{"gene":"CNIH2","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2010,"finding":"CNIH-2 associates with TARP γ-8 in hippocampal postsynaptic densities, and CNIH-2 protein levels are markedly diminished in γ-8 knockout mice. CNIH-2 abrogates γ-8-mediated AMPAR resensitization and modifies AMPAR pharmacology and gating to match hippocampal neurons. Manipulating neuronal CNIH-2 levels modulates electrophysiological properties of extrasynaptic and synaptic γ-8-containing AMPA receptors.","method":"Co-immunoprecipitation from hippocampal postsynaptic densities, γ-8 knockout mouse analysis, recombinant expression electrophysiology, neuronal CNIH-2 knockdown/overexpression with patch-clamp recordings","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, knockout mouse validation, electrophysiology in recombinant and native systems across multiple orthogonal methods","pmids":["21172611"],"is_preprint":false},{"year":2013,"finding":"CNIH-2 and CNIH-3 are required for synaptic expression of GluA1-containing AMPARs (GluA1A2 heteromers) in hippocampus. Conditional knockout of CNIH-2/-3 causes profound reduction of AMPAR synaptic transmission with selective loss of surface GluA1-containing AMPARs, leaving a residual pool of GluA2A3 heteromers with faster kinetics. TARP γ-8 prevents functional association of CNIHs with non-GluA1 subunits.","method":"CNIH-2 and CNIH-3 conditional knockout mice, electrophysiology (synaptic recordings), surface biotinylation, immunoprecipitation","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout with defined cellular phenotype, multiple orthogonal methods (electrophysiology + biochemistry), epistasis with γ-8","pmids":["23522044"],"is_preprint":false},{"year":2021,"finding":"Cryo-EM structure of native hippocampal GluA1-GluA2 AMPAR complexes shows TARP-γ8 and CNIH2-SynDIG4 are non-stochastically positioned at distinct sites (B'/D' and A'/C' positions respectively) within the receptor complex. CNIH2 and TARP-γ8 stoichiometry explains mechanism of submaximal inhibition by a brain-region-specific allosteric inhibitor.","method":"Immunoaffinity purification of native hippocampal AMPAR complexes, single-molecule fluorescence, cryo-electron microscopy","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure of native complexes with functional validation of stoichiometry-dependent pharmacology","pmids":["33981040"],"is_preprint":false},{"year":2021,"finding":"Cryo-EM structures of GluA1-GluA2 assembled with both TARP-γ8 and CNIH2 in resting and active states reveal two TARP-γ8 and two CNIH2 subunits insert at distinct sites beneath ligand-binding domains. CNIH2 achieves gating modulation through a uniquely extended M2 helix. Upon receptor activation, CNIH2 pivots toward the pore exit extending its reach to cytoplasmic receptor elements. Site-specific lipids shape each auxiliary subunit interaction and affect gating regulation.","method":"Cryo-electron microscopy of recombinant GluA1-GluA2/TARP-γ8/CNIH2 complexes in resting and active states, mutagenesis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution cryo-EM structures in multiple functional states with mechanistic interpretation of the extended M2 helix","pmids":["34079129"],"is_preprint":false},{"year":2012,"finding":"CNIH-2 functions as an evolutionarily conserved cargo exporter from the endoplasmic reticulum, cycling between ER and Golgi in a COPII-dependent manner. GluA subunits recruit CNIH-2 to the cell surface, commandeering its ancestral ER-export role as a bona fide auxiliary subunit that modifies receptor signaling.","method":"Heterologous cell expression, ER/Golgi fractionation, COPII-dependent transport assays, primary rat neuron studies","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiments with functional consequence, single lab with multiple orthogonal methods","pmids":["22292017"],"is_preprint":false},{"year":2012,"finding":"CNIH-2 and CNIH-3 (but not CNIH-1) slow deactivation and desensitization of both GluA2-containing calcium-impermeable and GluA2-lacking calcium-permeable AMPARs. CNIH-2/-3 also enhance glutamate sensitivity, single-channel conductance, and calcium permeability of CP-AMPARs while decreasing their block by intracellular polyamines. CNIH-3 overexpression in oligodendrocyte precursor cells markedly slows AMPAR desensitization.","method":"Whole-cell patch clamp in tsA201 cells, single-channel recordings, CNIH-3 overexpression in rat optic nerve OPCs, anti-CNIH-2/3 antibody surface labeling","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with electrophysiology, single-channel analysis, and native cell overexpression validating gating modulation","pmids":["22815494"],"is_preprint":false},{"year":2011,"finding":"CNIH-2 coexpressed with GluA/TARP complexes reduces TARP stoichiometry within AMPA receptors. In hippocampal neurons, CNIH-2 associates with AMPARs on the neuronal surface in a γ-8-dependent manner to dictate receptor pharmacology. In Purkinje neurons lacking γ-8 surface expression, CNIH-2 does not reach the neuronal surface, explaining region-specific modulation.","method":"Tandem GluA/TARP construct electrophysiology to constrain stoichiometry, surface biotinylation in hippocampal and cerebellar neurons, recombinant expression assays","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — stoichiometry-constrained recombinant system combined with native neuron surface biochemistry across two cell types","pmids":["21543622"],"is_preprint":false},{"year":2011,"finding":"CNIH-2 modulation of AMPAR gating depends on the TARP isoform composition: with γ-8 (hippocampal TARP), CNIH-2 slows deactivation kinetics, increases cyclothiazide potency, and occludes resensitization; with γ-2 (cerebellar TARP), CNIH-2 has minimal effect on deactivation and recovery from desensitization.","method":"Electrophysiology in heterologous expression system with defined GluA/TARP/CNIH-2 combinations, pharmacological assays","journal":"The European journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — rigorous in vitro reconstitution electrophysiology but single lab, single study","pmids":["22211840"],"is_preprint":false},{"year":2011,"finding":"CNIH-2 coexpression confers partial sensitivity of the AMPAR potentiator [(3)H]-LY450295 binding to displacement by non-competitive antagonists, demonstrating that CNIH-2 allosterically links potentiator and antagonist sites on the AMPAR complex.","method":"Radioligand binding assay [(3)H]-LY450295, autoradiography in brain sections, recombinant expression with CNIH-2","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — direct in vitro binding assay with pharmacological readout, single lab","pmids":["21343286"],"is_preprint":false},{"year":2014,"finding":"CNIH-2 knockdown in hilar mossy cell synapses markedly accelerates EPSC decay without altering amplitude, while CNIH-2 expression in aspiny interneurons (which normally lack CNIH-2) slows their rapidly decaying EPSCs, establishing CNIH-2 as the molecular determinant of slow vs. fast EPSC phenotypes at individual hippocampal synapses.","method":"Paired