LPAR5 is a class-A seven-transmembrane G protein-coupled receptor that binds extracellular lysophosphatidic acid at the plasma membrane. Recombinant human receptor studies establish nanomolar LPA binding and activation of Gq-linked phosphoinositide signaling, G12/13-Rho signaling, and Gs-linked cAMP production. Farnesyl pyrophosphate and N-arachidonylglycine can also activate LPAR5 in heterologous assays, with ligand-dependent differences in Gq/11 and Gs branch use; these activities do not establish which agonists dominate in native tissues. A 2.96-angstrom cryo-EM structure captures 1-oleoyl-LPA-bound LPAR5 coupled to Gq, defining polar recognition of the phosphate headgroup, burial of the acyl tail, and a noncanonical receptor–Gq interface. This structure represents the activated signaling state rather than a constitutive stable complex. LPA also induces LPAR5 internalization in a tagged-receptor system. LPAR5 is expressed in multiple human tissues and is enriched in small-intestinal intraepithelial CD8-positive T cells, sensory dorsal-root ganglia, and platelet-lineage cells. Mouse Lpar5 loss protects against injury-induced neuropathic pain without a gross baseline phenotype, while human megakaryocytic-cell perturbation supports LPAR5-dependent LPA responses in the platelet lineage. Reduced LPAR5 expression promotes LPA-induced migration in EBV-associated nasopharyngeal carcinoma cells. These pain, platelet, atherosclerotic-plaque, and cancer phenotypes are tissue-, species-, or disease-context outputs of receptor signaling rather than additional core molecular activities.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0048266 behavioral response to pain | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Retained as a pain-related organismal outcome inferred from mouse Lpar5 biology. Reason: Mouse genetic evidence supports a role for Lpar5 in behavioral responses to pain, making the phylogenetic inference biologically plausible. Pain behavior is nevertheless an organism-, neural-context-, and stimulus-level output of receptor signaling rather than the core molecular activity of human LPAR5. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: MGI:MGI:2685918 SUPPORTS TRANSFER Exact WITH/FROM source; the transfer is biologically plausible but represents contextual organismal physiology rather than core receptor activity. PANTHER:PTN002796778 SUPPORTS TRANSFER Exact WITH/FROM source; the transfer is biologically plausible but represents contextual organismal physiology rather than core receptor activity. |
| GO:0004930 G protein-coupled receptor activity | IEA GO_REF:0000002 | MODIFY | Summary: Generic GPCR activity is valid but should be represented by the established ligand-specific receptor activity. Reason: LPAR5 is a seven-transmembrane receptor for lysophosphatidic acid. The ligand-specific molecular-function term is more informative than the broad GPCR parent term. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: InterPro:IPR000276 SUPPORTS TRANSFER Exact WITH/FROM source; it supports the broad concept, while established LPAR5 biology supports the more precise replacement. Proposed replacements: lysophosphatidic acid receptor activity |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Accepted as the core membrane location of LPAR5. Reason: The UniProt subcellular-location mapping agrees with the receptor’s integral seven-transmembrane topology and curated plasma-membrane pathway placement. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0039 SUPPORTS TRANSFER Exact WITH/FROM source; the propagated assignment agrees with established human LPAR5 biology. |
| GO:0007186 G protein-coupled receptor signaling pathway | IEA GO_REF:0000002 | ACCEPT | Summary: Accepted as the core signaling process initiated by LPA-bound LPAR5. Reason: The rhodopsin-like GPCR family mapping and curated LPA-receptor pathway events support heterotrimeric G-protein signaling by LPAR5. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR000276 SUPPORTS TRANSFER Exact WITH/FROM source; the propagated assignment agrees with established human LPAR5 biology. |
