depressive-like behaviors, while GPR158 ablation produces antidepressant-like phenotype and stress resiliency. GPR158 exerts these effects by modulating synaptic strength via AMPA receptor activity.\",\n      \"method\": \"Chronic stress mouse model, viral overexpression, GPR158 knockout, behavioral assays, glucocorticoid treatment, AMPA receptor activity measurements\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional genetic manipulation (KO and OE) with defined behavioral and synaptic phenotypes, glucocorticoid-dependent mechanism established\",\n      \"pmids\": [\"29419376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"GPR158 acts as a postsynaptic binding partner for heparan sulfate proteoglycan glypican 4 (GPC4), which is enriched on hippocampal mossy fiber axons; GPR158-induced presynaptic differentiation requires cell-surface GPC4 and co-receptor LAR. Loss of GPR158 increases mossy fiber synapse density but disrupts bouton morphology, active zone and postsynaptic density ultrastructure, and reduces synaptic strength selectively at mossy fiber-CA3 synapses.\",\n      \"method\": \"Co-immunoprecipitation, pulldown assay, immunofluorescence, GPR158 knockout mouse, electron microscopy, electrophysiology\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding assays, mouse KO, ultrastructural and electrophysiological phenotyping, multiple orthogonal methods\",\n      \"pmids\": [\"30290982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RbAp48/Rbbp4 controls expression of GPR158 and BDNF in the hippocampus; inhibition of RbAp48 inhibits OCN/GPR158-dependent cognition; disruption of OCN/GPR158 signaling downregulates RbAp48, and activation of OCN/GPR158 pathway increases RbAp48 expression in the aged dentate gyrus to rescue age-related memory loss, establishing a feedback loop between RbAp48 and GPR158.\",\n      \"method\": \"Hippocampal RbAp48 inhibition (mouse), GPR158 knockout, behavioral memory assays, western blot for protein expression\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function genetic manipulations with defined molecular and behavioral readouts, single lab\",\n      \"pmids\": [\"30355501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"GPR158 forms a physical complex with RGS7 that controls A-type potassium channel Kv4.2 subunit in layer 2/3 PFC pyramidal neurons; GPR158 physically associates with Kv4.2 and promotes its function by suppressing inhibitory cAMP-PKA-mediated phosphorylation, thereby controlling neuronal excitability and stress-induced depressive-like behaviors.\",\n      \"method\": \"Co-immunoprecipitation (GPR158-Kv4.2 association), patch-clamp electrophysiology, GPR158/RGS7 knockout mice, chronic stress paradigm, cAMP-PKA assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP for physical association, mouse KO with defined electrophysiological and behavioral phenotypes, molecular mechanism (cAMP-PKA-Kv4.2) supported by multiple methods\",\n      \"pmids\": [\"31311860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Gpr158 deficiency in mice impairs hippocampal CA1 dendritic architecture (reduced dendritic length, surface, branching in apical but not basal dendrites) and reduces Schaffer collateral-mediated postsynaptic currents while increasing intrinsic excitability of CA1 pyramidal neurons; these morphological deficits correlate with spatial memory impairments.\",\n      \"method\": \"Gpr158 knockout mouse, Morris water maze, passive avoidance test, patch-clamp electrophysiology, dendritic morphology analysis (ex vivo and in vitro)\",\n      \"journal\": \"Frontiers in cellular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with defined morphological, electrophysiological and behavioral phenotypes, single lab\",\n      \"pmids\": [\"31749686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cryo-EM structures of human GPR158 alone and in complex with RGS7-Gβ5 reveal: (1) GPR158 forms a homodimer stabilized by a pair of phospholipids; (2) it possesses an extracellular Cache domain as an unusual ligand-binding domain; (3) the structural basis of GPR158 coupling to RGS7-Gβ5 is provided by interaction of the C terminus intracellular coiled-coil region with RGS7.\",\n      \"method\": \"Single-particle cryo-electron microscopy (cryo-EM), structural determination of apo and RGS7-Gβ5-bound states\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution cryo-EM structure of GPR158 alone and in complex, 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: GPR158 dimerizes through Per-Arnt-Sim (PAS)-fold extracellular and TM domains connected by an EGF-like linker; ICL2, ICL3, TM3, and first helix of the cytoplasmic coiled-coil provide a platform for the DHEX domain of one RGS7, while the second helix recruits another RGS7; the unique RGS7-binding site underlies selectivity of GPR158 for RGS7.