electrophysiological recordings at identified MFB–mossy cell and MFB–interneuron synapses, selective CNIH-2 knockdown and virus-directed overexpression","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — paired recordings with cell-type specific KD and OE demonstrating bidirectional control of EPSC kinetics","pmids":["24853943"],"is_preprint":false},{"year":2014,"finding":"Peptide array screening and mutagenesis identified two clusters of conserved membrane-proximal residues in CNIHs that mediate direct AMPAR binding. Residues in the extracellular loop of CNIH-2/3 (absent in CNIH-1/4) are critical for both AMPAR interaction and gating modulation. The AMPAR ligand-binding domain and a linker connecting it to the fourth membrane-spanning segment is the principal contact point with the CNIH-3 extracellular loop. A CNIH-3 mutant was identified that preserves AMPAR binding but has attenuated gating modulation, demonstrating binding and gating modulation are dissociable.","method":"Peptide array screening, in vitro mutagenesis, single-particle electron microscopy, co-immunoprecipitation, electrophysiology","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple orthogonal methods including mutagenesis, structural EM, and functional electrophysiology establishing domain-level mechanism","pmids":["25186755"],"is_preprint":false},{"year":2007,"finding":"CNIH2 (CNIL) facilitates the secretion of HB-EGF in chick embryos; perturbation of CNIL function disrupts cranial neural crest cell distribution and results in abnormal nerve fiber connections similar to ErbB4 knockout phenotype. CNIH2 confines HB-EGF action to rhombomeres 3 and 5.","method":"Forced expression of truncated CNIL in chick embryos, siRNA knockdown of CNIL or HB-EGF, cell culture secretion assays","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo loss-of-function with defined phenotype plus cell culture secretion assay, single lab","pmids":["17229890"],"is_preprint":false},{"year":2016,"finding":"GSG1L association with AMPARs inhibits CNIH2-induced slowing of AMPAR deactivation/desensitization in heterologous cells, establishing that GSG1L and CNIH2 have opposing effects on AMPAR gating and can functionally antagonize each other within the same receptor complex.","method":"Heterologous cell electrophysiology with co-expression of GSG1L and CNIH2, co-immunoprecipitation","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct functional antagonism shown by electrophysiology in heterologous cells, single lab","pmids":["26932439"],"is_preprint":false},{"year":2016,"finding":"PORCN knockdown in hippocampal neurons depletes TARP γ-8 from AMPAR complexes and accelerates AMPAR desensitization, an effect linked to the reduction of CNIH-2/3 within the complex. CNIH-2/3 co-purify as part of the AMPAR complex that is regulated by PORCN.","method":"PORCN knockdown in rat hippocampal neurons, co-immunoprecipitation of AMPAR complexes, electrophysiology","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — co-IP and electrophysiology in neurons with KD, single lab","pmids":["26776514"],"is_preprint":false},{"year":2018,"finding":"SAP102-mediated rescue of AMPAR-evoked EPSCs requires the AMPAR auxiliary subunit CNIH-2, whereas CNIH-2 knockdown does not affect PSD-95-mediated AMPAR regulation, indicating that SAP102 and PSD-95 regulate AMPAR function through distinct auxiliary subunit pathways with CNIH-2 specifically mediating SAP102's effect.","method":"Cell-restricted molecular replacement (SAP102 expression with PSD-95 knockdown), CNIH-2 knockdown, whole-cell patch clamp recordings of EPSCs","journal":"Journal of neurophysiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis established by double manipulation with electrophysiological readout, single lab","pmids":["30067114"],"is_preprint":false},{"year":2023,"finding":"CNIH-2 enhances tetramerization of wild-type and mutant AMPARs, primarily through interactions with the transmembrane domain of the receptor, increasing stability of the tetrameric complex. CNIH-2 enhances both GluA1 and GluA2 tetramerization, whereas CNIH-3 only weakly enhances GluA1 tetramerization. CNIH-2 enhances surface expression of functional AMPARs to a greater extent than TARP γ-2.","method":"Blue native PAGE tetramerization assays, surface biotinylation, mutagenesis of transmembrane domains, heterologous expression","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical tetramerization assay with mutagenesis and surface expression measurement, single lab","pmids":["37673338"],"is_preprint":false},{"year":2013,"finding":"CNIH-2 and CNIH-3 show maximum mRNA and protein expression early after birth, declining toward adulthood, with an excess of AMPAR-free CNIH-2/3 early in development. During development, the proportion of CNIH-2/3 integrated into AMPAR complexes increases while AMPAR-free CNIH-2/3 subsides, reflecting a developmental transition from ancestral cargo exporter role to AMPAR auxiliary subunit role.","method":"Western blotting, qRT-PCR, co-immunoprecipitation at multiple postnatal timepoints in rat brain","journal":"Molecular and cellular neurosciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — developmental co-IP and expression profiling at multiple time points, single lab","pmids":["23403072"],"is_preprint":false},{"year":2022,"finding":"GluA1/2 receptors co-purify TARP-γ8, SynDIG4, and CNIH-2 with highest abundances, while GluA2/3 receptors show strongest co-purification of CNIH-2, TARP-γ2, and Noelin1. CNIH-2 associates preferentially with both major hippocampal AMPAR subtypes but shows subtype-specific differences in partner proteins.","method":"Interaction proteomics/co-immunoprecipitation from hippocampi of wildtype and Gria1- or Gria3-knockout mice, mass spectrometry","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic co-IP proteomics from knockout mice establishing subtype-specific interactomes, single lab","pmids":["36429079"],"is_preprint":false},{"year":2024,"finding":"CPSF3 promotes use of the proximal poly(A) site in the 3'UTR of CNIH2 mRNA; CPSF3 knockdown favors use of the distal poly(A) site producing a long-3'UTR CNIH2 isoform that is targeted by miR-125a-5p, resulting in reduced CNIH2 protein. CPSF3-induced ESCC tumorigenicity is mediated by CNIH2, establishing CNIH2 protein level as downstream of CPSF3-regulated alternative polyadenylation in esophageal squamous cell carcinoma.","method":"Iso-Seq and RNA-seq, CPSF3 knockdown/overexpression, luciferase reporter assays, in vitro proliferation/migration assays, in vivo tumor growth in nude mice","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Iso-Seq, functional assays, in vivo) establishing APA-mediated regulation of CNIH2 protein, single lab","pmids":["38718887"],"is_preprint":false},{"year":2025,"finding":"CNIH-2 mRNA is abundant in dendrites and CNIH-2 protein is locally synthesized. CNIH-2 local synthesis increases after chemical LTP induction. Local translation of CNIH-2 is required for plasma membrane insertion of GluA2-containing (calcium-impermeable) AMPARs