{"gene":"CHRNA4","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":1997,"finding":"An insertion of three nucleotides (GCT) at position 776 in the M2 domain of CHRNA4 does not prevent receptor function but increases apparent affinity for ACh and significantly lowers calcium permeability, corresponding to a loss of function at the cellular level.","method":"Receptor reconstitution and physiological investigation in heterologous expression system","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1 — reconstituted mutant receptor and measured functional parameters (ACh affinity, calcium permeability)","pmids":["9175743"],"is_preprint":false},{"year":1999,"finding":"The S252L (Ser252Leu) missense mutation in the M2 transmembrane domain of CHRNA4, affecting a conserved serine, causes autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) in a Japanese family, implicating this residue in channel function.","method":"SSCP, direct sequencing, and segregation analysis","journal":"Neurology","confidence":"Medium","confidence_rationale":"Tier 2 — mutation identified and segregated; functional role of M2 serine inferred from conservation, no direct in vitro functional assay in this paper","pmids":["10563623"],"is_preprint":false},{"year":2003,"finding":"The CHRNA4 α4-T265I mutation at the extracellular end of TM2 increases ACh sensitivity of reconstituted receptors, as demonstrated by expression in Xenopus oocytes.","method":"Expression in Xenopus oocytes and electrophysiology","journal":"Epilepsia","confidence":"High","confidence_rationale":"Tier 1 — direct functional assay in Xenopus oocyte expression system measuring ACh sensitivity","pmids":["12823585"],"is_preprint":false},{"year":2003,"finding":"The mouse Chrna4 A529T polymorphism in the second intracellular loop alters the ratio of high- to low-affinity α4β2 nAChR populations and changes receptor sensitivity to DHβE blockade when expressed heterologously, identifying this domain as a functional determinant of receptor affinity states.","method":"Heterologous expression of variant α4 subunits with β2 subunit; electrophysiology","journal":"Neuropharmacology","confidence":"High","confidence_rationale":"Tier 1 — reconstituted receptors with variant subunits, functional electrophysiological characterization","pmids":["12871652"],"is_preprint":false},{"year":2003,"finding":"The mouse Chrna4 A/T polymorphism at position 529 modulates enhancement of α4β2 nAChR function by ethanol: strains carrying the A variant show ethanol-induced increases in maximal ion flux, while strains with the T variant do not, indicating the polymorphism controls ethanol sensitivity of the receptor.","method":"86Rb+ efflux assay in thalamic synaptosomes from inbred mouse strains and F2 intercross animals","journal":"Alcoholism, clinical and experimental research","confidence":"High","confidence_rationale":"Tier 1/2 — functional in vitro assay replicated across six strains and F2 animals","pmids":["12766617"],"is_preprint":false},{"year":2008,"finding":"Transgenic rats harboring the CHRNA4 S284L mutation exhibit attenuation of synaptic and extrasynaptic GABAergic transmission and abnormal glutamate release during slow-wave sleep, producing an ADNFLE-like seizure phenotype.","method":"Transgenic rat model; electrophysiological measurements of GABAergic and glutamatergic neurotransmission; behavioral seizure monitoring","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — clean knock-in model with defined cellular phenotype (altered GABAergic and glutamatergic transmission) and behavioral readout","pmids":["19020039"],"is_preprint":false},{"year":2010,"finding":"Chrna4 A529 knock-in mice show greater sensitivity to nicotine-induced hypothermia, reduced oral nicotine consumption, lack of conditioned place preference, and altered α4β2* nAChR function (maximal efflux and high-sensitivity receptor proportion) in midbrain, confirming that the T529A polymorphism in the second intracellular loop modulates α4β2* receptor function and behavioral responses to nicotine.","method":"Knock-in mouse model; behavioral pharmacology; 86Rb+ efflux assay from midbrain synaptosomes","journal":"Pharmacogenetics and genomics","confidence":"High","confidence_rationale":"Tier 2 — genetic knock-in with multiple orthogonal functional readouts (receptor pharmacology, multiple behaviors)","pmids":["20061993"],"is_preprint":false},{"year":2014,"finding":"Rare CHRNA4 variants (α4R336C, α4P451L, α4R487Q) alter α4β2 nAChR expression, subcellular distribution, sensitivity to nicotine-induced receptor upregulation, intracellular interactome composition (by LC-MS/MS), and functional parameters of agonist activation in Xenopus oocytes, demonstrating that these variants produce receptors more sensitive to nicotine than those with the common variant.","method":"[3H]epibatidine binding, immunoprecipitation/LC-MS/MS proteomics, voltage-clamp electrophysiology in Xenopus oocytes, HEK293 cell expression","journal":"The Journal of pharmacology and experimental therapeutics","confidence":"High","confidence_rationale":"Tier 1 — multiple orthogonal methods including binding assay, proteomics, and electrophysiology in the same study","pmids":["24385388"],"is_preprint":false},{"year":2015,"finding":"A splice site acceptor variant (rs2273500-C) in CHRNA4 results in an alternate transcript predicted to be targeted for nonsense-mediated decay and is associated with decreased CHRNA4 expression in postmortem human brain, establishing rs2273500 as a functional regulatory variant.","method":"GWAS meta-analysis combined with eQTL analysis of brain expression data","journal":"Translational psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 — eQTL evidence in human brain tissue for functional regulatory effect; mechanism inferred from splice site prediction and expression data","pmids":["26440539"],"is_preprint":false},{"year":2023,"finding":"CHRNA4 is expressed specifically in hepatocytes and functions as a subunit of nicotinic acetylcholine receptors activated by acetylcholine from immune cells or nicotine, inducing calcium influx and activation of inflammatory signaling pathways that promote MASH (metabolic dysfunction-associated steatohepatitis); genetic and pharmacological inhibition of CHRNA4 protected mice from diet-induced MASH.","method":"Liver-specific Chrna4 knockout mice, calcium influx assays, inflammatory signaling readouts, dietary MASH mouse model, human patient correlation","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 — clean genetic KO with defined cellular mechanism (calcium influx, inflammatory signaling) and in vivo phenotypic rescue","pmids":["38056431"],"is_preprint":false},{"year":2023,"finding":"METTL3-mediated m6A modification is enriched on Chrna4 mRNA in hippocampal neurons following BPA exposure, leading to decreased Chrna4 expression; inhibition of METTL3 restored Chrna4 levels and rescued abnormal synaptic transmission and spatial memory deficits.","method":"m6A sequencing/MeRIP, METTL3 knockdown (shRNA) and pharmacological inhibition, electrophysiology, behavioral testing in rats","journal":"Environmental research","confidence":"Medium","confidence_rationale":"Tier 2 — m6A mapping on Chrna4 mRNA with functional rescue, but single lab and BPA-specific context","pmids":["37495067"],"is_preprint":false},{"year":1996,"finding":"CHRNA4 consists of six exons distributed over approximately 17 kb of genomic DNA, enabling PCR-based amplification of the complete coding region including the functionally critical transmembrane domains.","method":"Genomic sequencing and exon-intron structure determination","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 — direct genomic structural determination enabling all subsequent mutation analyses","pmids":["8833159"],"is_preprint":false},{"year":2016,"finding":"The rare CHRNA4 R336C missense variant reduces the sensitivity of the human α4β2 channel isoform to its agonists following nicotine incubation, as shown by functional studies of the channel.","method":"Functional electrophysiology of α4β2 channels carrying R336C variant","journal":"Molecular psychiatry","confidence":"Medium","confidence_rationale":"Tier 1 — direct electrophysiological functional assay; single study","pmids":["26952864"],"is_preprint":false}],"current_model":"CHRNA4 encodes the α4 subunit of the high-affinity neuronal nicotinic acetylcholine receptor (α4β2 nAChR); mutations or variants in its M2 transmembrane domain and intracellular loops alter receptor ACh/agonist sensitivity, calcium permeability, and the ratio of high- to low-affinity receptor states, while in hepatocytes CHRNA4 couples acetylcholine/nicotine stimulation to calcium influx and inflammatory signaling promoting MASH, and its expression is post-transcriptionally regulated by METTL3-mediated m6A modification."