\",\n      \"method\": \"Cryo-EM structural determination, domain analysis, structure-based selectivity analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — independent cryo-EM structure replicating and extending findings of PMID:34793198, multiple structural features defined\",\n      \"pmids\": [\"34815401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"GPR158 is a metabotropic glycine receptor (mGlyR): glycine and taurine directly bind to the extracellular Cache domain of GPR158; glycine binding inhibits the RGS7-Gβ5 signaling complex associated with the receptor and inhibits cAMP production; glycine (but not taurine) acts through GPR158 to regulate neuronal excitability in cortical neurons.\",\n      \"method\": \"Ligand binding assays (Cache domain), in vitro signaling assays (cAMP measurement), electrophysiology in cortical neurons, GPR158 knockout comparison\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct binding demonstrated, in vitro signaling assay, electrophysiology with KO controls; multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"36996198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In trabecular meshwork cells, glucocorticoid treatment increases GPR158 expression through transcriptional mechanisms; endogenous and overexpressed GPR158 localizes almost entirely to the nucleus via a bipartite nuclear localization signal (NLS) in the 8th helix; inhibition of clathrin-mediated endocytosis shifts GPR158 to the plasma membrane; NLS mutation abrogates GPR158-mediated enhancement of cell proliferation and cyclin D1 upregulation, demonstrating a functional requirement for nuclear localization.\",\n      \"method\": \"siRNA knockdown, transient overexpression, clathrin endocytosis inhibitors, NLS mutagenesis, subcellular fractionation/immunofluorescence, cell proliferation assays, western blot\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — NLS mutagenesis with functional consequence, endocytosis inhibitor experiments, multiple orthogonal methods; single lab\",\n      \"pmids\": [\"23451275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"GPR158 promotes prostate cancer cell proliferation independently of androgen receptor (AR) functionality, and this requires nuclear localization; GPR158 expression is stimulated by androgens and GPR158 stimulates AR expression (positive feedback); GPR158 promotes anchorage-independent colony formation and its nuclear localization co-localizes with elevated AR in the Pten knockout mouse prostate tumor model.\",\n      \"method\": \"siRNA knockdown, overexpression, nuclear localization analysis (immunofluorescence), anchorage-independent colony assay, conditional Pten KO mouse model, AR/androgen treatment\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — loss/gain-of-function with defined cellular phenotypes, nuclear localization established, in vivo mouse model; single lab\",\n      \"pmids\": [\"25693195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"GPR158 overexpression enhances cAMP production in response to epinephrine in trabecular meshwork cells; Gpr158 knockout mice show altered intraocular pressure response to epinephrine (pressure-lowering effect negated), identifying GPR158 as a homeostatic regulator of intraocular pressure via cAMP signaling.\",\n      \"method\": \"GPR158 overexpression, Gpr158 knockout mouse, cAMP measurement, intraocular pressure measurement, epinephrine challenge\",\n      \"journal\": \"Journal of ocular pharmacology and therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with defined physiological phenotype, cAMP signaling mechanism, single lab\",\n      \"pmids\": [\"30855200\"],\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, reduces M-current (Kv7/KCNQ channels) amplitude, and this effect requires PKA and ERK signaling; GPR158 activation increases ERK phosphorylation and Kv7.2 serine phosphorylation, establishing a GPR158/PKA/ERK/Kv7.2 signaling pathway controlling MSN excitability.\",\n      \"method\": \"Whole-cell patch-clamp recordings, pharmacological inhibitors of PKA and ERK, phosphorylation assays (ERK, Kv7.2), Kv7 channel blockers (occlusion experiments)\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — electrophysiology with pharmacological dissection and phosphorylation assays, occlusion experiments; single lab\",\n      \"pmids\": [\"38884814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GPR158 in pyramidal neurons of the medial PFC controls social novelty behavior; loss of GPR158 reduces excitatory synaptic transmission, glutamate vesicle abundance, and expression/phosphorylation of GluN2B in the mPFC; reintroduction of GPR158 in the mPFC or chemogenetic activation of GPR158-ablated pyramidal neurons rescues the social novelty deficit.