but not GluA1-homomeric AMPARs, selectively enabling the trafficking of GluA2-containing receptors during LTP.","method":"FISH for dendritic mRNA localization, puromycin-based local translation assay, chemical LTP induction with GluA subtype-specific surface insertion measurement","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct localization and translation assays with functional consequence, preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.02.08.637220"],"is_preprint":true},{"year":2026,"finding":"Human CNIH2 expressed in S. cerevisiae in place of yeast Erv14 functionally complements phenotypes related to Erv14's role in monovalent-cation homeostasis and supports plasma-membrane targeting of the Na+/H+ antiporter NHA2, identifying NHA2 as a novel cargo of CNIH2 COPII cargo receptor activity.","method":"Yeast complementation assay, plasma-membrane targeting assays, AlphaFold3 modeling of CNIH-Sec24 interactions","journal":"Protein science","confidence":"Low","confidence_rationale":"Tier 3 / Weak — yeast heterologous complementation with single lab, computational modeling supplementing functional data","pmids":["41676957"],"is_preprint":false}],"current_model":"CNIH2 is a transmembrane AMPAR auxiliary subunit that functions as both an ancestral COPII cargo receptor (facilitating ER-to-Golgi export of AMPARs and other proteins including NHA2) and a powerful modulator of AMPAR gating: it inserts at defined positions (A'/C') within the native hippocampal GluA1-GluA2/TARP-γ8 complex, slows AMPAR deactivation and desensitization through its extended M2 helix, enhances AMPAR tetramerization via transmembrane domain contacts, promotes surface trafficking of GluA1-containing heteromers in a γ-8-dependent manner, is locally translated in dendrites to selectively enable GluA2-containing AMPAR membrane insertion during LTP, and synergizes with TARP-γ8 to set the kinetics and pharmacology of hippocampal synaptic transmission."},"narrative":{"mechanistic_narrative":"CNIH2 is a transmembrane AMPA receptor (AMPAR) auxiliary subunit that controls the assembly, surface delivery, and gating kinetics of hippocampal glutamate receptors while retaining an ancestral role as a COPII-dependent ER-to-Golgi cargo exporter [PMID:21172611, PMID:22292017]. In neurons it physically associates with AMPAR complexes in a TARP-γ8-dependent manner, and its surface expression and stability depend on γ-8: CNIH2 protein is depleted in γ-8 knockout mice, and in Purkinje neurons lacking surface γ-8 it fails to reach the membrane, explaining region-specific modulation [PMID:21172611, PMID:21543622]. CNIH2 and the related CNIH3 are required for synaptic expression of GluA1-containing heteromers; their conditional deletion profoundly reduces AMPAR transmission and selectively removes surface GluA1-containing receptors [PMID:23522044]. Functionally, CNIH2 slows AMPAR deactivation and desensitization, alters channel conductance, calcium permeability and pharmacology, and acts as the molecular determinant of slow versus fast EPSC kinetics at individual synapses, with effects that depend on TARP isoform composition and that can be antagonized by GSG1L [PMID:22815494, PMID:24853943, PMID:22211840, PMID:26932439]. Cryo-EM of native and reconstituted GluA1-GluA2 complexes places two CNIH2 subunits at defined A'/C' positions beneath the ligand-binding domains, where a uniquely extended M2 helix mediates gating modulation and the subunit pivots toward the pore exit upon activation [PMID:33981040, PMID:34079129]. Binding and gating modulation are dissociable functions mapped to conserved membrane-proximal residues and a CNIH2/3-specific extracellular loop, and CNIH2 additionally enhances AMPAR tetramerization and stability through transmembrane-domain contacts [PMID:25186755, PMID:37673338]. Beyond AMPARs, CNIH2 functions as a conserved cargo receptor: it facilitates HB-EGF secretion to spatially confine signaling during neural crest patterning [PMID:17229890], and it supports plasma-membrane targeting of the Na+/H+ antiporter NHA2 [PMID:41676957].","teleology":[{"year":2007,"claim":"Established CNIH2 as a secretory cargo regulator in vivo before its neuronal role was known, showing it confines a growth-factor signal to spatial domains during development.","evidence":"Truncated CNIL expression and siRNA knockdown in chick embryos with cell-culture HB-EGF secretion assays","pmids":["17229890"],"confidence":"Medium","gaps":["Mechanism of cargo selectivity not defined","Relationship to AMPAR role not addressed","Single ortholog/system"]},{"year":2010,"claim":"Identified CNIH2 as a native AMPAR-associated protein that works with TARP γ-8 to set hippocampal receptor pharmacology and gating, answering whether CNIH2 is a bona fide neuronal auxiliary subunit.","evidence":"Co-IP from hippocampal postsynaptic densities, γ-8 knockout mice, and patch-clamp electrophysiology in recombinant and native systems","pmids":["21172611"],"confidence":"High","gaps":["Stoichiometry within the complex unresolved","Structural basis of gating modulation unknown"]},{"year":2011,"claim":"Resolved how CNIH2 reaches the neuronal surface and competes with TARPs, showing γ-8-dependent surface access and reduced TARP stoichiometry, and that modulation depends on which TARP isoform is present.","evidence":"Tandem GluA/TARP stoichiometry-constrained electrophysiology, surface biotinylation in hippocampal vs cerebellar neurons, radioligand binding ([3H]-LY450295)","pmids":["21543622","22211840","21343286"],"confidence":"High","gaps":["Physical positions of subunits not directly visualized","Allosteric coupling between drug sites inferred pharmacologically"]},{"year":2012,"claim":"Defined the dual identity of CNIH2 as an ancestral COPII cargo exporter co-opted as an AMPAR subunit, and quantified its gating effects across AMPAR subtypes.","evidence":"ER/Golgi fractionation and COPII transport assays in heterologous cells and neurons; whole-cell and single-channel electrophysiology in tsA201 cells and OPCs","pmids":["22292017","22815494"],"confidence":"High","gaps":["Cargo repertoire beyond GluA subunits unmapped","How surface recruitment overrides ER cycling unclear"]},{"year":2013,"claim":"Demonstrated that CNIH2/3 are obligatory for surface and synaptic GluA1-containing AMPARs, and that γ-8 gates which subunits CNIHs can associate with, defining their physiological necessity.","evidence":"CNIH-2/-3 conditional knockout mice with synaptic recordings, surface biotinylation, immunoprecipitation; developmental expression profiling by WB/qRT-PCR/co-IP","pmids":["23522044","23403072"],"confidence":"High","gaps":["Residual GluA2A3 pool regulation not fully explained","Trigger for developmental shift from cargo role to auxiliary role unknown"]},{"year":2014,"claim":"Showed CNIH2 is the molecular switch for synaptic EPSC kinetics and mapped the binding versus gating determinants to distinct CNIH2/3-specific residues, separating its two functions.","evidence":"Paired recordings at identified hippocampal synapses with cell-type-specific