| GO:0016020 membrane | IEA GO_REF:0000002 | MODIFY | Summary: The generic membrane term should be replaced by the established plasma-membrane location. Reason: LPAR5 is an integral membrane receptor, but the reviewed location and curated signaling events support the more informative plasma membrane term. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: InterPro:IPR000276 SUPPORTS TRANSFER Exact WITH/FROM source; it supports the broad concept, while established LPAR5 biology supports the more precise replacement. InterPro:IPR017452 SUPPORTS TRANSFER Exact WITH/FROM source; it supports the broad concept, while established LPAR5 biology supports the more precise replacement. Proposed replacements: plasma membrane |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-379048 | ACCEPT | Summary: Accepted as the plasma-membrane location used in curated proximal Gq/11 signaling. Reason: Reactome places LPAR5 in a liganded GPCR step at the plasma membrane that activates Gq/11, consistent with receptor topology and LPA signaling. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-380073 | ACCEPT | Summary: Accepted as the plasma-membrane location used in curated proximal Gi signaling. Reason: Reactome places LPAR5 in a liganded GPCR step at the plasma membrane that activates Gi, consistent with its receptor role. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-419389 | ACCEPT | Summary: Accepted as the plasma-membrane location of the curated LPA-binding receptor event. Reason: Reactome places human LPAR5 among plasma-membrane receptors that bind lysophosphatidic acid. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-749448 | ACCEPT | Summary: Accepted as the plasma-membrane location used in curated Gq binding. Reason: Reactome places liganded LPAR5 at the plasma membrane when binding inactive heterotrimeric Gq; this is appropriate pathway context for the receptor. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-749452 | ACCEPT | Summary: Accepted as the plasma-membrane location used in the curated Gq activation cycle. Reason: Reactome models dissociation of the liganded receptor–Gq complex at the plasma membrane, consistent with LPAR5 signaling topology. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-749454 | ACCEPT | Summary: Accepted as the plasma-membrane location used in the curated Gi activation cycle. Reason: Reactome models dissociation of the liganded receptor–Gi complex at the plasma membrane, consistent with LPAR5 signaling topology. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-749456 | ACCEPT | Summary: Accepted as the plasma-membrane location used in curated Gi binding. Reason: Reactome places liganded LPAR5 at the plasma membrane when binding inactive heterotrimeric Gi; this is appropriate pathway context for the receptor. |
| GO:0035727 lysophosphatidic acid binding | IDA PMID:16651401 Lysophosphatidic acid binds to and activates GPR92, a G prot... | NEW | Summary: Proposed as a new annotation for directly measured high-affinity LPA binding by LPAR5. Reason: Recombinant human GPR92/LPAR5 binds LPA with nanomolar affinity, and independent membrane-binding experiments and the LPA-bound receptor structure confirm direct ligand recognition. Supporting Evidence: PMID:16651401 The binding of LPA to GPR92 was of high affinity (K(D) = 6.4 +/- 0.9 nM) and led to an increase in both phosphoinositide hydrolysis and cAMP production. |
| GO:0007189 adenylate cyclase-activating G protein-coupled receptor signaling pathway | IDA PMID:16651401 Lysophosphatidic acid binds to and activates GPR92, a G prot... | NEW | Summary: Proposed as a new annotation for the directly demonstrated Gs/cAMP branch of LPAR5 signaling. Reason: LPA stimulation of recombinant human LPAR5 increases cAMP, and ligand-comparison experiments identify Gs-mediated signaling for LPA and FPP. This establishes activating receptor capability while leaving native tissue coupling weights open. Supporting Evidence: PMID:16651401 The binding of LPA to GPR92 was of high affinity (K(D) = 6.4 +/- 0.9 nM) and led to an increase in both phosphoinositide hydrolysis and cAMP production. |
| GO:0007200 phospholipase C-activating G protein-coupled receptor signaling pathway | IDA PMID:16651401 Lysophosphatidic acid binds to and activates GPR92, a G prot... | NEW | Summary: Proposed as a new annotation for the directly demonstrated Gq/phosphoinositide branch of LPAR5 signaling. Reason: LPA-bound LPAR5 drives phosphoinositide hydrolysis, multiple agonists activate Gq/11 signaling, and the 2026 cryo-EM structure directly captures activated LPA-bound LPAR5 coupled to Gq. Supporting Evidence: PMID:16651401 The binding of LPA to GPR92 was of high affinity (K(D) = 6.4 +/- 0.9 nM) and led to an increase in both phosphoinositide hydrolysis and cAMP production. |
