Atypical class C G protein-coupled receptor of the brain, highly expressed in cortex, hippocampus, striatum and the aqueous outflow pathway of the eye. GPR158 is a homodimer built from an extracellular Cache-like domain, a seven-transmembrane bundle and a long cytoplasmic coiled-coil; it lacks the Venus flytrap ligand-binding domain of other class C receptors. Its defining feature is that it does not signal by activating a heterotrimeric G protein. Instead it binds, stabilises and allosterically enhances the RGS7-Gbeta5 GTPase-activating complex, recruiting it to the plasma membrane and thereby accelerating deactivation of Galpha(i/o) produced by neighbouring receptors; through this route GPR158 sets cAMP tone and controls A-type and M-type potassium currents and neuronal excitability. Glycine, and more weakly taurine, bind the Cache domain and inhibit the associated RGS7-Gbeta5 complex, so GPR158 has been designated a metabotropic glycine receptor; this ligand assignment is one of three models advanced for the receptor, alongside a proposed role as a neuronal receptor for the bone hormone osteocalcin and a ligand-independent role as a postsynaptic organiser. In the latter capacity GPR158 forms a complex with the constitutively active phospholipase PLCXD2 that controls spine apparatus abundance and dendritic spine maturation, and it acts as a synaptic organiser at hippocampal mossy fibre-CA3 synapses. GPR158 is implicated in stress-induced depressive states, cognition, and glucocorticoid-induced ocular hypertension.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004930 G protein-coupled receptor activity | IEA GO_REF:0000002 | MODIFY | Summary: InterPro signature-based assignment of generic G protein-coupled receptor activity. Reason: Correct in kind but under-specific, and the mechanism the term implies is the one thing GPR158 demonstrably does not do. Hajj et al. found no constitutive or canonical activation of Go by GPR158 and concluded it acts by trapping Galpha(o) and by scaffolding RGS7-Gbeta5 rather than by nucleotide exchange. The informative molecular function terms for this receptor are the ligand-specific GO:0160079 and the effector-specific GO:0008047, both of which the gene already carries with IDA support. Proposed replacements: G protein-coupled glycine receptor activity Supporting Evidence: PMID:31189666 no constitutive activity of GPR158 could be detected through the measurement of various G-protein-mediated downstream responses |
| GO:0005634 nucleus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Nuclear localisation propagated from the UniProt subcellular-location vocabulary, which in turn derives from the two ocular-cell studies below. Reason: Reported by a single group in trabecular meshwork and ocular cells, both for endogenous and overexpressed protein, and not reproduced in any of the neuronal or structural work. UniProt itself flags the observation as mechanistically unexplained for a multi-pass membrane protein. Retained because the underlying observations are experimental and were not read here in full, but it cannot be a core location for a dimeric seven-transmembrane receptor whose function is to hold RGS7-Gbeta5 at the plasma membrane. Supporting Evidence: PMID:23451275 Both endogenous and overexpressed GPR158 show an unusual subcellular localization pattern, being found almost entirely in the nucleus. |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Plasma membrane localisation, consistent with the cryo-EM structures and with all functional work. Reason: Core location. GPR158 is a multi-pass plasma membrane protein and its function is to recruit RGS7-Gbeta5 to this membrane. |
| GO:0007186 G protein-coupled receptor signaling pathway | IEA GO_REF:0000002 | MODIFY | Summary: Generic GPCR-pathway assignment from the InterPro signature. Reason: GPR158 participates in G protein signalling as a regulator of other receptors' signalling rather than as a canonical transducer. It stabilises and allosterically activates RGS7-Gbeta5, accelerating Galpha(i/o) deactivation; glycine binding then relieves that inhibition. The regulation term captures this, and the gene already carries it with IDA support. Proposed replacements: regulation of G protein-coupled receptor signaling pathway Supporting Evidence: PMID:34815401 Among class C GPCRs, GPR158 is unique as it lacks a Venus flytrap-fold ligand-binding domain and terminates GΞ±i/o protein signaling through the RGS7-GΞ²5 heterodimer. |
| GO:0016020 membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Generic membrane localisation. Reason: Correct, though the plasma membrane and postsynaptic density membrane annotations carried by this gene are more informative. |