\",\n      \"method\": \"Constitutive and conditional Gpr158 knockout, viral GPR158 re-expression, DREADD chemogenetics, behavioral assays, western blot (GluN2B expression/phosphorylation), electron microscopy (glutamate vesicles)\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional genetic manipulation with defined behavioral and molecular phenotypes, rescue experiments; single lab\",\n      \"pmids\": [\"39383040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GPR158 forms a postsynaptic complex with PLCXD2 (a constitutively active PLC family member) that controls spine apparatus (SA) abundance in dendritic spines; in the absence of GPR158, unrestrained PLCXD2 activity impedes SA incorporation and hampers structural and functional dendritic spine maturation; extracellular HSPG binding modulates the GPR158-PLCXD2 interaction, providing spatiotemporal control; this establishes a direct GPCR-like receptor-to-PLC signaling pathway bypassing canonical G protein-mediated PLC regulation.\",\n      \"method\": \"Sparse genetic manipulation of mouse cortical neurons in vivo, co-immunoprecipitation (GPR158-PLCXD2), electron microscopy (spine apparatus), electrophysiology, HSPG binding assays\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of complex, in vivo genetic manipulation with ultrastructural and functional phenotypes; novel mechanism, single lab\",\n      \"pmids\": [\"40393451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Trilobatin directly binds to GPR158 and decreases its protein expression level; GPR158 deficiency promotes mitophagy and attenuates depressive-like behaviors; trilobatin's antidepressant effect was strengthened in GPR158-deficient mice, supporting GPR158 as its direct target.\",\n      \"method\": \"Direct binding assay (trilobatin-GPR158), GPR158 knockout mouse, CUMS chronic stress model, mitophagy assays, autophagy-associated protein expression, behavioral assays\",\n      \"journal\": \"Journal of agricultural and food chemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — direct binding assay reported but limited mechanistic detail in abstract; single lab, single compound study\",\n      \"pmids\": [\"39962827\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GPR158 is a class C orphan GPCR that forms a homodimer (stabilized by phospholipids) with an extracellular Cache domain that directly binds glycine and taurine (acting as a metabotropic glycine receptor, mGlyR), and an intracellular C terminus that physically recruits and allosterically potentiates the RGS7-Gβ5 GAP complex to suppress Gαi/o signaling and cAMP production; at synapses, GPR158 interacts with heparan sulfate proteoglycans (GPC4) to organize mossy fiber-CA3 synapse architecture, associates with Kv4.2 to suppress cAMP-PKA-mediated phosphorylation and control neuronal excitability, forms a complex with PLCXD2 to regulate spine apparatus abundance, and is regulated by glucocorticoids to modulate stress-induced depression in the prefrontal cortex.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"GPR158 is a class C orphan GPCR that functions as a synaptic organizing receptor and a master regulator of inhibitory G protein signaling in the brain [#0, #2]. Its intracellular C terminus stabilizes the RGS7-Gβ5 GAP complex post-transcriptionally, maintains its membrane association, and allosterically enhances RGS7 GAP activity, thereby suppressing Gαi/o signaling and cAMP production [#1]. Cryo-EM structures show GPR158 assembles as a phospholipid-stabilized homodimer with an extracellular Cache/PAS-fold domain and a cytoplasmic coiled-coil that provides a selective docking platform recruiting one or two RGS7-Gβ5 heterodimers [#8, #9]. The extracellular Cache domain directly binds glycine and taurine, defining GPR158 as a metabotropic glycine receptor (mGlyR) whose glycine binding inhibits the associated RGS7-Gβ5 complex and cAMP production to regulate cortical neuronal excitability [#10]. Downstream, GPR158 controls neuronal excitability by associating with the Kv4.2 channel and suppressing inhibitory cAMP-PKA-mediated phosphorylation [#6], and a glycine/GPR158/PKA/ERK/Kv7.2 pathway tunes firing of nucleus accumbens medium spiny neurons [#14]. At synapses, GPR158 acts as a postsynaptic partner for the heparan sulfate proteoglycan glypican-4 (GPC4) together with the co-receptor LAR to organize mossy fiber-CA3 synapse architecture and presynaptic differentiation [#4], and forms a complex with the constitutively active PLCXD2 to restrain