KD/OE; peptide arrays, mutagenesis, single-particle EM, co-IP","pmids":["24853943","25186755"],"confidence":"High","gaps":["Atomic-resolution contact geometry not yet defined","How extracellular-loop contacts translate to channel gating unresolved"]},{"year":2016,"claim":"Placed CNIH2 within a network of antagonistic and modulatory auxiliary factors, showing GSG1L opposes its gating effect and PORCN sustains its incorporation via γ-8.","evidence":"Heterologous co-expression electrophysiology with GSG1L; PORCN knockdown in hippocampal neurons with co-IP and electrophysiology","pmids":["26932439","26776514"],"confidence":"Medium","gaps":["Direct GSG1L–CNIH2 structural relationship unknown","How PORCN biochemically stabilizes the complex unclear"]},{"year":2018,"claim":"Linked CNIH2 to a specific scaffold-dependent regulatory pathway, showing SAP102 but not PSD-95 acts on AMPARs through CNIH2.","evidence":"Molecular replacement of SAP102/PSD-95 with CNIH-2 knockdown and whole-cell EPSC recordings","pmids":["30067114"],"confidence":"Medium","gaps":["Mechanism connecting SAP102 to CNIH2 unknown","Single-lab epistasis"]},{"year":2021,"claim":"Provided the structural basis for CNIH2 action, defining its non-stochastic A'/C' positions, the extended M2 helix that drives gating, and its activation-coupled pivot toward the pore.","evidence":"Cryo-EM of native and recombinant GluA1-GluA2/TARP-γ8/CNIH2 complexes in resting and active states, single-molecule fluorescence, mutagenesis","pmids":["33981040","34079129"],"confidence":"High","gaps":["Conformational dynamics of the pivot during gating cycle inferred from static states","Role of specific lipids not functionally dissected in neurons"]},{"year":2023,"claim":"Established a distinct biochemical contribution of CNIH2, showing it promotes AMPAR tetramerization and stability via transmembrane contacts independent of gating.","evidence":"Blue native PAGE tetramerization assays, surface biotinylation, transmembrane-domain mutagenesis in heterologous cells","pmids":["37673338"],"confidence":"Medium","gaps":["Whether tetramerization role operates in native neurons untested","Subunit-specific differences with CNIH3 mechanistically unexplained"]},{"year":2024,"claim":"Identified post-transcriptional control of CNIH2 protein levels, showing alternative polyadenylation and miRNA targeting set its abundance with consequences for tumorigenicity.","evidence":"Iso-Seq/RNA-seq, CPSF3 KD/OE, luciferase reporters, proliferation/migration assays, and xenograft tumor growth in nude mice","pmids":["38718887"],"confidence":"Medium","gaps":["CNIH2 effector mechanism in carcinoma cells undefined","Link to its neuronal/cargo functions unclear"]},{"year":2025,"claim":"Connected CNIH2 to synaptic plasticity, showing dendritic local translation of CNIH2 selectively enables GluA2-containing AMPAR insertion during LTP.","evidence":"FISH for dendritic mRNA, puromycin local-translation assay, chemical LTP with subtype-specific surface insertion (preprint)","pmids":["bio_10.1101_2025.02.08.637220"],"confidence":"Medium","gaps":["Not yet peer-reviewed","Signaling that triggers local CNIH2 synthesis unknown","GluA2-selectivity mechanism not defined"]},{"year":2026,"claim":"Extended CNIH2's cargo-receptor repertoire beyond AMPARs by identifying the Na+/H+ antiporter NHA2 as a cargo via Erv14-like COPII function.","evidence":"Yeast (Erv14-replacement) complementation, plasma-membrane targeting assays, AlphaFold3 modeling of CNIH-Sec24 interactions","pmids":["41676957"],"confidence":"Low","gaps":["Heterologous yeast system, not validated in mammalian cells","Direct CNIH2-Sec24 interaction computational only","NHA2 cargo role single lab"]},{"year":null,"claim":"How CNIH2 toggles between its ancestral COPII cargo-export function and its surface AMPAR-gating role, and what signals govern this developmental and activity-dependent switch, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking cargo cycling and surface auxiliary roles","Triggers for activity-dependent local synthesis undefined","Full mammalian cargo repertoire unmapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,5,7,9,10,3]},{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[4,11,20]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,6,15,19]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[4]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,1,9]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[4,11,20]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[4]}],"complexes":["GluA1-GluA2/TARP-γ8/CNIH2 AMPAR complex"],"partners":["GRIA1","GRIA2","CACNG8","CNIH3","GSG1L","PRRT1","PORCN","NHA2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6PI25","full_name":"Protein cornichon homolog 2","aliases":["Cornichon family AMPA receptor auxiliary protein 2","Cornichon-like protein"],"length_aa":160,"mass_kda":18.9,"function":"Regulates the trafficking and gating properties of AMPA-selective glutamate receptors (AMPARs). Promotes their targeting to the cell membrane and synapses and modulates their gating properties by regulating their rates of activation, deactivation and desensitization. Blocks CACNG8-mediated resensitization of AMPA receptors","subcellular_location":"Endoplasmic reticulum membrane; Postsynaptic cell membrane; Cell projection, dendrite; Cell projection, dendritic spine; Postsynaptic density","url":"https://www.uniprot.org/uniprotkb/Q6PI25/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CNIH2","classification":"Not Classified","n_dependent_lines":45,"n_total_lines":1208,"dependency_fraction":0.037251655629139076},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CNIH2","total_profiled":1310},"omim":[{"mim_id":"617492","title":"OLFACTOMEDIN 2; OLFM2","url":"https://www.omim.org/entry/617492"},{"mim_id":"617483","title":"CORNICHON FAMILY AMPA RECEPTOR AUXILIARY PROTEIN 4; CNIH4","url":"https://www.omim.org/entry/617483"},{"mim_id":"617161","title":"GSG1-LIKE PROTEIN; GSG1L","url":"https://www.omim.org/entry/617161"},{"mim_id":"611288","title":"CORNICHON FAMILY AMPA RECEPTOR AUXILIARY PROTEIN 2; CNIH2","url":"https://www.omim.org/entry/611288"},{"mim_id":"611287","title":"CORNICHON FAMILY AMPA RECEPTOR AUXILIARY PROTEIN 1; CNIH1","url":"https://www.omim.org/entry/611287"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":424.2}],"url":"https://www.proteinatlas.org/search/CNIH2"},"hgnc":{"alias_symbol":["MGC50896","Cnil","CNIH-2"],"prev_symbol":[]},"alphafold":{"accession":"Q6PI25","domains":[{"cath_id":"-","chopping":"4-158","consensus_level":"high","plddt":87.3848,"start":4,"end":158}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6PI25","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6PI25-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6PI25-F1-predicted_aligned_error_v6.png","plddt_mean":87.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CNIH2","jax_strain_url":"https://www.jax.org/strain/search?query=CNIH2"},"sequence":{"accession":"Q6PI25","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6PI25.