| GO:0002031 G protein-coupled receptor internalization | IDA PMID:16774927 GPR92 as a new G12/13- and Gq-coupled lysophosphatidic acid ... | NEW | Summary: Proposed as a new non-core annotation for directly observed agonist-dependent LPAR5 internalization. Reason: Epitope-tagged LPAR5 internalizes after LPA exposure but not after related lysophospholipids in the same heterologous system. This is a receptor-regulatory state, while its endogenous route and consequences remain unresolved. Supporting Evidence: PMID:16774927 LPA-dependent receptor internalization following exposure to LPA but not related lysophospholipids was observed. |
| GO:0035025 positive regulation of Rho protein signal transduction | IDA PMID:16774927 GPR92 as a new G12/13- and Gq-coupled lysophosphatidic acid ... | NEW | Summary: Proposed as a new annotation for the directly demonstrated G12/13 signaling branch of LPAR5. Reason: LPA activates G12/13 through recombinant human LPAR5, and independent ligand-response experiments place Rho downstream of this receptor branch. This supports proximal positive regulation of Rho signaling while leaving downstream tissue phenotypes context dependent. Supporting Evidence: PMID:16774927 Furthermore, LPA induced concentration-dependent activation of G(12/13) and G(q) and increased cAMP levels. |
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Download this section (compressed HTML)Q: What are the endogenous Gq/11, G12/13, Gs, Gi/o, and beta-arrestin coupling weights of human LPAR5 in its major native cell types?
Q: Which of LPA, FPP, NAG, and alkyl glycerol phosphate occupies and activates LPAR5 under physiological conditions?
Q: How is ligand-specific LPAR5 internalization controlled, and does it alter signaling bias or resensitization?
Q: Is the Lpar5-dependent neuropathic-pain mechanism conserved in human sensory neurons?
Q: Which LPAR5 outputs are specific to platelet-lineage, intestinal immune, plaque, or nasopharyngeal-carcinoma contexts?
Q: Are any endogenous LPAR5 isoforms or stable regulatory partners functionally distinct?
Experiment: CRISPR-tag endogenous LPAR5 and measure Gq/11, G12/13, Gs, Gi/o, beta-arrestin, phosphoinositide, cAMP, calcium, and Rho responses to LPA, FPP, NAG, and alkyl glycerol phosphate with selective G-alpha knockout and rescue.
Hypothesis: Native LPAR5 coupling weights and ligand bias differ across intestinal immune, sensory-neuron, and platelet-lineage cells.
Type: endogenous multiplexed coupling and ligand-bias analysis
Experiment: Combine targeted extracellular and membrane lipidomics with LPAR5 knockout, genomic rescue, and receptor-occupancy or functional competition assays in native-expression human cells.
Hypothesis: Local lipid abundance determines which agonist class dominates native LPAR5.
Type: native ligand competition and lipidomics
Experiment: Endogenously tag LPAR5, map agonist-dependent phosphorylation and arrestin recruitment, and quantify internalization, recycling, degradation, and signaling recovery after matched agonist pulses.
Hypothesis: LPA and alternative agonists produce distinct LPAR5 trafficking and resensitization states.
Type: endogenous ligand-resolved receptor trafficking
Experiment: Perturb LPAR5 in human iPSC-derived sensory neurons, apply injury-associated lipid mixtures, and measure excitability, calcium, cAMP, Rho, and CREB responses with genetic rescue and comparison to mouse neurons.
Hypothesis: Human sensory-neuron LPAR5 reproduces the injury-dependent CREB and excitability program inferred from Lpar5-null mice.
Type: mouse-to-human pain-mechanism conservation
Experiment: Perform matched endogenous knockout/rescue and branch-resolved signaling in primary or stem-cell-derived models, then connect proximal responses to shape change, activation, immune effector behavior, plaque response, or migration.
Hypothesis: LPAR5 uses different coupling branches in platelet-lineage, intestinal immune, and epithelial tumor cells.
Type: lineage-resolved receptor physiology
Experiment: Reconcile transcripts by targeted long-read sequencing and proteomics, then use endogenous proximity labeling before and after agonist exposure followed by partner knockout and signaling/trafficking rescue assays.
Hypothesis: Only one predominant LPAR5 proteoform is expressed, while a small set of inducible partners controls tissue-specific signaling.