},"narrative":{"teleology":[{"year":1996,"claim":"Determination of the six-exon genomic structure of CHRNA4 provided the foundation for systematic mutation scanning across all coding and transmembrane domains.","evidence":"Genomic sequencing and exon-intron boundary mapping of the CHRNA4 locus","pmids":["8833159"],"confidence":"Medium","gaps":["no functional data from this study alone","regulatory elements outside coding exons not characterized"]},{"year":1997,"claim":"Reconstitution of an ADNFLE-associated M2 domain insertion mutant established that CHRNA4 mutations do not abolish channel function but instead alter ACh affinity and reduce calcium permeability, defining a gain-of-function/altered-function disease mechanism.","evidence":"Heterologous expression of wild-type and 776ins3 α4β2 receptors with electrophysiology and calcium permeability measurements","pmids":["9175743"],"confidence":"High","gaps":["mechanism linking reduced calcium permeability to seizure generation not resolved","stoichiometry effects not tested"]},{"year":1999,"claim":"Identification of the S252L mutation in a Japanese ADNFLE family confirmed that the M2 transmembrane domain is a recurrent mutational hotspot for epilepsy, broadening the allelic spectrum beyond the original Australian kindred.","evidence":"SSCP screening, Sanger sequencing, and segregation analysis in a Japanese pedigree","pmids":["10563623"],"confidence":"Medium","gaps":["no electrophysiological characterization of S252L in this study","penetrance modifiers not explored"]},{"year":2003,"claim":"Functional studies of the T265I mutation and the mouse A529T intracellular-loop polymorphism demonstrated that both the extracellular end of M2 and the second intracellular loop tune ACh sensitivity and the equilibrium between high- and low-affinity receptor populations, extending functional determinants beyond the channel pore lining.","evidence":"Xenopus oocyte electrophysiology (T265I); heterologous expression and 86Rb+ efflux in synaptosomes across inbred mouse strains and F2 animals (A529T)","pmids":["12823585","12871652","12766617"],"confidence":"High","gaps":["structural basis for intracellular-loop modulation of affinity states unknown","whether human orthologue polymorphism has identical effects not tested"]},{"year":2008,"claim":"A transgenic rat carrying the S284L mutation revealed the downstream circuit-level mechanism: the mutant α4 subunit attenuates GABAergic inhibition and causes abnormal glutamate release selectively during slow-wave sleep, producing an ADNFLE-like phenotype.","evidence":"Transgenic knock-in rat with electrophysiological recording of synaptic currents and behavioral seizure monitoring","pmids":["19020039"],"confidence":"High","gaps":["whether GABAergic attenuation is direct (presynaptic α4β2 on GABAergic terminals) or indirect not fully resolved","relevance of specific mutation (S284L) versus other ADNFLE alleles not compared in same model"]},{"year":2010,"claim":"Knock-in of the Chrna4 A529 allele in mice confirmed that the intracellular-loop polymorphism modulates nicotine pharmacology in vivo, altering hypothermia sensitivity, voluntary nicotine consumption, and reward-related behavior, linking receptor-level affinity changes to whole-animal addiction-relevant phenotypes.","evidence":"Knock-in mouse model with behavioral pharmacology and midbrain synaptosome 86Rb+ efflux","pmids":["20061993"],"confidence":"High","gaps":["human translational relevance of A529T not established","downstream signaling mediating behavioral differences not identified"]},{"year":2014,"claim":"Characterization of rare human coding variants (R336C, P451L, R487Q) showed they alter surface expression, interactome composition, and agonist responsiveness of α4β2 receptors, establishing that CHRNA4 variation outside M2 also produces functional consequences relevant to nicotine dependence risk.","evidence":"[3H]epibatidine binding, LC-MS/MS interactome profiling, Xenopus oocyte electrophysiology, HEK293 expression","pmids":["24385388"],"confidence":"High","gaps":["interactome changes not validated by reciprocal pull-downs","in vivo consequences of these rare variants not tested"]},{"year":2016,"claim":"Follow-up electrophysiology on the R336C variant demonstrated that it specifically reduces agonist sensitivity after chronic nicotine exposure, suggesting this variant alters receptor desensitization or upregulation dynamics rather than baseline function.","evidence":"Electrophysiology of α4β2 channels carrying R336C with nicotine pre-incubation","pmids":["26952864"],"confidence":"Medium","gaps":["molecular mechanism of altered upregulation not resolved","single variant tested in isolation"]},{"year":2023,"claim":"Discovery of functional CHRNA4 expression in hepatocytes established a non-neuronal role: acetylcholine or nicotine activates hepatocyte α4-containing nAChRs to drive calcium influx and downstream inflammatory signaling that promotes MASH, and liver-specific Chrna4 deletion protects against diet-induced steatohepatitis.","evidence":"Liver-specific Chrna4 knockout mice, calcium imaging, inflammatory pathway readouts, dietary MASH model, human liver expression correlation","pmids":["38056431"],"confidence":"High","gaps":["precise stoichiometry and partner subunits of hepatocyte nAChR not defined","whether hepatocyte CHRNA4 contributes to other liver diseases unknown"]},{"year":2023,"claim":"METTL3-mediated m6A methylation of Chrna4 mRNA was identified as a post-transcriptional regulatory mechanism controlling α4 subunit expression in hippocampal neurons, with functional consequences for synaptic transmission and spatial memory.","evidence":"MeRIP-seq, METTL3 shRNA knockdown and pharmacological inhibition, electrophysiology, and behavioral testing in BPA-exposed rats","pmids":["37495067"],"confidence":"Medium","gaps":["whether m6A regulation of CHRNA4 operates under physiological (non-BPA) conditions unknown","reader protein mediating Chrna4 mRNA decay not identified","single-lab finding"]},{"year":null,"claim":"The structural basis for how intracellular-loop and non-M2 variants allosterically modulate channel gating, the subunit composition of hepatocyte nAChRs containing α4, and the physiological regulators of CHRNA4 m6A modification remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["no high-resolution structure of disease-mutant α4β2 receptors","hepatocyte nAChR stoichiometry undefined","m6A regulation of CHRNA4 not confirmed outside BPA exposure context"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,2,3,4,7,9]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2,7,9]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,2,3,5,6]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,5,9]}],"complexes":["α4β2 nicotinic acetylcholine receptor"],"partners":["CHRNB2","METTL3"],"other_free_text":[]},"mechanistic_narrative":"CHRNA4 encodes the α4 subunit of neuronal nicotinic acetylcholine receptors (nAChRs), principally forming α4β2 heteropentameric ligand-gated cation channels that mediate fast cholinergic neurotransmission and modulate GABAergic and glutamatergic circuits. Disease-causing mutations clustered in the M2 transmembrane domain (e.g., S248F insertion, S252L, T265I, S284L) alter ACh sensitivity, calcium permeability, and the ratio of high- to low-affinity receptor states, while a polymorphism in the second intracellular loop (A529T) controls ethanol and nicotine sensitivity of the channel and associated behavioral responses [PMID:9175743, PMID:12823585, PMID:12871652, PMID:12766617, PMID:20061993]. Gain-of-function or altered-function CHRNA4 mutations cause autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) by disrupting the balance of synaptic inhibition and excitation during slow-wave sleep [PMID:10563623, PMID:19020039]. Beyond the nervous system, hepatocyte-expressed CHRNA4 couples acetylcholine or nicotine stimulation to calcium influx and inflammatory signaling that drives metabolic dysfunction-associated steatohepatitis (MASH), and its expression is post-transcriptionally regulated by METTL3-dependent m6A modification [PMID:38056431, PMID:37495067]."