PLC activity and control spine apparatus abundance and dendritic spine maturation [#16]. GPR158 transduces osteocalcin signaling in CA3 neurons to regulate memory and anxiety via IP3 and BDNF [#2], and is upregulated by glucocorticoids in the prefrontal cortex where it drives stress-induced depressive-like behavior through effects on AMPA receptor-mediated synaptic strength [#3]. Beyond its neuronal roles, GPR158 has also been reported to localize to the nucleus via a bipartite NLS and promote cell proliferation in non-neuronal cells [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established that GPR158 is a binding partner that recruits RGS7 complexes to the membrane and compartmentalizes G protein signaling, answering what cellular function this orphan receptor serves.\",\n      \"evidence\": \"Reciprocal Co-IP, subcellular fractionation, and a GPR179 night-blindness mouse KO with defined postsynaptic targeting phenotype\",\n      \"pmids\": [\"22689652\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the structural basis or the C-terminal element mediating RGS recruitment\", \"Endogenous ligand and signaling output unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Mapped the C-terminal determinants by which GPR158 stabilizes RGS7, maintains its membrane association, and allosterically enhances its GAP activity, defining the molecular mechanism of signaling regulation.\",\n      \"evidence\": \"GPR158 KO mouse, in vitro GAP assays, and C-terminal domain mapping/mutagenesis\",\n      \"pmids\": [\"25792749\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic structure of the GPR158-RGS7 interface not resolved\", \"Upstream activating signal still unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified GPR158 as a neuronal receptor for osteocalcin in CA3, linking a peripheral hormone to hippocampal memory and anxiety circuits.\",\n      \"evidence\": \"KO mice, electrophysiology, behavioral assays, and IP3/BDNF molecular readouts\",\n      \"pmids\": [\"28851741\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct osteocalcin binding to GPR158 not biochemically demonstrated\", \"Relationship between OCN signaling and RGS7 GAP activity unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed GPR158 is a glucocorticoid-induced driver of stress-induced depression in the PFC acting through synaptic AMPA receptor strength, establishing a behavioral pathophysiological role.\",\n      \"evidence\": \"Chronic stress model with bidirectional viral overexpression and KO, plus AMPA receptor activity measurements\",\n      \"pmids\": [\"29419376\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between GPR158/RGS7 signaling and AMPA receptor regulation not fully defined\", \"Ligand driving GPR158 activity in stress unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined GPR158 as a postsynaptic GPC4 binding partner that organizes mossy fiber-CA3 synapse architecture, identifying a trans-synaptic adhesion function distinct from G protein signaling.\",\n      \"evidence\": \"Reciprocal binding assays, KO mouse, electron microscopy, and electrophysiology\",\n      \"pmids\": [\"30290982\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How HSPG binding couples to intracellular signaling not resolved at this stage\", \"Generalizability beyond mossy fiber-CA3 synapses unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected GPR158 to a transcriptional feedback loop with RbAp48/Rbbp4 governing memory, implicating it in age-related cognitive decline.\",\n      \"evidence\": \"Hippocampal RbAp48 inhibition, GPR158 KO, and behavioral memory assays with protein expression analysis\",\n      \"pmids\": [\"30355501\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking GPR158 signaling to RbAp48 transcription not defined\", \"Single lab; feedback loop not independently confirmed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated GPR158 physically associates with Kv4.2 and promotes its function by suppressing cAMP-PKA phosphorylation, defining an effector channel mechanism controlling excitability and depression.\",\n      \"evidence\": \"Co-IP, patch-clamp electrophysiology, GPR158/RGS7 KO mice, and cAMP-PKA assays\",\n      \"pmids\": [\"31311860\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether GPR158-Kv4.2 association is direct or scaffolded not established\", \"Stoichiometry with the RGS7 complex unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed GPR158 deficiency impairs CA1 dendritic architecture and Schaffer collateral synaptic transmission, broadening its structural role beyond mossy fiber synapses.