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6PI25/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6PI25"}},"corpus_meta":[{"pmid":"21172611","id":"PMC_21172611","title":"Hippocampal AMPA receptor gating controlled by both TARP and cornichon proteins.","date":"2010","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/21172611","citation_count":143,"is_preprint":false},{"pmid":"25646370","id":"PMC_25646370","title":"Genome-wide association study of clinically defined gout identifies multiple risk loci and its association with clinical subtypes.","date":"2015","source":"Annals of the rheumatic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/25646370","citation_count":139,"is_preprint":false},{"pmid":"23522044","id":"PMC_23522044","title":"Cornichon proteins determine the subunit composition of synaptic AMPA receptors.","date":"2013","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/23522044","citation_count":127,"is_preprint":false},{"pmid":"33981040","id":"PMC_33981040","title":"Hippocampal AMPA receptor assemblies and mechanism of allosteric 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CNIH-2 abrogates γ-8-mediated AMPAR resensitization and modifies AMPAR pharmacology and gating to match hippocampal neurons. Manipulating neuronal CNIH-2 levels modulates electrophysiological properties of extrasynaptic and synaptic γ-8-containing AMPA receptors.\",\n      \"method\": \"Co-immunoprecipitation from hippocampal postsynaptic densities, γ-8 knockout mouse analysis, recombinant expression electrophysiology, neuronal CNIH-2 knockdown/overexpression with patch-clamp recordings\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, knockout mouse validation, electrophysiology in recombinant and native systems across multiple orthogonal methods\",\n      \"pmids\": [\"21172611\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CNIH-2 and CNIH-3 are required for synaptic expression of GluA1-containing AMPARs (GluA1A2 heteromers) in hippocampus. Conditional knockout of CNIH-2/-3 causes profound reduction of AMPAR synaptic transmission with selective loss of surface GluA1-containing AMPARs, leaving a residual pool of GluA2A3 heteromers with faster kinetics. TARP γ-8 prevents functional association of CNIHs with non-GluA1 subunits.\",\n      \"method\": \"CNIH-2 and CNIH-3 conditional knockout mice, electrophysiology (synaptic recordings), surface biotinylation, immunoprecipitation\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout with defined cellular phenotype, multiple orthogonal methods (electrophysiology + biochemistry), epistasis with γ-8\",\n      \"pmids\": [\"23522044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cryo-EM structure of native hippocampal GluA1-GluA2 AMPAR complexes shows TARP-γ8 and CNIH2-SynDIG4 are non-stochastically positioned at distinct sites (B'/D' and A'/C' positions respectively) within the receptor complex. CNIH2 and TARP-γ8 stoichiometry explains mechanism of submaximal inhibition by a brain-region-specific allosteric inhibitor.\",\n      \"method\": \"Immunoaffinity purification of native hippocampal AMPAR complexes, single-molecule fluorescence, cryo-electron microscopy\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure of native complexes with functional validation of stoichiometry-dependent pharmacology\",\n      \"pmids\": [\"33981040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cryo-EM structures of GluA1-GluA2 assembled with both TARP-γ8 and CNIH2 in resting and active states reveal two TARP-γ8 and two CNIH2 subunits insert at distinct sites beneath ligand-binding domains. CNIH2 achieves gating modulation through a uniquely extended M2 helix. Upon receptor activation, CNIH2 pivots toward the pore exit extending its reach to cytoplasmic receptor elements. Site-specific lipids shape each auxiliary subunit interaction and affect gating regulation.\",\n      \"method\": \"Cryo-electron microscopy of recombinant GluA1-GluA2/TARP-γ8/CNIH2 complexes in resting and active states, mutagenesis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution cryo-EM structures in multiple functional states with mechanistic interpretation of the extended M2 helix\",\n      \"pmids\": [\"34079129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CNIH-2 functions as an evolutionarily conserved cargo exporter from the endoplasmic reticulum, cycling between ER and Golgi in a COPII-dependent manner. GluA subunits recruit CNIH-2 to the cell surface, commandeering its ancestral ER-export role as a bona fide auxiliary subunit that modifies receptor signaling.\",\n      \"method\": \"Heterologous cell expression, ER/Golgi fractionation, COPII-dependent transport assays, primary rat neuron studies\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiments with functional consequence, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"22292017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CNIH-2 and CNIH-3 (but not CNIH-1) slow deactivation and desensitization of both GluA2-containing calcium-impermeable and GluA2-lacking calcium-permeable AMPARs. CNIH-2/-3 also enhance glutamate sensitivity, single-channel conductance, and calcium permeability of CP-AMPARs while decreasing their block by intracellular polyamines. CNIH-3 overexpression in oligodendrocyte precursor cells markedly slows AMPAR desensitization.\",\n      \"method\": \"Whole-cell patch clamp in tsA201 cells, single-channel recordings, CNIH-3 overexpression in rat optic nerve OPCs, anti-CNIH-2/3 antibody surface labeling\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with electrophysiology, single-channel analysis, and native cell overexpression validating gating modulation\",\n      \"pmids\": [\"22815494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CNIH-2 coexpressed with GluA/TARP complexes reduces TARP stoichiometry within AMPA receptors. In hippocampal neurons, CNIH-2 associates with AMPARs on the neuronal surface in a γ-8-dependent manner to dictate receptor pharmacology. In Purkinje neurons lacking γ-8 surface expression, CNIH-2 does not reach the neuronal surface, explaining region-specific modulation.\",\n      \"method\": \"Tandem GluA/TARP construct electrophysiology to constrain stoichiometry, surface biotinylation in hippocampal and cerebellar neurons, recombinant expression assays\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — stoichiometry-constrained recombinant system combined with native neuron surface biochemistry across two cell types\",\n      \"pmids\": [\"21543622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CNIH-2 modulation of AMPAR gating depends on the TARP isoform composition: with γ-8 (hippocampal TARP), CNIH-2 slows deactivation kinetics, increases cyclothiazide potency, and occludes resensitization; with γ-2 (cerebellar TARP), CNIH-2 has minimal effect on deactivation and recovery from desensitization.