},"prefetch_data":{"uniprot":{"accession":"P43681","full_name":"Neuronal acetylcholine receptor subunit alpha-4","aliases":[],"length_aa":627,"mass_kda":70.0,"function":"Component of neuronal acetylcholine receptors (nAChRs) that function as pentameric, ligand-gated cation channels with high calcium permeability among other activities. nAChRs are excitatory neurotrasnmitter receptors formed by a collection of nAChR subunits known to mediate synaptic transmission in the nervous system and the neuromuscular junction. Each nAchR subunit confers differential attributes to channel properties, including activation, deactivation and desensitization kinetics, pH sensitivity, cation permeability, and binding to allosteric modulators (PubMed:22361591, PubMed:27698419, PubMed:29720657, PubMed:38454578). CHRNA4 forms heteropentameric neuronal acetylcholine receptors with CHRNB2 and CHRNB4, as well as CHRNA5 and CHRNB3 as accesory subunits. Is the most abundant nAChR subtype expressed in the central nervous system (PubMed:16835356, PubMed:22361591, PubMed:27698419, PubMed:29720657, PubMed:38454578). Found in two major stoichiometric forms,(CHRNA4)3:(CHRNB2)2 and (CHRNA4)2:(CHRNB2)3, the two stoichiometric forms differ in their unitary conductance, calcium permeability, ACh sensitivity and potentiation by divalent cation (PubMed:27698419, PubMed:29720657, PubMed:38454578). Involved in the modulation of calcium-dependent signaling pathways, influences the release of neurotransmitters, including dopamine, glutamate and GABA (By similarity)","subcellular_location":"Synaptic cell membrane; Cell membrane","url":"https://www.uniprot.org/uniprotkb/P43681/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CHRNA4","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CHRNA4","total_profiled":1310},"omim":[{"mim_id":"615005","title":"EPILEPSY, NOCTURNAL FRONTAL LOBE, 5; ENFL5","url":"https://www.omim.org/entry/615005"},{"mim_id":"614168","title":"PHOSPHOENOLPYRUVATE CARBOXYKINASE 1, SOLUBLE; PCK1","url":"https://www.omim.org/entry/614168"},{"mim_id":"610509","title":"RIC3 ACETYLCHOLINE RECEPTOR CHAPERONE; RIC3","url":"https://www.omim.org/entry/610509"},{"mim_id":"607834","title":"ANXIETY","url":"https://www.omim.org/entry/607834"},{"mim_id":"606888","title":"CHOLINERGIC RECEPTOR, NEURONAL NICOTINIC, ALPHA POLYPEPTIDE 6; CHRNA6","url":"https://www.omim.org/entry/606888"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"liver","ntpm":82.6}],"url":"https://www.proteinatlas.org/search/CHRNA4"},"hgnc":{"alias_symbol":["BFNC"],"prev_symbol":["EBN","EBN1"]},"alphafold":{"accession":"P43681","domains":[{"cath_id":"2.70.170.10","chopping":"34-242","consensus_level":"high","plddt":94.0011,"start":34,"end":242},{"cath_id":"1.20.58","chopping":"248-363_584-626","consensus_level":"high","plddt":86.631,"start":248,"end":626}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P43681","model_url":"https://alphafold.ebi.ac.uk/files/AF-P43681-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P43681-F1-predicted_aligned_error_v6.png","plddt_mean":71.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CHRNA4","jax_strain_url":"https://www.jax.org/strain/search?query=CHRNA4"},"sequence":{"accession":"P43681","fasta_url":"https://rest.uniprot.org/uniprotkb/P43681.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P43681/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P43681"}},"corpus_meta":[{"pmid":"9175743","id":"PMC_9175743","title":"An insertion mutation of the CHRNA4 gene in a family with autosomal dominant nocturnal frontal lobe epilepsy.","date":"1997","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9175743","citation_count":300,"is_preprint":false},{"pmid":"15551059","id":"PMC_15551059","title":"The genome sequence of an anaerobic aromatic-degrading denitrifying bacterium, strain EbN1.","date":"2004","source":"Archives of microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/15551059","citation_count":190,"is_preprint":false},{"pmid":"10563623","id":"PMC_10563623","title":"A novel mutation of CHRNA4 responsible for autosomal dominant nocturnal frontal lobe epilepsy.","date":"1999","source":"Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/10563623","citation_count":169,"is_preprint":false},{"pmid":"15790597","id":"PMC_15790597","title":"Ethnic- and gender-specific association of the nicotinic acetylcholine receptor alpha4 subunit gene (CHRNA4) with nicotine dependence.","date":"2005","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15790597","citation_count":158,"is_preprint":false},{"pmid":"15249611","id":"PMC_15249611","title":"A novel mutation in KCNQ2 associated with BFNC, drug resistant epilepsy, and mental retardation.","date":"2004","source":"Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/15249611","citation_count":127,"is_preprint":false},{"pmid":"17768273","id":"PMC_17768273","title":"CHRNA4 and tobacco dependence: from gene regulation to treatment outcome.","date":"2007","source":"Archives of general psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/17768273","citation_count":93,"is_preprint":false},{"pmid":"12420173","id":"PMC_12420173","title":"Genes involved in the anaerobic degradation of ethylbenzene in a denitrifying bacterium, strain EbN1.","date":"2002","source":"Archives of microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/12420173","citation_count":88,"is_preprint":false},{"pmid":"15687214","id":"PMC_15687214","title":"Substrate-dependent regulation of anaerobic degradation pathways for toluene and ethylbenzene in a denitrifying bacterium, strain EbN1.","date":"2005","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/15687214","citation_count":75,"is_preprint":false},{"pmid":"17549795","id":"PMC_17549795","title":"Functional proteomic view of metabolic regulation in \"Aromatoleum aromaticum\" strain EbN1.","date":"2007","source":"Proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/17549795","citation_count":74,"is_preprint":false},{"pmid":"26440539","id":"PMC_26440539","title":"Genome-wide meta-analysis reveals common splice site acceptor variant in CHRNA4 associated with nicotine dependence.","date":"2015","source":"Translational psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/26440539","citation_count":73,"is_preprint":false},{"pmid":"16388583","id":"PMC_16388583","title":"Crystal structure and enzyme kinetics of the (S)-specific 1-phenylethanol dehydrogenase of the denitrifying bacterium strain EbN1.","date":"2006","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16388583","citation_count":72,"is_preprint":false},{"pmid":"10448807","id":"PMC_10448807","title":"Autosomal dominant nocturnal frontal lobe epilepsy in a Spanish family with a Ser252Phe mutation in the CHRNA4 gene.","date":"1999","source":"Archives of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/10448807","citation_count":72,"is_preprint":false},{"pmid":"16869227","id":"PMC_16869227","title":"Interactive effects of APOE and CHRNA4 on attention and white matter volume in healthy middle-aged and older adults.","date":"2006","source":"Cognitive, affective & behavioral neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/16869227","citation_count":72,"is_preprint":false},{"pmid":"10802757","id":"PMC_10802757","title":"Independent