\",\n      \"evidence\": \"KO mouse with dendritic morphology analysis, electrophysiology, and spatial memory tests\",\n      \"pmids\": [\"31749686\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular pathway driving dendritic morphology not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Resolved cryo-EM structures of GPR158 alone and bound to RGS7-Gβ5, revealing a phospholipid-stabilized homodimer, an extracellular Cache/PAS-fold ligand-binding domain, and the coiled-coil platform underlying selective RGS7 recruitment.\",\n      \"evidence\": \"Single-particle cryo-EM of apo and RGS7-Gβ5-bound states, independently in two studies\",\n      \"pmids\": [\"34793198\", \"34815401\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous ligand for the Cache domain not identified in these structures\", \"Activation/conformational coupling between ligand site and RGS complex unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified glycine and taurine as direct Cache-domain ligands, establishing GPR158 as a metabotropic glycine receptor that inhibits RGS7-Gβ5 signaling and cAMP to control cortical excitability.\",\n      \"evidence\": \"Cache-domain binding assays, in vitro cAMP signaling, and cortical neuron electrophysiology with KO controls\",\n      \"pmids\": [\"36996198\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological glycine concentration ranges relevant in vivo not fully mapped\", \"Distinct roles of taurine versus glycine downstream incompletely defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended ligand-driven GPR158 signaling to a PKA/ERK/Kv7.2 (M-current) pathway in nucleus accumbens MSNs, linking glycine sensing to a second channel effector.\",\n      \"evidence\": \"Patch-clamp, PKA/ERK pharmacology, phosphorylation assays, and Kv7 occlusion experiments\",\n      \"pmids\": [\"38884814\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect Kv7.2 regulation not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed mPFC GPR158 controls social novelty behavior through excitatory transmission and GluN2B regulation, with rescue establishing causality.\",\n      \"evidence\": \"Constitutive/conditional KO, viral re-expression, DREADD chemogenetics, western blot, and electron microscopy\",\n      \"pmids\": [\"39383040\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link from GPR158 signaling to GluN2B phosphorylation not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a GPR158-PLCXD2 postsynaptic complex that restrains constitutive PLC activity to control spine apparatus abundance and spine maturation, revealing a non-canonical receptor-to-PLC pathway gated by HSPG binding.\",\n      \"evidence\": \"In vivo sparse genetic manipulation, Co-IP, electron microscopy, electrophysiology, and HSPG binding assays\",\n      \"pmids\": [\"40393451\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How HSPG binding mechanistically modulates the GPR158-PLCXD2 interaction not fully resolved\", \"Single lab; PLCXD2 activity regulation by GPR158 not biochemically reconstituted\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Reported the natural compound trilobatin as a direct GPR158 binder that lowers its expression and links GPR158 to mitophagy and depression, suggesting a pharmacological handle.\",\n      \"evidence\": \"Direct binding assay, GPR158 KO, CUMS stress model, and mitophagy/autophagy protein readouts\",\n      \"pmids\": [\"39962827\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Binding site and mechanism of expression reduction not defined\", \"Single compound, single lab; mitophagy link not independently confirmed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ligand binding at the extracellular Cache domain is conformationally transmitted across the dimer to switch the intracellular RGS7-Gβ5 GAP activity, and how this integrates with the adhesion (GPC4) and PLCXD2 effector arms, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure capturing a ligand-bound active state coupled to RGS7\", \"Integration of glycine sensing, trans-synaptic adhesion, and PLC signaling into one mechanistic model is incomplete\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [10, 2]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 8, 9]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 8]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [11, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 10]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [6, 10, 14]}\n    ],\n    \"complexes\": [\n      \"GPR158-RGS7-Gβ5 complex\",\n      \"GPR158 homodimer\",\n      \"GPR158-PLCXD2 complex\"\n    ],\n    \"partners\": [\n      \"RGS7\",\n      \"GNB5\",\n      \"GPC4\",\n      \"KCND2\",\n      \"PLCXD2\",\n      \"LAR\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}