Type: proteoform reconciliation and endogenous interactome validation
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The quantitative Gq/11, G12/13, Gs, Gi/o, and beta-arrestin coupling profile of endogenous human LPAR5 is unresolved across native cell types and ligands.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: Heterologous assays establish Gq, G12/13, and Gs capability and ligand-dependent branch use; the LPA-bound structure directly resolves Gq coupling. Seeded Reactome Gi events are pathway models, while the audited primary studies do not establish receptor-specific Gi coupling.
Significance: Native coupling weights determine how LPAR5 controls phosphoinositides, cAMP, cytoskeletal signaling, and tissue-specific physiology.
What would resolve it: Measure endogenous LPAR5 with parallel Gq/11, G12/13, Gs, Gi/o, beta-arrestin, phosphoinositide, cAMP, calcium, and Rho biosensors across matched LPA, FPP, and NAG dose and time courses.
Gap: The physiological competition and relative importance of LPA, FPP, NAG, and alkyl glycerol phosphate as endogenous LPAR5 agonists are unknown.
OPEN BIOLOGY
What is known: Recombinant assays support all four ligand classes and reveal different potency or pathway profiles, but do not establish their local concentrations, receptor occupancy, or dominant native-tissue effects.
Significance: Physiological ligand identity may determine signaling bias and reconcile divergent tissue phenotypes.
What would resolve it: Combine quantitative lipidomics with endogenous LPAR5 knockout/rescue and branch-resolved pharmacology in intestinal immune, sensory, and platelet-lineage human cells.
Gap: The endogenous mechanism and consequences of LPA-induced LPAR5 internalization are unresolved.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: Tagged recombinant LPAR5 internalizes selectively after LPA exposure, but the route, phosphorylation sites, arrestin dependence, recycling, degradation, and native-cell kinetics have not been established.
Significance: Trafficking controls signal duration and may vary with ligand and tissue context.
What would resolve it: Endogenously tag LPAR5 and perturb candidate kinases, arrestins, and endocytic machinery while quantifying ligand-specific internalization, recycling, degradation, and signaling resensitization.
Gap: The conservation and human relevance of Lpar5-dependent neuropathic-pain physiology remain uncertain.
OPEN BIOLOGY
What is known: Mouse Lpar5 deletion protects against injury-induced neuropathic pain without a gross baseline phenotype, and human DRG expresses LPAR5, but causal human sensory neuron evidence is lacking.
Significance: Establishing conservation is essential before assigning a constitutive human pain role or pursuing receptor-directed analgesia.
What would resolve it: Test LPAR5 loss and rescue in human sensory-neuron models with injury-associated lipid mixtures and compare neuronal excitability and CREB-pathway outputs with the mouse phenotype.
Gap: The native roles of LPAR5 in human platelet-lineage, intestinal immune, plaque, and cancer contexts require further separation.
OPEN BIOLOGY
What is known: Megakaryocytic-cell knockdown supports receptor-specific LPA responses, whereas mature platelet pharmacology is less genetically tractable. Intestinal T-cell enrichment, plaque-induced shape change, and nasopharyngeal-carcinoma migration each establish distinct contexts rather than a universal cellular function.
Significance: Context resolution will distinguish normal receptor physiology from disease- or lineage-specific signaling.
What would resolve it: Use endogenous knockout/rescue in primary or stem-cell-derived platelet, intestinal immune, vascular-plaque, and epithelial tumor models with matched ligand and coupling measurements.
Gap: Whether LPAR5 has functionally distinct endogenous protein isoforms or stable receptor-specific partners is unknown.
OPEN BIOLOGYCURATION
What is known: Transcript databases list multiple accessions, but the reviewed protein record and audited literature do not establish isoform-specific function. No decisive stable endogenous receptor partner was identified; the LPA-bound Gq structure is an activated signaling state, not evidence of constitutive complex membership.
Significance: Unverified isoforms or partners should not be used to explain tissue-specific signaling without direct evidence.
What would resolve it: Reconcile full-length transcripts by long-read sequencing and proteomics, then combine endogenous proximity labeling with genetic perturbation to identify reproducible signaling or trafficking partners.
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