occurrence of the CHRNA4 Ser248Phe mutation in a Norwegian family with nocturnal frontal lobe epilepsy.","date":"2000","source":"Epilepsia","url":"https://pubmed.ncbi.nlm.nih.gov/10802757","citation_count":68,"is_preprint":false},{"pmid":"12823585","id":"PMC_12823585","title":"A new Chrna4 mutation with low penetrance in nocturnal frontal lobe epilepsy.","date":"2003","source":"Epilepsia","url":"https://pubmed.ncbi.nlm.nih.gov/12823585","citation_count":66,"is_preprint":false},{"pmid":"17613539","id":"PMC_17613539","title":"Association of attentional network function with exon 5 variations of the CHRNA4 gene.","date":"2007","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17613539","citation_count":59,"is_preprint":false},{"pmid":"19803686","id":"PMC_19803686","title":"The association between dopamine DRD2 polymorphisms and working memory capacity is modulated by a functional polymorphism on the nicotinic receptor gene CHRNA4.","date":"2010","source":"Journal of cognitive neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/19803686","citation_count":56,"is_preprint":false},{"pmid":"14735297","id":"PMC_14735297","title":"Genes involved in the anaerobic degradation of toluene in a denitrifying bacterium, strain EbN1.","date":"2004","source":"Archives of microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/14735297","citation_count":55,"is_preprint":false},{"pmid":"18263750","id":"PMC_18263750","title":"Solvent stress response of the denitrifying bacterium \"Aromatoleum aromaticum\" strain EbN1.","date":"2008","source":"Applied and environmental microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/18263750","citation_count":55,"is_preprint":false},{"pmid":"18534558","id":"PMC_18534558","title":"Gene-gene interactions among CHRNA4, CHRNB2, BDNF, and NTRK2 in nicotine dependence.","date":"2008","source":"Biological psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/18534558","citation_count":52,"is_preprint":false},{"pmid":"19020039","id":"PMC_19020039","title":"Rats harboring S284L Chrna4 mutation show attenuation of synaptic and extrasynaptic GABAergic transmission and exhibit the nocturnal frontal lobe epilepsy phenotype.","date":"2008","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/19020039","citation_count":52,"is_preprint":false},{"pmid":"22722381","id":"PMC_22722381","title":"The role of the CHRNA4 gene in Internet addiction: a case-control study.","date":"2012","source":"Journal of addiction medicine","url":"https://pubmed.ncbi.nlm.nih.gov/22722381","citation_count":48,"is_preprint":false},{"pmid":"11479712","id":"PMC_11479712","title":"(S)-1-phenylethanol dehydrogenase of Azoarcus sp. strain EbN1, an enzyme of anaerobic ethylbenzene catabolism.","date":"2001","source":"Archives of microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/11479712","citation_count":47,"is_preprint":false},{"pmid":"12887446","id":"PMC_12887446","title":"Evidence for S284L mutation of the CHRNA4 in a white family with autosomal dominant nocturnal frontal lobe epilepsy.","date":"2003","source":"Epilepsia","url":"https://pubmed.ncbi.nlm.nih.gov/12887446","citation_count":44,"is_preprint":false},{"pmid":"18539747","id":"PMC_18539747","title":"Anaerobic degradation of p-ethylphenol by \"Aromatoleum aromaticum\" strain EbN1: pathway, regulation, and involved proteins.","date":"2008","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/18539747","citation_count":43,"is_preprint":false},{"pmid":"11175290","id":"PMC_11175290","title":"Benign familial neonatal convulsions (BFNC) resulting from mutation of the KCNQ2 voltage sensor.","date":"2000","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/11175290","citation_count":43,"is_preprint":false},{"pmid":"8833159","id":"PMC_8833159","title":"Exon-intron structure of the human neuronal nicotinic acetylcholine receptor alpha 4 subunit (CHRNA4).","date":"1996","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/8833159","citation_count":40,"is_preprint":false},{"pmid":"16041578","id":"PMC_16041578","title":"Functional genomics of an anaerobic aromatic-degrading denitrifying bacterium, strain EbN1.","date":"2005","source":"Applied microbiology and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/16041578","citation_count":39,"is_preprint":false},{"pmid":"26976767","id":"PMC_26976767","title":"In vitro and in vivo mechanism of immunomodulatory and antiviral activity of Edible Bird's Nest (EBN) against influenza A virus (IAV) infection.","date":"2016","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/26976767","citation_count":39,"is_preprint":false},{"pmid":"15727510","id":"PMC_15727510","title":"Modulation of nicotine but not ethanol preference by the mouse Chrna4 A529T polymorphism.","date":"2005","source":"Behavioral neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/15727510","citation_count":39,"is_preprint":false},{"pmid":"15026168","id":"PMC_15026168","title":"Candidate gene association studies of the alpha 4 (CHRNA4) and beta 2 (CHRNB2) neuronal nicotinic acetylcholine receptor subunit genes in Alzheimer's disease.","date":"2004","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/15026168","citation_count":38,"is_preprint":false},{"pmid":"15902904","id":"PMC_15902904","title":"Association of polymorphisms in nicotinic acetylcholine receptor alpha 4 subunit gene (CHRNA4), mu-opioid receptor gene (OPRM1), and ethanol-metabolizing enzyme genes with alcoholism in Korean patients.","date":"2004","source":"Alcohol (Fayetteville, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/15902904","citation_count":37,"is_preprint":false},{"pmid":"17590520","id":"PMC_17590520","title":"Nicotine receptor gene CHRNA4 modulates early event-related potentials in auditory and visual oddball target detection tasks.","date":"2007","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/17590520","citation_count":37,"is_preprint":false},{"pmid":"12766617","id":"PMC_12766617","title":"A polymorphism in the alpha4 nicotinic receptor gene (Chrna4) modulates enhancement of nicotinic receptor function by ethanol.","date":"2003","source":"Alcoholism, clinical and experimental research","url":"https://pubmed.ncbi.nlm.nih.gov/12766617","citation_count":36,"is_preprint":false},{"pmid":"19058950","id":"PMC_19058950","title":"A novel mutation of the nicotinic acetylcholine receptor gene CHRNA4 in sporadic nocturnal frontal lobe epilepsy.","date":"2008","source":"Epilepsy research","url":"https://pubmed.ncbi.nlm.nih.gov/19058950","citation_count":35,"is_preprint":false},{"pmid":"21992551","id":"PMC_21992551","title":"Effects of edible bird's nest (EBN) on cultured rabbit corneal keratocytes.","date":"2011","source":"BMC complementary and alternative medicine","url":"https://pubmed.ncbi.nlm.nih.gov/21992551","citation_count":34,"is_preprint":false},{"pmid":"9129724","id":"PMC_9129724","title":"Neuronal nicotinic acetylcholine receptor alpha 4 subunit (CHRNA4) and panic disorder: an association study.","date":"1997","source":"American journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9129724","citation_count":34,"is_preprint":false},{"pmid":"22373960","id":"PMC_22373960","title":"A cognitive phenotype for a polymorphism in the nicotinic receptor gene CHRNA4.","date":"2012","source":"Neuroscience and biobehavioral reviews","url":"https://pubmed.ncbi.nlm.nih.gov/22373960","citation_count":32,"is_preprint":false},{"pmid":"9216991","id":"PMC_9216991","title":"A nonsense mutation in the alpha4 subunit of the nicotinic acetylcholine receptor (CHRNA4) cosegregates with 20q-linked benign neonatal familial convulsions (EBNI).","date":"1994","source":"Neurobiology of disease","url":"https://pubmed.ncbi.nlm.nih.gov/9216991","citation_count":29,"is_preprint":false},{"pmid":"16332175","id":"PMC_16332175","title":"Polymorphisms of the CHRNA4 gene encoding the alpha4 subunit of nicotinic acetylcholine receptor as related to the oxidative DNA damage and the level of apoptotic proteins in lymphocytes of the patients with Alzheimer's disease.","date":"2005","source":"DNA