| GO:0042734 presynaptic membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Presynaptic membrane localisation from the UniProt subcellular-location mapping, itself inferred by similarity to mouse Gpr158. Reason: A real but minor pool. UniProt records that GPR158 mainly localises to the postsynaptic membrane with only a small portion presynaptic, and the functional and structural work (RGS7-Gbeta5 anchoring, PLCXD2 complex, spine apparatus control) is postsynaptic. Kept as a secondary location. |
| GO:0045211 postsynaptic membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Postsynaptic membrane localisation transferred from mouse Gpr158. Reason: Core location. The postsynaptic pool is where the RGS7-Gbeta5 and PLCXD2 complexes act. |
| GO:0001956 positive regulation of neurotransmitter secretion | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Orthology-transferred process, reflecting the presynaptic differentiation that GPR158 induces in contacting axons at mossy fibre-CA3 synapses. Reason: A downstream circuit-level consequence of synaptic organisation rather than an activity GPR158 carries out; it is also trans-synaptic, so the receptor is not the agent in the secreting cell. |
| GO:0004888 transmembrane signaling receptor activity | IEA GO_REF:0000107 | MODIFY | Summary: Generic transmembrane receptor activity transferred from mouse Gpr158. Reason: True but uninformative. The ligand and the transduction step are both known, so the specific term should be used. Proposed replacements: G protein-coupled glycine receptor activity |
| GO:0007420 brain development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Organism-level developmental process transferred from mouse. Reason: Distal organismal phenotype of losing a synaptic signalling module, not a process the protein directly executes. |
| GO:0008047 enzyme activator activity | IEA GO_REF:0000107 | ACCEPT | Summary: Orthology transfer of the RGS7-activating function, which is independently supported by human IDA evidence. Reason: Core molecular function. GPR158 binds the RGS7-Gbeta5 heterodimer through its cytoplasmic region and allosterically enhances RGS7 GTPase-activator activity; this is the best-established and most reproducible thing the receptor does, and it is the effector step through which the glycine signal is read out. Supporting Evidence: PMID:25792749 The results of this study establish GPR158 as an essential regulator of RGS7 in the native nervous system with a critical role in controlling its expression, membrane localization, and catalytic activity. |
| GO:0050807 regulation of synapse organization | IEA GO_REF:0000107 | ACCEPT | Summary: Synaptic organiser role transferred from mouse Gpr158. Reason: Well supported and mechanistically resolved. GPR158 forms a postsynaptic complex with the constitutively active phospholipase PLCXD2 that controls spine apparatus abundance and dendritic spine maturation, and it induces presynaptic differentiation at hippocampal mossy fibre-CA3 synapses. Supporting Evidence: PMID:40393451 Here, we identify a postsynaptic signaling complex comprising the G protein-coupled receptor (GPCR)- GPR158 and a constitutively active phospholipase C (PLC) family member, PLC X-domain containing 2 (PLCXD2), that controls SA abundance. |
| GO:0050890 cognition | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Behavioural phenotype transferred from mouse Gpr158 knockouts. Reason: Organismal behavioural readout, several steps removed from the molecular function. Real (it is the basis of both the osteocalcin and the stress/depression literature) but not a process the protein carries out. |
| GO:0098839 postsynaptic density membrane | IEA GO_REF:0000107 | ACCEPT | Summary: Activity localised to the postsynaptic density membrane, transferred from mouse. Reason: Correct and specific; this is where the receptor holds RGS7-Gbeta5 and PLCXD2. |
| GO:0001956 positive regulation of neurotransmitter secretion | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Curator-judged sequence-similarity transfer of the same mouse process. Reason: A downstream circuit-level consequence of synaptic organisation rather than an activity GPR158 carries out; it is also trans-synaptic, so the receptor is not the agent in the secreting cell. |
| GO:0007420 brain development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Curator-judged sequence-similarity transfer from mouse Gpr158. Reason: Distal organismal phenotype of losing a synaptic signalling module, not a process the protein directly executes. |