\",\n      \"method\": \"Electrophysiology in heterologous expression system with defined GluA/TARP/CNIH-2 combinations, pharmacological assays\",\n      \"journal\": \"The European journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — rigorous in vitro reconstitution electrophysiology but single lab, single study\",\n      \"pmids\": [\"22211840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CNIH-2 coexpression confers partial sensitivity of the AMPAR potentiator [(3)H]-LY450295 binding to displacement by non-competitive antagonists, demonstrating that CNIH-2 allosterically links potentiator and antagonist sites on the AMPAR complex.\",\n      \"method\": \"Radioligand binding assay [(3)H]-LY450295, autoradiography in brain sections, recombinant expression with CNIH-2\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — direct in vitro binding assay with pharmacological readout, single lab\",\n      \"pmids\": [\"21343286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CNIH-2 knockdown in hilar mossy cell synapses markedly accelerates EPSC decay without altering amplitude, while CNIH-2 expression in aspiny interneurons (which normally lack CNIH-2) slows their rapidly decaying EPSCs, establishing CNIH-2 as the molecular determinant of slow vs. fast EPSC phenotypes at individual hippocampal synapses.\",\n      \"method\": \"Paired electrophysiological recordings at identified MFB–mossy cell and MFB–interneuron synapses, selective CNIH-2 knockdown and virus-directed overexpression\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — paired recordings with cell-type specific KD and OE demonstrating bidirectional control of EPSC kinetics\",\n      \"pmids\": [\"24853943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Peptide array screening and mutagenesis identified two clusters of conserved membrane-proximal residues in CNIHs that mediate direct AMPAR binding. Residues in the extracellular loop of CNIH-2/3 (absent in CNIH-1/4) are critical for both AMPAR interaction and gating modulation. The AMPAR ligand-binding domain and a linker connecting it to the fourth membrane-spanning segment is the principal contact point with the CNIH-3 extracellular loop. A CNIH-3 mutant was identified that preserves AMPAR binding but has attenuated gating modulation, demonstrating binding and gating modulation are dissociable.\",\n      \"method\": \"Peptide array screening, in vitro mutagenesis, single-particle electron microscopy, co-immunoprecipitation, electrophysiology\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple orthogonal methods including mutagenesis, structural EM, and functional electrophysiology establishing domain-level mechanism\",\n      \"pmids\": [\"25186755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CNIH2 (CNIL) facilitates the secretion of HB-EGF in chick embryos; perturbation of CNIL function disrupts cranial neural crest cell distribution and results in abnormal nerve fiber connections similar to ErbB4 knockout phenotype. CNIH2 confines HB-EGF action to rhombomeres 3 and 5.\",\n      \"method\": \"Forced expression of truncated CNIL in chick embryos, siRNA knockdown of CNIL or HB-EGF, cell culture secretion assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo loss-of-function with defined phenotype plus cell culture secretion assay, single lab\",\n      \"pmids\": [\"17229890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"GSG1L association with AMPARs inhibits CNIH2-induced slowing of AMPAR deactivation/desensitization in heterologous cells, establishing that GSG1L and CNIH2 have opposing effects on AMPAR gating and can functionally antagonize each other within the same receptor complex.\",\n      \"method\": \"Heterologous cell electrophysiology with co-expression of GSG1L and CNIH2, co-immunoprecipitation\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct functional antagonism shown by electrophysiology in heterologous cells, single lab\",\n      \"pmids\": [\"26932439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PORCN knockdown in hippocampal neurons depletes TARP γ-8 from AMPAR complexes and accelerates AMPAR desensitization, an effect linked to the reduction of CNIH-2/3 within the complex. CNIH-2/3 co-purify as part of the AMPAR complex that is regulated by PORCN.\",\n      \"method\": \"PORCN knockdown in rat hippocampal neurons, co-immunoprecipitation of AMPAR complexes, electrophysiology\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — co-IP and electrophysiology in neurons with KD, single lab\",\n      \"pmids\": [\"26776514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SAP102-mediated rescue of AMPAR-evoked EPSCs requires the AMPAR auxiliary subunit CNIH-2, whereas CNIH-2 knockdown does not affect PSD-95-mediated AMPAR regulation, indicating that SAP102 and PSD-95 regulate AMPAR function through distinct auxiliary subunit pathways with CNIH-2 specifically mediating SAP102's effect.\",\n      \"method\": \"Cell-restricted molecular replacement (SAP102 expression with PSD-95 knockdown), CNIH-2 knockdown, whole-cell patch clamp recordings of EPSCs\",\n      \"journal\": \"Journal of neurophysiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis established by double manipulation with electrophysiological readout, single lab\",\n      \"pmids\": [\"30067114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CNIH-2 enhances tetramerization of wild-type and mutant AMPARs, primarily through interactions with the transmembrane domain of the receptor, increasing stability of the tetrameric complex. CNIH-2 enhances both GluA1 and GluA2 tetramerization, whereas CNIH-3 only weakly enhances GluA1 tetramerization. CNIH-2 enhances surface expression of functional AMPARs to a greater extent than TARP γ-2.\",\n      \"method\": \"Blue native PAGE tetramerization assays, surface biotinylation, mutagenesis of transmembrane domains, heterologous expression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical tetramerization assay with mutagenesis and surface expression measurement, single lab\",\n      \"pmids\": [\"37673338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CNIH-2 and CNIH-3 show maximum mRNA and protein expression early after birth, declining toward adulthood, with an excess of AMPAR-free CNIH-2/3 early in development. During development, the proportion of CNIH-2/3 integrated into AMPAR complexes increases while AMPAR-free CNIH-2/3 subsides, reflecting a developmental transition from ancestral cargo exporter role to AMPAR auxiliary subunit role.\",\n      \"method\": \"Western blotting, qRT-PCR, co-immunoprecipitation at multiple postnatal timepoints in rat brain\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — developmental co-IP and expression profiling at multiple time points, single lab\",\n      \"pmids\": [\"23403072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"GluA1/2 receptors co-purify TARP-γ8, SynDIG4, and CNIH-2 with highest abundances, while GluA2/3 receptors show strongest co-purification of CNIH-2, TARP-γ2, and Noelin1. CNIH-2 associates preferentially with both major hippocampal AMPAR subtypes but shows subtype-specific differences in partner proteins.