and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/16332175","citation_count":29,"is_preprint":false},{"pmid":"22366417","id":"PMC_22366417","title":"Physiological and proteomic adaptation of \"Aromatoleum aromaticum\" EbN1 to low growth rates in benzoate-limited, anoxic chemostats.","date":"2012","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/22366417","citation_count":28,"is_preprint":false},{"pmid":"21500914","id":"PMC_21500914","title":"The nicotinic acetylcholine receptor gene CHRNA4 is associated with negative emotionality.","date":"2011","source":"Emotion (Washington, D.C.)","url":"https://pubmed.ncbi.nlm.nih.gov/21500914","citation_count":28,"is_preprint":false},{"pmid":"26952864","id":"PMC_26952864","title":"A rare missense mutation in CHRNA4 associates with smoking behavior and its consequences.","date":"2016","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/26952864","citation_count":27,"is_preprint":false},{"pmid":"19822871","id":"PMC_19822871","title":"Deletions involving both KCNQ2 and CHRNA4 present with benign familial neonatal seizures.","date":"2009","source":"Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/19822871","citation_count":27,"is_preprint":false},{"pmid":"22589189","id":"PMC_22589189","title":"Proteogenomic evidence for β-oxidation of plant-derived 3-phenylpropanoids in \"Aromatoleum aromaticum\" EbN1.","date":"2012","source":"Proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/22589189","citation_count":27,"is_preprint":false},{"pmid":"32097883","id":"PMC_32097883","title":"Remarkable effect of transdermal nicotine in children with CHRNA4-related autosomal dominant sleep-related hypermotor epilepsy.","date":"2020","source":"Epilepsy & behavior : E&B","url":"https://pubmed.ncbi.nlm.nih.gov/32097883","citation_count":27,"is_preprint":false},{"pmid":"22008229","id":"PMC_22008229","title":"Association of CHRNA4 polymorphism with depression and loneliness in elderly males.","date":"2011","source":"Genes, brain, and behavior","url":"https://pubmed.ncbi.nlm.nih.gov/22008229","citation_count":25,"is_preprint":false},{"pmid":"16686649","id":"PMC_16686649","title":"A novel splicing mutation in KCNQ2 in a multigenerational family with BFNC followed for 25 years.","date":"2006","source":"Epilepsia","url":"https://pubmed.ncbi.nlm.nih.gov/16686649","citation_count":25,"is_preprint":false},{"pmid":"17504247","id":"PMC_17504247","title":"Association study of the nicotinic acetylcholine receptor alpha4 subunit gene, CHRNA4, in attention-deficit hyperactivity disorder.","date":"2007","source":"Genes, brain, and behavior","url":"https://pubmed.ncbi.nlm.nih.gov/17504247","citation_count":25,"is_preprint":false},{"pmid":"29454195","id":"PMC_29454195","title":"CHRNA4 variant causes paroxysmal kinesigenic dyskinesia and genetic epilepsy with febrile seizures plus?","date":"2018","source":"Seizure","url":"https://pubmed.ncbi.nlm.nih.gov/29454195","citation_count":24,"is_preprint":false},{"pmid":"22081395","id":"PMC_22081395","title":"Benzoate mediates repression of C(4)-dicarboxylate utilization in \"Aromatoleum aromaticum\" EbN1.","date":"2011","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/22081395","citation_count":24,"is_preprint":false},{"pmid":"21445957","id":"PMC_21445957","title":"Association of CHRNA4 polymorphisms with smoking behavior in two populations.","date":"2011","source":"American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21445957","citation_count":23,"is_preprint":false},{"pmid":"23350800","id":"PMC_23350800","title":"Nominal association with CHRNA4 variants and nicotine dependence.","date":"2013","source":"Genes, brain, and behavior","url":"https://pubmed.ncbi.nlm.nih.gov/23350800","citation_count":23,"is_preprint":false},{"pmid":"28330214","id":"PMC_28330214","title":"Production kinetics of polyhydroxyalkanoates by using Pseudomonas aeruginosa gamma ray mutant strain EBN-8 cultured on soybean oil.","date":"2016","source":"3 Biotech","url":"https://pubmed.ncbi.nlm.nih.gov/28330214","citation_count":23,"is_preprint":false},{"pmid":"12871652","id":"PMC_12871652","title":"The mouse Chrna4 A529T polymorphism alters the ratio of high to low affinity alpha 4 beta 2 nAChRs.","date":"2003","source":"Neuropharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/12871652","citation_count":23,"is_preprint":false},{"pmid":"16235065","id":"PMC_16235065","title":"Functional analysis of novel KCNQ2 and KCNQ3 gene variants found in a large pedigree with benign familial neonatal convulsions (BFNC).","date":"2005","source":"Neurogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/16235065","citation_count":22,"is_preprint":false},{"pmid":"9579905","id":"PMC_9579905","title":"Benign childhood epilepsy with centrotemporal spikes and electroencephalography trait are not linked to EBN1 and EBN2 of benign neonatal familial convulsions.","date":"1997","source":"Epilepsia","url":"https://pubmed.ncbi.nlm.nih.gov/9579905","citation_count":22,"is_preprint":false},{"pmid":"30766522","id":"PMC_30766522","title":"Characterization of an Aldehyde Oxidoreductase From the Mesophilic Bacterium Aromatoleum aromaticum EbN1, a Member of a New Subfamily of Tungsten-Containing Enzymes.","date":"2019","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/30766522","citation_count":22,"is_preprint":false},{"pmid":"21203548","id":"PMC_21203548","title":"Nicotinic receptor gene CHRNA4 interacts with processing load in attention.","date":"2010","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21203548","citation_count":21,"is_preprint":false},{"pmid":"10450598","id":"PMC_10450598","title":"SER252PHE and 776INS3 mutations in the CHRNA4 gene are rare in the Italian ADNFLE population.","date":"1999","source":"Sleep","url":"https://pubmed.ncbi.nlm.nih.gov/10450598","citation_count":21,"is_preprint":false},{"pmid":"38056431","id":"PMC_38056431","title":"Hepatocyte CHRNA4 mediates the MASH-promotive effects of immune cell-produced acetylcholine and smoking exposure in mice and humans.","date":"2023","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/38056431","citation_count":20,"is_preprint":false},{"pmid":"26488297","id":"PMC_26488297","title":"Molecular Genetic and Crystal Structural Analysis of 1-(4-Hydroxyphenyl)-Ethanol Dehydrogenase from 'Aromatoleum aromaticum' EbN1.","date":"2015","source":"Journal of molecular microbiology and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/26488297","citation_count":20,"is_preprint":false},{"pmid":"22947540","id":"PMC_22947540","title":"The dopamine D2 receptor gene DRD2 and the nicotinic acetylcholine receptor gene CHRNA4 interact on striatal gray matter volume: evidence from a genetic imaging study.","date":"2012","source":"NeuroImage","url":"https://pubmed.ncbi.nlm.nih.gov/22947540","citation_count":20,"is_preprint":false},{"pmid":"17851150","id":"PMC_17851150","title":"Ring chromosome 20 syndrome without deletions of the subtelomeric and CHRNA4--KCNQ2 genes loci.","date":"2007","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17851150","citation_count":19,"is_preprint":false},{"pmid":"16825790","id":"PMC_16825790","title":"Mass spectrometric identification of proteins in complex post-genomic projects. Soluble proteins of the metabolically versatile, denitrifying 'Aromatoleum' sp. strain EbN1.","date":"2006","source":"Journal of molecular microbiology and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/16825790","citation_count":19,"is_preprint":false},{"pmid":"29240768","id":"PMC_29240768","title":"The association between the nicotinic acetylcholine receptor α4 subunit gene (CHRNA4) rs1044396 and Internet gaming disorder in Korean male adults.