| GO:0005634 nucleus | EXP PMID:23451275 GPR158, an orphan member of G protein-coupled receptor Famil... | KEEP AS NON CORE | Summary: Endogenous and overexpressed GPR158 found almost entirely in the nucleus of cultured trabecular meshwork cells, with a bipartite NLS in helix 8 required both for nuclear localisation and for the proliferative effect. Reason: Experimental and therefore retained, but cell-type-restricted, reported only by this group, and mechanistically unexplained for a multi-pass membrane protein - a caveat UniProt itself records. It is not a core location for a receptor whose established job is to hold RGS7-Gbeta5 at the plasma and postsynaptic membranes. Supporting Evidence: PMID:23451275 Both endogenous and overexpressed GPR158 show an unusual subcellular localization pattern, being found almost entirely in the nucleus. |
| GO:0005634 nucleus | EXP PMID:30855200 GPR158 in the Visual System: Homeostatic Role in Regulation ... | KEEP AS NON CORE | Summary: Follow-up ocular study from the same group, again placing GPR158 in the nucleus. Reason: Experimental and therefore retained, but cell-type-restricted, reported only by this group, and mechanistically unexplained for a multi-pass membrane protein - a caveat UniProt itself records. It is not a core location for a receptor whose established job is to hold RGS7-Gbeta5 at the plasma and postsynaptic membranes. |
| GO:0005886 plasma membrane | EXP PMID:23451275 GPR158, an orphan member of G protein-coupled receptor Famil... | ACCEPT | Summary: GPR158 shifts to the plasma membrane when clathrin-mediated endocytosis is blocked, indicating that the plasma membrane is its delivery destination. Reason: Core location, consistent with all structural and neuronal work. Supporting Evidence: PMID:23451275 These results suggest that newly synthesized GPR158 first traffics to the plasma membrane, where it rapidly undergoes endocytosis and translocation to the nucleus. |
| GO:0005886 plasma membrane | EXP PMID:30855200 GPR158 in the Visual System: Homeostatic Role in Regulation ... | ACCEPT | Summary: Experimental plasma membrane localisation in ocular tissue, in a study that also reviews the plasma-membrane RGS7-recruitment function. Reason: Core location. Supporting Evidence: PMID:30855200 Similarly, GPR158 is necessary for the plasma membrane recruitment of RGS7 in the brain, and its activity in terminating signaling of conventional GPCRs. |
| GO:0042734 presynaptic membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Presynaptic localisation projected from mouse Gpr158 by curator judgement. Reason: A real but minor pool. UniProt records that GPR158 mainly localises to the postsynaptic membrane with only a small portion presynaptic, and the functional and structural work is postsynaptic. |
| GO:0045211 postsynaptic membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Postsynaptic membrane localisation projected from mouse Gpr158. Reason: Core location. |
| GO:0008277 regulation of G protein-coupled receptor signaling pathway | IDA PMID:36996198 Orphan receptor GPR158 serves as a metabotropic glycine rece... | ACCEPT | Summary: Glycine binding to the GPR158 Cache domain inhibits the receptor-associated RGS7-Gbeta5 complex, thereby changing the deactivation rate of Galpha(i/o) and the cAMP output of neighbouring GPCRs. Reason: Core biological process, and the most accurate statement of what GPR158 does in G protein signalling. It regulates other receptors' signalling rather than transducing its own through Galpha. Supporting Evidence: PMID:36996198 Glycine and a related modulator, taurine, directly bind to a Cache domain of GPR158, and this event inhibits the activity of the intracellular signaling complex regulator of G protein signaling 7-G protein Ξ²5 (RGS7-GΞ²5), which is associated with the receptor. PMID:36996198 Glycine signals through mGlyR to inhibit production of the second messenger adenosine 3',5'-monophosphate. |
| GO:0160079 G protein-coupled glycine receptor activity | IDA PMID:36996198 Orphan receptor GPR158 serves as a metabotropic glycine rece... | ACCEPT | Summary: Direct binding of glycine (and, more weakly, taurine) to the extracellular Cache domain, with a defined intracellular readout and a cellular electrophysiological consequence. Reason: Core molecular function, and the best-supported of the three competing ligand models for GPR158. Independent functional replication exists in a different laboratory and a different brain region: Aceto et al. showed glycine-dependent activation of GPR158 increases firing of nucleus accumbens medium spiny neurons through Kv7/M-current modulation (PMID:38884814). UniProt has adopted mGlyR as the recommended protein name. The