\",\n      \"method\": \"Interaction proteomics/co-immunoprecipitation from hippocampi of wildtype and Gria1- or Gria3-knockout mice, mass spectrometry\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic co-IP proteomics from knockout mice establishing subtype-specific interactomes, single lab\",\n      \"pmids\": [\"36429079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CPSF3 promotes use of the proximal poly(A) site in the 3'UTR of CNIH2 mRNA; CPSF3 knockdown favors use of the distal poly(A) site producing a long-3'UTR CNIH2 isoform that is targeted by miR-125a-5p, resulting in reduced CNIH2 protein. CPSF3-induced ESCC tumorigenicity is mediated by CNIH2, establishing CNIH2 protein level as downstream of CPSF3-regulated alternative polyadenylation in esophageal squamous cell carcinoma.\",\n      \"method\": \"Iso-Seq and RNA-seq, CPSF3 knockdown/overexpression, luciferase reporter assays, in vitro proliferation/migration assays, in vivo tumor growth in nude mice\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Iso-Seq, functional assays, in vivo) establishing APA-mediated regulation of CNIH2 protein, single lab\",\n      \"pmids\": [\"38718887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CNIH-2 mRNA is abundant in dendrites and CNIH-2 protein is locally synthesized. CNIH-2 local synthesis increases after chemical LTP induction. Local translation of CNIH-2 is required for plasma membrane insertion of GluA2-containing (calcium-impermeable) AMPARs but not GluA1-homomeric AMPARs, selectively enabling the trafficking of GluA2-containing receptors during LTP.\",\n      \"method\": \"FISH for dendritic mRNA localization, puromycin-based local translation assay, chemical LTP induction with GluA subtype-specific surface insertion measurement\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct localization and translation assays with functional consequence, preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.02.08.637220\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Human CNIH2 expressed in S. cerevisiae in place of yeast Erv14 functionally complements phenotypes related to Erv14's role in monovalent-cation homeostasis and supports plasma-membrane targeting of the Na+/H+ antiporter NHA2, identifying NHA2 as a novel cargo of CNIH2 COPII cargo receptor activity.\",\n      \"method\": \"Yeast complementation assay, plasma-membrane targeting assays, AlphaFold3 modeling of CNIH-Sec24 interactions\",\n      \"journal\": \"Protein science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — yeast heterologous complementation with single lab, computational modeling supplementing functional data\",\n      \"pmids\": [\"41676957\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CNIH2 is a transmembrane AMPAR auxiliary subunit that functions as both an ancestral COPII cargo receptor (facilitating ER-to-Golgi export of AMPARs and other proteins including NHA2) and a powerful modulator of AMPAR gating: it inserts at defined positions (A'/C') within the native hippocampal GluA1-GluA2/TARP-γ8 complex, slows AMPAR deactivation and desensitization through its extended M2 helix, enhances AMPAR tetramerization via transmembrane domain contacts, promotes surface trafficking of GluA1-containing heteromers in a γ-8-dependent manner, is locally translated in dendrites to selectively enable GluA2-containing AMPAR membrane insertion during LTP, and synergizes with TARP-γ8 to set the kinetics and pharmacology of hippocampal synaptic transmission.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CNIH2 is a transmembrane AMPA receptor (AMPAR) auxiliary subunit that controls the assembly, surface delivery, and gating kinetics of hippocampal glutamate receptors while retaining an ancestral role as a COPII-dependent ER-to-Golgi cargo exporter [#0, #4]. In neurons it physically associates with AMPAR complexes in a TARP-\\u03b38-dependent manner, and its surface expression and stability depend on \\u03b3-8: CNIH2 protein is depleted in \\u03b3-8 knockout mice, and in Purkinje neurons lacking surface \\u03b3-8 it fails to reach the membrane, explaining region-specific modulation [#0, #6]. CNIH2 and the related CNIH3 are required for synaptic expression of GluA1-containing heteromers; their conditional deletion profoundly reduces AMPAR transmission and selectively removes surface GluA1-containing receptors [#1]. Functionally, CNIH2 slows AMPAR deactivation and desensitization, alters channel conductance, calcium permeability and pharmacology, and acts as the molecular determinant of slow versus fast EPSC kinetics at individual synapses, with effects that depend on TARP isoform composition and that can be antagonized by GSG1L [#5, #9, #7, #12]. Cryo-EM of native and reconstituted GluA1-GluA2 complexes places two CNIH2 subunits at defined A'/C' positions beneath the ligand-binding domains, where a uniquely extended M2 helix mediates gating modulation and the subunit pivots toward the pore exit upon activation [#2, #3]. Binding and gating modulation are dissociable functions mapped to conserved membrane-proximal residues and a CNIH2/3-specific extracellular loop, and CNIH2 additionally enhances AMPAR tetramerization and stability through transmembrane-domain contacts [#10, #15]. Beyond AMPARs, CNIH2 functions as a conserved cargo receptor: it facilitates HB-EGF secretion to spatially confine signaling during neural crest patterning [#11], and it supports plasma-membrane targeting of the Na+/H+ antiporter NHA2 [#20].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established CNIH2 as a secretory cargo regulator in vivo before its neuronal role was known, showing it confines a growth-factor signal to spatial domains during development.\",\n      \"evidence\": \"Truncated CNIL expression and siRNA knockdown in chick embryos with cell-culture HB-EGF secretion assays\",\n      \"pmids\": [\"17229890\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of cargo selectivity not defined\", \"Relationship to AMPAR role not addressed\", \"Single ortholog/system\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified CNIH2 as a native AMPAR-associated protein that works with TARP \\u03b3-8 to set hippocampal receptor pharmacology and gating, answering whether CNIH2 is a bona fide neuronal auxiliary subunit.\",\n      \"evidence\": \"Co-IP from hippocampal postsynaptic densities, \\u03b3-8 knockout mice, and patch-clamp electrophysiology in recombinant and native systems\",\n      \"pmids\": [\"21172611\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry within the complex unresolved\", \"Structural basis of gating modulation unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Resolved how CNIH2 reaches the neuronal surface and competes with TARPs, showing \\u03b3-8-dependent surface access and reduced TARP stoichiometry, and that modulation depends on which TARP isoform is present.