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/29240768","citation_count":19,"is_preprint":false},{"pmid":"20061993","id":"PMC_20061993","title":"Chrna4 A529 knock-in mice exhibit altered nicotine sensitivity.","date":"2010","source":"Pharmacogenetics and genomics","url":"https://pubmed.ncbi.nlm.nih.gov/20061993","citation_count":19,"is_preprint":false},{"pmid":"31721431","id":"PMC_31721431","title":"Characterization of Polar and Non-Polar Compounds of House Edible Bird's Nest (EBN) from Johor, Malaysia.","date":"2020","source":"Chemistry & biodiversity","url":"https://pubmed.ncbi.nlm.nih.gov/31721431","citation_count":18,"is_preprint":false},{"pmid":"21432576","id":"PMC_21432576","title":"Polymorphisms in the neural nicotinic acetylcholine receptor α4 subunit (CHRNA4) are associated with ADHD in a genetic isolate.","date":"2009","source":"Attention deficit and hyperactivity disorders","url":"https://pubmed.ncbi.nlm.nih.gov/21432576","citation_count":18,"is_preprint":false},{"pmid":"19693267","id":"PMC_19693267","title":"Financial and psychological risk attitudes associated with two single nucleotide polymorphisms in the nicotine receptor (CHRNA4) gene.","date":"2009","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/19693267","citation_count":18,"is_preprint":false},{"pmid":"19577488","id":"PMC_19577488","title":"The 1674+11C>T polymorphism of CHRNA4 is associated with juvenile myoclonic epilepsy.","date":"2009","source":"Seizure","url":"https://pubmed.ncbi.nlm.nih.gov/19577488","citation_count":17,"is_preprint":false},{"pmid":"24385388","id":"PMC_24385388","title":"Rare human nicotinic acetylcholine receptor α4 subunit (CHRNA4) variants affect expression and function of high-affinity nicotinic acetylcholine receptors.","date":"2014","source":"The Journal of pharmacology and experimental therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/24385388","citation_count":17,"is_preprint":false},{"pmid":"26079805","id":"PMC_26079805","title":"Nicotinergic Modulation of Attention-Related Neural Activity Differentiates Polymorphisms of DRD2 and CHRNA4 Receptor Genes.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26079805","citation_count":16,"is_preprint":false},{"pmid":"32468613","id":"PMC_32468613","title":"Recovery of value-added glycopeptides from edible bird's nest (EBN) co-products: enzymatic hydrolysis, physicochemical characteristics and bioactivity.","date":"2020","source":"Journal of the science of food and agriculture","url":"https://pubmed.ncbi.nlm.nih.gov/32468613","citation_count":16,"is_preprint":false},{"pmid":"18818489","id":"PMC_18818489","title":"Development of a genetic system for the denitrifying bacterium 'Aromatoleum aromaticum' strain EbN1.","date":"2008","source":"Journal of molecular microbiology and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/18818489","citation_count":16,"is_preprint":false},{"pmid":"24428733","id":"PMC_24428733","title":"Association of the CHRNA4 neuronal nicotinic receptor subunit gene with frequency of binge drinking in young adults.","date":"2014","source":"Alcoholism, clinical and experimental research","url":"https://pubmed.ncbi.nlm.nih.gov/24428733","citation_count":15,"is_preprint":false},{"pmid":"28877969","id":"PMC_28877969","title":"Overdominant Effect of a CHRNA4 Polymorphism on Cingulo-Opercular Network Activity and Cognitive Control.","date":"2017","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/28877969","citation_count":15,"is_preprint":false},{"pmid":"30605790","id":"PMC_30605790","title":"Effects of EBN on embryo implantation, plasma concentrations of reproductive hormones, and uterine expressions of genes of PCNA, steroids, growth factors and their receptors in rats.","date":"2018","source":"Theriogenology","url":"https://pubmed.ncbi.nlm.nih.gov/30605790","citation_count":14,"is_preprint":false},{"pmid":"19167866","id":"PMC_19167866","title":"Lack of potassium current in W309R mutant KCNQ3 channel causing benign familial neonatal convulsions (BFNC).","date":"2009","source":"Epilepsy research","url":"https://pubmed.ncbi.nlm.nih.gov/19167866","citation_count":13,"is_preprint":false},{"pmid":"21753767","id":"PMC_21753767","title":"Autosomal dominant nocturnal frontal lobe epilepsy: a genotypic comparative study of Japanese and Korean families carrying the CHRNA4 Ser284Leu mutation.","date":"2011","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21753767","citation_count":13,"is_preprint":false},{"pmid":"11121188","id":"PMC_11121188","title":"Failure to replicate association between the gene for the neuronal nicotinic acetylcholine receptor alpha 4 subunit (CHRNA4) and IGE.","date":"2000","source":"American journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11121188","citation_count":13,"is_preprint":false},{"pmid":"37495067","id":"PMC_37495067","title":"Decreased expression of Chrna4 by METTL3-mediated m6A modification participates in BPA-induced spatial memory deficit.","date":"2023","source":"Environmental research","url":"https://pubmed.ncbi.nlm.nih.gov/37495067","citation_count":12,"is_preprint":false},{"pmid":"24498031","id":"PMC_24498031","title":"Massive withdrawal symptoms and affective vulnerability are associated with variants of the CHRNA4 gene in a subgroup of smokers.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24498031","citation_count":12,"is_preprint":false},{"pmid":"1492743","id":"PMC_1492743","title":"The genes coding for phosphoenolpyruvate carboxykinase-1 (PCK1) and neuronal nicotinic acetylcholine receptor alpha 4 subunit (CHRNA4) map to human chromosome 20, extending the known region of homology with mouse chromosome 2.","date":"1992","source":"Annals of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/1492743","citation_count":12,"is_preprint":false},{"pmid":"27611310","id":"PMC_27611310","title":"CHRNA4 and ANKK1 Polymorphisms Influence Smoking-Induced Nicotinic Acetylcholine Receptor Upregulation.","date":"2016","source":"Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco","url":"https://pubmed.ncbi.nlm.nih.gov/27611310","citation_count":11,"is_preprint":false},{"pmid":"32536355","id":"PMC_32536355","title":"Variants in CHRNB2 and CHRNA4 Identified in Patients with Insular Epilepsy.","date":"2020","source":"The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques","url":"https://pubmed.ncbi.nlm.nih.gov/32536355","citation_count":11,"is_preprint":false},{"pmid":"25647695","id":"PMC_25647695","title":"Modulation of nicotine effects on selective attention by DRD2 and CHRNA4 gene polymorphisms.","date":"2015","source":"Psychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/25647695","citation_count":11,"is_preprint":false},{"pmid":"18246739","id":"PMC_18246739","title":"A novel missense mutation (N258S) in the KCNQ2 gene in a Turkish family afflicted with benign familial neonatal convulsions (BFNC).","date":"2007","source":"The Turkish journal of pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/18246739","citation_count":11,"is_preprint":false},{"pmid":"23240931","id":"PMC_23240931","title":"A novel differential susceptibility gene: CHRNA4 and moderation of the effect of maltreatment on child personality.","date":"2012","source":"Journal of child psychology and psychiatry, and allied disciplines","url":"https://pubmed.ncbi.nlm.nih.gov/23240931","citation_count":11,"is_preprint":false},{"pmid":"7607646","id":"PMC_7607646","title":"Detection of a CfoI polymorphism within exon 5 of the human neuronal nicotinic acetylcholine receptor alpha 4 subunit gene (CHRNA4).","date":"1995","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/7607646","citation_count":11,"is_preprint":false},{"pmid":"17488453","id":"PMC_17488453","title":"Effects of APOE and CHRNA4 genotypes on retinal nerve fibre layer thickness at the optic disc and on risk for developing exfoliation syndrome.","date":"2007","source":"Acta ophthalmologica Scandinavica","url":"https://pubmed.ncbi.nlm.nih.gov/17488453","citation_count":11,"is_preprint":false},{"pmid":"25639542","id":"PMC_25639542","title":"Individual response speed is modulated by variants of the gene encoding the alpha 4 sub-unit of the nicotinic acetylcholine receptor (CHRNA4).","date":"2015","source":"Behavioural brain research","url":"https://pubmed.ncbi.nlm.nih.gov/25639542","citation_count":11,"is_preprint":false},{"pmid":"23037950","id":"PMC_23037950","title":"Possible association of nicotinic acetylcholine receptor gene (CHRNA4 and CHRNB2) polymorphisms with nicotine dependence in Japanese males: an exploratory