competing models are recorded rather than suppressed: osteocalcin is asserted as a GPR158 ligand in mouse genetic and behavioural work (PMID:28851741) and is still stated flatly in reviews (PMID:40337551), but no direct binding site has been defined; and a 2025 Dev Cell study describes a postsynaptic GPR158-PLCXD2 module controlling spine apparatus abundance with no ligand invoked at all (PMID:40393451). The honest reading is that GPR158 is a glycine receptor whose ligand-independent scaffolding functions are equally real, not that one model displaces the other. Supporting Evidence: PMID:36996198 We identified an orphan G protein-coupled receptor, GPR158, as a metabotropic glycine receptor (mGlyR). PMID:36996198 We further show that glycine, but not taurine, acts through mGlyR to regulate neuronal excitability in cortical neurons. PMID:38884814 we found that glycine-dependent activation of GPR158 increased the firing rate of NAc medium spiny neurons (MSNs) |
| GO:0004888 transmembrane signaling receptor activity | ISS GO_REF:0000024 | MODIFY | Summary: Generic transmembrane receptor activity projected from mouse Gpr158. Reason: True but uninformative. The ligand and the transduction step are both known, so the specific term should be used. Proposed replacements: G protein-coupled glycine receptor activity |
| GO:0008047 enzyme activator activity | IDA PMID:36996198 Orphan receptor GPR158 serves as a metabotropic glycine rece... | ACCEPT | Summary: GPR158 holds RGS7-Gbeta5 and, in the absence of glycine, promotes its GTPase-activator activity; glycine binding switches this off. Reason: Core molecular function. This is the effector arm of the receptor and the step that both cryo-EM structures resolve at the interface level. Supporting Evidence: PMID:36996198 Glycine and a related modulator, taurine, directly bind to a Cache domain of GPR158, and this event inhibits the activity of the intracellular signaling complex regulator of G protein signaling 7-G protein Ξ²5 (RGS7-GΞ²5), which is associated with the receptor. PMID:34793198 We further demonstrate the structural basis of GPR158 coupling to RGS7-GΞ²5. |
| GO:0050890 cognition | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Behavioural phenotype projected from mouse. Reason: Organismal behavioural readout, several steps removed from the molecular function. |
| GO:0005886 plasma membrane | IDA PMID:31189666 Nonclassical Ligand-Independent Regulation of Go Protein by ... | ACCEPT | Summary: GPR158 is active at the plasma membrane, where it recruits and stabilises RGS7-Gbeta5. Reason: Core location. Supporting Evidence: PMID:31189666 GPR158 forms a complex with RGS7-Ξ²5, leading to the regulation of neighboring GPCR-induced Go protein activity. |
| GO:0007186 G protein-coupled receptor signaling pathway | IDA PMID:31189666 Nonclassical Ligand-Independent Regulation of Go Protein by ... | MODIFY | Summary: Direct assay of GPR158's effect on Go signalling, which the authors conclude is non-canonical. Reason: The same study that supports this annotation shows that GPR158 does not activate Go in the canonical way; its effect is attributed to trapping Galpha(o) via the VCPWE motifs and to scaffolding RGS7-Gbeta5. The regulation term states this accurately without asserting canonical transduction. Proposed replacements: regulation of G protein-coupled receptor signaling pathway Supporting Evidence: PMID:31189666 GPR158 forms a complex with RGS7-Ξ²5, leading to the regulation of neighboring GPCR-induced Go protein activity. PMID:31189666 no constitutive activity of GPR158 could be detected through the measurement of various G-protein-mediated downstream responses |
| GO:0008047 enzyme activator activity | IDA PMID:31189666 Nonclassical Ligand-Independent Regulation of Go Protein by ... | ACCEPT | Summary: GPR158 interacts with and stabilises RGS7-Gbeta5 through a defined 50-residue cytoplasmic region, increasing the amount and activity of the complex. Reason: Core molecular function, independently supported by this laboratory and by the Martemyanov group. Supporting Evidence: PMID:31189666 We observed that GPR158 interacted with and stabilized the amount of RGS7-Ξ²5 through a 50-residue region downstream of its transmembrane domain and upstream of the VCPWE motifs. |
| GO:0050807 regulation of synapse organization | ISS GO_REF:0000024 | ACCEPT | Summary: Synaptic organiser role projected from mouse Gpr158. Reason: Well supported and mechanistically resolved through the postsynaptic GPR158-PLCXD2 complex that controls spine apparatus abundance and dendritic spine maturation. Supporting Evidence: PMID:40393451 Together, our findings uncover a direct GPCR-like receptor-to-PLC signaling pathway that bypasses canonical PLC regulation via G proteins. |