\",\n      \"evidence\": \"Tandem GluA/TARP stoichiometry-constrained electrophysiology, surface biotinylation in hippocampal vs cerebellar neurons, radioligand binding ([3H]-LY450295)\",\n      \"pmids\": [\"21543622\", \"22211840\", \"21343286\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physical positions of subunits not directly visualized\", \"Allosteric coupling between drug sites inferred pharmacologically\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined the dual identity of CNIH2 as an ancestral COPII cargo exporter co-opted as an AMPAR subunit, and quantified its gating effects across AMPAR subtypes.\",\n      \"evidence\": \"ER/Golgi fractionation and COPII transport assays in heterologous cells and neurons; whole-cell and single-channel electrophysiology in tsA201 cells and OPCs\",\n      \"pmids\": [\"22292017\", \"22815494\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cargo repertoire beyond GluA subunits unmapped\", \"How surface recruitment overrides ER cycling unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated that CNIH2/3 are obligatory for surface and synaptic GluA1-containing AMPARs, and that \\u03b3-8 gates which subunits CNIHs can associate with, defining their physiological necessity.\",\n      \"evidence\": \"CNIH-2/-3 conditional knockout mice with synaptic recordings, surface biotinylation, immunoprecipitation; developmental expression profiling by WB/qRT-PCR/co-IP\",\n      \"pmids\": [\"23522044\", \"23403072\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Residual GluA2A3 pool regulation not fully explained\", \"Trigger for developmental shift from cargo role to auxiliary role unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed CNIH2 is the molecular switch for synaptic EPSC kinetics and mapped the binding versus gating determinants to distinct CNIH2/3-specific residues, separating its two functions.\",\n      \"evidence\": \"Paired recordings at identified hippocampal synapses with cell-type-specific KD/OE; peptide arrays, mutagenesis, single-particle EM, co-IP\",\n      \"pmids\": [\"24853943\", \"25186755\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-resolution contact geometry not yet defined\", \"How extracellular-loop contacts translate to channel gating unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed CNIH2 within a network of antagonistic and modulatory auxiliary factors, showing GSG1L opposes its gating effect and PORCN sustains its incorporation via \\u03b3-8.\",\n      \"evidence\": \"Heterologous co-expression electrophysiology with GSG1L; PORCN knockdown in hippocampal neurons with co-IP and electrophysiology\",\n      \"pmids\": [\"26932439\", \"26776514\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct GSG1L\\u2013CNIH2 structural relationship unknown\", \"How PORCN biochemically stabilizes the complex unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linked CNIH2 to a specific scaffold-dependent regulatory pathway, showing SAP102 but not PSD-95 acts on AMPARs through CNIH2.\",\n      \"evidence\": \"Molecular replacement of SAP102/PSD-95 with CNIH-2 knockdown and whole-cell EPSC recordings\",\n      \"pmids\": [\"30067114\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting SAP102 to CNIH2 unknown\", \"Single-lab epistasis\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided the structural basis for CNIH2 action, defining its non-stochastic A'/C' positions, the extended M2 helix that drives gating, and its activation-coupled pivot toward the pore.\",\n      \"evidence\": \"Cryo-EM of native and recombinant GluA1-GluA2/TARP-\\u03b38/CNIH2 complexes in resting and active states, single-molecule fluorescence, mutagenesis\",\n      \"pmids\": [\"33981040\", \"34079129\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conformational dynamics of the pivot during gating cycle inferred from static states\", \"Role of specific lipids not functionally dissected in neurons\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established a distinct biochemical contribution of CNIH2, showing it promotes AMPAR tetramerization and stability via transmembrane contacts independent of gating.\",\n      \"evidence\": \"Blue native PAGE tetramerization assays, surface biotinylation, transmembrane-domain mutagenesis in heterologous cells\",\n      \"pmids\": [\"37673338\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether tetramerization role operates in native neurons untested\", \"Subunit-specific differences with CNIH3 mechanistically unexplained\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified post-transcriptional control of CNIH2 protein levels, showing alternative polyadenylation and miRNA targeting set its abundance with consequences for tumorigenicity.\",\n      \"evidence\": \"Iso-Seq/RNA-seq, CPSF3 KD/OE, luciferase reporters, proliferation/migration assays, and xenograft tumor growth in nude mice\",\n      \"pmids\": [\"38718887\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CNIH2 effector mechanism in carcinoma cells undefined\", \"Link to its neuronal/cargo functions unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected CNIH2 to synaptic plasticity, showing dendritic local translation of CNIH2 selectively enables GluA2-containing AMPAR insertion during LTP.\",\n      \"evidence\": \"FISH for dendritic mRNA, puromycin local-translation assay, chemical LTP with subtype-specific surface insertion (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.02.08.637220\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Not yet peer-reviewed\", \"Signaling that triggers local CNIH2 synthesis unknown\", \"GluA2-selectivity mechanism not defined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Extended CNIH2's cargo-receptor repertoire beyond AMPARs by identifying the Na+/H+ antiporter NHA2 as a cargo via Erv14-like COPII function.\",\n      \"evidence\": \"Yeast (Erv14-replacement) complementation, plasma-membrane targeting assays, AlphaFold3 modeling of CNIH-Sec24 interactions\",\n      \"pmids\": [\"41676957\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Heterologous yeast system, not validated in mammalian cells\", \"Direct CNIH2-Sec24 interaction computational only\", \"NHA2 cargo role single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CNIH2 toggles between its ancestral COPII cargo-export function and its surface AMPAR-gating role, and what signals govern this developmental and activity-dependent switch, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking cargo cycling and surface auxiliary roles\", \"Triggers for activity-dependent local synthesis undefined\", \"Full mammalian cargo repertoire unmapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 5, 7, 9, 10, 3]},\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [4, 11, 20]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 6, 15, 19]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 1, 9]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [4, 11, 20]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [\n      \"GluA1-GluA2/TARP-\\u03b38/CNIH2 AMPAR complex\"\n    ],\n    \"partners\": [\n      \"GRIA1\",\n      \"GRIA2\",\n      \"CACNG8\",\n      \"CNIH3\",\n      \"GSG1L\",\n      \"PRRT1\",\n      \"PORCN\",\n      \"NHA2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}