study.","date":"2012","source":"Pharmacopsychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/23037950","citation_count":11,"is_preprint":false},{"pmid":"36445109","id":"PMC_36445109","title":"Systems Biology of Aromatic Compound Catabolism in Facultative Anaerobic Aromatoleum aromaticum EbN1T.","date":"2022","source":"mSystems","url":"https://pubmed.ncbi.nlm.nih.gov/36445109","citation_count":10,"is_preprint":false},{"pmid":"20331911","id":"PMC_20331911","title":"Epistasis between APOE and nicotinic receptor gene CHRNA4 in age related cognitive function and decline.","date":"2010","source":"Journal of the International Neuropsychological Society : JINS","url":"https://pubmed.ncbi.nlm.nih.gov/20331911","citation_count":10,"is_preprint":false},{"pmid":"20185932","id":"PMC_20185932","title":"Stress-induced changes of phospholipids in betaproteobacterium Aromatoleum aromaticum strain EbN1 due to alkylbenzene growth substrates.","date":"2010","source":"Journal of molecular microbiology and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/20185932","citation_count":10,"is_preprint":false},{"pmid":"18762859","id":"PMC_18762859","title":"Genetic association analysis of tagging SNPs in alpha4 and beta2 subunits of neuronal nicotinic acetylcholine receptor genes (CHRNA4 and CHRNB2) with schizophrenia in the Japanese population.","date":"2008","source":"Journal of neural transmission (Vienna, Austria : 1996)","url":"https://pubmed.ncbi.nlm.nih.gov/18762859","citation_count":10,"is_preprint":false},{"pmid":"28582665","id":"PMC_28582665","title":"The influence of CHRNA4, COMT, and maternal sensitivity on orienting and executive attention in 6-month-old infants.","date":"2017","source":"Brain and cognition","url":"https://pubmed.ncbi.nlm.nih.gov/28582665","citation_count":9,"is_preprint":false},{"pmid":"33741621","id":"PMC_33741621","title":"Responsiveness of Aromatoleum aromaticum EbN1T to Lignin-Derived Phenylpropanoids.","date":"2021","source":"Applied and environmental microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/33741621","citation_count":9,"is_preprint":false},{"pmid":"26309560","id":"PMC_26309560","title":"Mutational analysis of CHRNB2, CHRNA2 and CHRNA4 genes in Chinese population with autosomal dominant nocturnal frontal lobe epilepsy.","date":"2015","source":"International journal of clinical and experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26309560","citation_count":9,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49402,"output_tokens":2801,"usd":0.095111},"stage2":{"model":"claude-opus-4-6","input_tokens":6236,"output_tokens":2629,"usd":0.145358},"total_usd":0.240469,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"An insertion of three nucleotides (GCT) at position 776 in the M2 domain of CHRNA4 does not prevent receptor function but increases apparent affinity for ACh and significantly lowers calcium permeability, corresponding to a loss of function at the cellular level.\",\n      \"method\": \"Receptor reconstitution and physiological investigation in heterologous expression system\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted mutant receptor and measured functional parameters (ACh affinity, calcium permeability)\",\n      \"pmids\": [\"9175743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The S252L (Ser252Leu) missense mutation in the M2 transmembrane domain of CHRNA4, affecting a conserved serine, causes autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) in a Japanese family, implicating this residue in channel function.\",\n      \"method\": \"SSCP, direct sequencing, and segregation analysis\",\n      \"journal\": \"Neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mutation identified and segregated; functional role of M2 serine inferred from conservation, no direct in vitro functional assay in this paper\",\n      \"pmids\": [\"10563623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The CHRNA4 α4-T265I mutation at the extracellular end of TM2 increases ACh sensitivity of reconstituted receptors, as demonstrated by expression in Xenopus oocytes.\",\n      \"method\": \"Expression in Xenopus oocytes and electrophysiology\",\n      \"journal\": \"Epilepsia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct functional assay in Xenopus oocyte expression system measuring ACh sensitivity\",\n      \"pmids\": [\"12823585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The mouse Chrna4 A529T polymorphism in the second intracellular loop alters the ratio of high- to low-affinity α4β2 nAChR populations and changes receptor sensitivity to DHβE blockade when expressed heterologously, identifying this domain as a functional determinant of receptor affinity states.\",\n      \"method\": \"Heterologous expression of variant α4 subunits with β2 subunit; electrophysiology\",\n      \"journal\": \"Neuropharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted receptors with variant subunits, functional electrophysiological characterization\",\n      \"pmids\": [\"12871652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The mouse Chrna4 A/T polymorphism at position 529 modulates enhancement of α4β2 nAChR function by ethanol: strains carrying the A variant show ethanol-induced increases in maximal ion flux, while strains with the T variant do not, indicating the polymorphism controls ethanol sensitivity of the receptor.\",\n      \"method\": \"86Rb+ efflux assay in thalamic synaptosomes from inbred mouse strains and F2 intercross animals\",\n      \"journal\": \"Alcoholism, clinical and experimental research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — functional in vitro assay replicated across six strains and F2 animals\",\n      \"pmids\": [\"12766617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Transgenic rats harboring the CHRNA4 S284L mutation exhibit attenuation of synaptic and extrasynaptic GABAergic transmission and abnormal glutamate release during slow-wave sleep, producing an ADNFLE-like seizure phenotype.\",\n      \"method\": \"Transgenic rat model; electrophysiological measurements of GABAergic and glutamatergic neurotransmission; behavioral seizure monitoring\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean knock-in model with defined cellular phenotype (altered GABAergic and glutamatergic transmission) and behavioral readout\",\n      \"pmids\": [\"19020039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Chrna4 A529 knock-in mice show greater sensitivity to nicotine-induced hypothermia, reduced oral nicotine consumption, lack of conditioned place preference, and altered α4β2* nAChR function (maximal efflux and high-sensitivity receptor proportion) in midbrain, confirming that the T529A polymorphism in the second intracellular loop modulates α4β2* receptor function and behavioral responses to nicotine.\",\n      \"method\": \"Knock-in mouse model; behavioral pharmacology; 86Rb+ efflux assay from midbrain synaptosomes\",\n      \"journal\": \"Pharmacogenetics and genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knock-in with multiple orthogonal functional readouts (receptor pharmacology, multiple behaviors)\",\n      \"pmids\": [\"20061993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Rare CHRNA4 variants (α4R336C, α4P451L, α4R487Q) alter α4β2 nAChR expression, subcellular distribution, sensitivity to nicotine-induced receptor upregulation, intracellular interactome composition (by LC-MS/MS), and functional parameters of agonist activation in Xenopus oocytes, demonstrating that these variants produce receptors more sensitive to nicotine than those with the common variant.\",\n      \"method\": \"[3H]epibatidine binding, immunoprecipitation/LC-MS/MS proteomics, voltage-clamp electrophysiology in Xenopus oocytes, HEK293 cell expression\",\n      \"journal\": \"The Journal of pharmacology and experimental therapeutics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple orthogonal methods including binding assay, proteomics, and electrophysiology in the same study\",\n      \"pmids\": [\"24385388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"A splice site acceptor variant (rs2273500-C) in CHRNA4 results in an alternate transcript predicted to be targeted for nonsense-mediated decay and is associated with decreased CHRNA4 expression in postmortem human brain, establishing rs2273500 as a functional regulatory variant.