| GO:0072659 protein localization to plasma membrane | IDA PMID:31189666 Nonclassical Ligand-Independent Regulation of Go Protein by ... | ACCEPT | Summary: GPR158 recruits the RGS7-Gbeta5 heterodimer to the plasma membrane and is required for its membrane association in brain. Reason: Core biological process and a direct readout of the anchoring function; loss of GPR158 in mice causes post-transcriptional destabilisation of RGS7 and loss of its membrane association. Supporting Evidence: PMID:22689652 We show that GPR158/179 recruited RGS complexes to the plasma membrane and augmented their ability to regulate GPCR signaling. PMID:25792749 The results of this study establish GPR158 as an essential regulator of RGS7 in the native nervous system with a critical role in controlling its expression, membrane localization, and catalytic activity. |
| GO:0045211 postsynaptic membrane | ISS GO_REF:0000024 | ACCEPT | Summary: GPR158 active in the postsynaptic membrane, projected from mouse. Reason: Core location. |
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Download this section (compressed HTML)Q: Is osteocalcin a direct ligand of GPR158, or does GPR158 act downstream of osteocalcin by an indirect route? No binding site, affinity or structure has been reported for the osteocalcin-GPR158 pair, in contrast with the Cache-domain glycine site, yet reviews continue to describe GPR158 as a critical receptor for osteocalcin.
Suggested experts: Gerard Karsenty, Kirill A Martemyanov
Q: Can glycine and osteocalcin engage GPR158 simultaneously or competitively, and does osteocalcin signalling also read out through inhibition of RGS7-Gbeta5?
Suggested experts: Franck Oury, Kirill A Martemyanov
Q: Are the postsynaptic phenotypes of GPR158 loss - spine apparatus abundance, spine maturation, mossy fibre-CA3 organisation - ligand-dependent, or purely structural? The GPR158-PLCXD2 study invokes no ligand and is modulated instead by extracellular heparan sulfate proteoglycan binding.
Suggested experts: Joris de Wit, Bram Verpoort
Q: What is the nuclear pool of GPR158 reported in trabecular meshwork cells - a proteolytic fragment, an overexpression artefact, or a genuine second localisation of the full-length multi-pass protein? UniProt records the observation but states that the trafficking mechanism is unclear.
Suggested experts: M Elizabeth Fini
Q: Given that GPR158 does not activate Galpha canonically, should GO carry a distinct molecular function term for RGS-anchoring class C receptors (GPR158, GPR179) rather than the generic enzyme activator activity?
Experiment: Perform quantitative binding measurements (surface plasmon resonance or microscale thermophoresis) of recombinant undercarboxylated osteocalcin against the purified GPR158 ectodomain and against full-length receptor in nanodiscs, with glycine competition, and attempt a cryo-EM structure of the complex. Include the Cache-pocket mutants that abolish glycine responses as specificity controls.
Hypothesis: Osteocalcin binds the GPR158 Cache domain at a site overlapping or adjacent to the glycine site.
Type: Biophysical binding and structural biology
Experiment: Rescue Gpr158 knockout cortical neurons in vivo with wild-type GPR158 versus Cache-domain pocket mutants that cannot bind glycine but retain RGS7-Gbeta5 and PLCXD2 binding, and score spine apparatus incorporation, spine maturation and miniature EPSC properties.
Hypothesis: Glycine occupancy is required for the spine apparatus and spine maturation phenotypes of GPR158.
Type: Structure-function rescue with imaging and electrophysiology
Experiment: In trabecular meshwork cells expressing GPR158 tagged at both the N- and C-termini with distinguishable epitopes, fractionate nuclei and immunoblot for both tags, with mass spectrometry of the nuclear species, and test whether protease inhibition or NLS mutation changes the apparent molecular weight of the nuclear pool.
Hypothesis: The nuclear GPR158 signal corresponds to a cleaved cytoplasmic fragment rather than the intact receptor.
Type: Subcellular fractionation with dual-tag immunoblotting and proteomics
Experiment: Repeat the gramicidin-perforated recordings of glycine-evoked excitability changes in organotypic hippocampal slices from Gpr158 knockout versus wild-type animals, using the same pharmacological isolation of metabotropic responses.
Hypothesis: Glycine-evoked excitability changes in hippocampal CA3 pyramidal cells are GPR158-dependent.
Type: Slice electrophysiology in a genetic knockout
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