\",\n      \"method\": \"GWAS meta-analysis combined with eQTL analysis of brain expression data\",\n      \"journal\": \"Translational psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — eQTL evidence in human brain tissue for functional regulatory effect; mechanism inferred from splice site prediction and expression data\",\n      \"pmids\": [\"26440539\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CHRNA4 is expressed specifically in hepatocytes and functions as a subunit of nicotinic acetylcholine receptors activated by acetylcholine from immune cells or nicotine, inducing calcium influx and activation of inflammatory signaling pathways that promote MASH (metabolic dysfunction-associated steatohepatitis); genetic and pharmacological inhibition of CHRNA4 protected mice from diet-induced MASH.\",\n      \"method\": \"Liver-specific Chrna4 knockout mice, calcium influx assays, inflammatory signaling readouts, dietary MASH mouse model, human patient correlation\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic KO with defined cellular mechanism (calcium influx, inflammatory signaling) and in vivo phenotypic rescue\",\n      \"pmids\": [\"38056431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"METTL3-mediated m6A modification is enriched on Chrna4 mRNA in hippocampal neurons following BPA exposure, leading to decreased Chrna4 expression; inhibition of METTL3 restored Chrna4 levels and rescued abnormal synaptic transmission and spatial memory deficits.\",\n      \"method\": \"m6A sequencing/MeRIP, METTL3 knockdown (shRNA) and pharmacological inhibition, electrophysiology, behavioral testing in rats\",\n      \"journal\": \"Environmental research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — m6A mapping on Chrna4 mRNA with functional rescue, but single lab and BPA-specific context\",\n      \"pmids\": [\"37495067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"CHRNA4 consists of six exons distributed over approximately 17 kb of genomic DNA, enabling PCR-based amplification of the complete coding region including the functionally critical transmembrane domains.\",\n      \"method\": \"Genomic sequencing and exon-intron structure determination\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct genomic structural determination enabling all subsequent mutation analyses\",\n      \"pmids\": [\"8833159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The rare CHRNA4 R336C missense variant reduces the sensitivity of the human α4β2 channel isoform to its agonists following nicotine incubation, as shown by functional studies of the channel.\",\n      \"method\": \"Functional electrophysiology of α4β2 channels carrying R336C variant\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — direct electrophysiological functional assay; single study\",\n      \"pmids\": [\"26952864\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CHRNA4 encodes the α4 subunit of the high-affinity neuronal nicotinic acetylcholine receptor (α4β2 nAChR); mutations or variants in its M2 transmembrane domain and intracellular loops alter receptor ACh/agonist sensitivity, calcium permeability, and the ratio of high- to low-affinity receptor states, while in hepatocytes CHRNA4 couples acetylcholine/nicotine stimulation to calcium influx and inflammatory signaling promoting MASH, and its expression is post-transcriptionally regulated by METTL3-mediated m6A modification.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CHRNA4 encodes the α4 subunit of neuronal nicotinic acetylcholine receptors (nAChRs), principally forming α4β2 heteropentameric ligand-gated cation channels that mediate fast cholinergic neurotransmission and modulate GABAergic and glutamatergic circuits. Disease-causing mutations clustered in the M2 transmembrane domain (e.g., S248F insertion, S252L, T265I, S284L) alter ACh sensitivity, calcium permeability, and the ratio of high- to low-affinity receptor states, while a polymorphism in the second intracellular loop (A529T) controls ethanol and nicotine sensitivity of the channel and associated behavioral responses [PMID:9175743, PMID:12823585, PMID:12871652, PMID:12766617, PMID:20061993]. Gain-of-function or altered-function CHRNA4 mutations cause autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) by disrupting the balance of synaptic inhibition and excitation during slow-wave sleep [PMID:10563623, PMID:19020039]. Beyond the nervous system, hepatocyte-expressed CHRNA4 couples acetylcholine or nicotine stimulation to calcium influx and inflammatory signaling that drives metabolic dysfunction-associated steatohepatitis (MASH), and its expression is post-transcriptionally regulated by METTL3-dependent m6A modification [PMID:38056431, PMID:37495067].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Determination of the six-exon genomic structure of CHRNA4 provided the foundation for systematic mutation scanning across all coding and transmembrane domains.\",\n      \"evidence\": \"Genomic sequencing and exon-intron boundary mapping of the CHRNA4 locus\",\n      \"pmids\": [\"8833159\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"no functional data from this study alone\", \"regulatory elements outside coding exons not characterized\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Reconstitution of an ADNFLE-associated M2 domain insertion mutant established that CHRNA4 mutations do not abolish channel function but instead alter ACh affinity and reduce calcium permeability, defining a gain-of-function/altered-function disease mechanism.\",\n      \"evidence\": \"Heterologous expression of wild-type and 776ins3 α4β2 receptors with electrophysiology and calcium permeability measurements\",\n      \"pmids\": [\"9175743\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"mechanism linking reduced calcium permeability to seizure generation not resolved\", \"stoichiometry effects not tested\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Identification of the S252L mutation in a Japanese ADNFLE family confirmed that the M2 transmembrane domain is a recurrent mutational hotspot for epilepsy, broadening the allelic spectrum beyond the original Australian kindred.\",\n      \"evidence\": \"SSCP screening, Sanger sequencing, and segregation analysis in a Japanese pedigree\",\n      \"pmids\": [\"10563623\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"no electrophysiological characterization of S252L in this study\", \"penetrance modifiers not explored\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Functional studies of the T265I mutation and the mouse A529T intracellular-loop polymorphism demonstrated that both the extracellular end of M2 and the second intracellular loop tune ACh sensitivity and the equilibrium between high- and low-affinity receptor populations, extending functional determinants beyond the channel pore lining.\",\n      \"evidence\": \"Xenopus oocyte electrophysiology (T265I); heterologous expression and 86Rb+ efflux in synaptosomes across inbred mouse strains and F2 animals (A529T)\",\n      \"pmids\": [\"12823585\", \"12871652\", \"12766617\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"structural basis for intracellular-loop modulation of affinity states unknown\", \"whether human orthologue polymorphism has identical effects not tested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"A transgenic rat carrying the S284L mutation revealed the downstream circuit-level mechanism: the mutant α4 subunit attenuates GABAergic inhibition and causes abnormal glutamate release selectively during slow-wave sleep, producing an ADNFLE-like phenotype.\",\n      \"evidence\": \"Transgenic knock-in rat with electrophysiological recording of synaptic currents and behavioral seizure monitoring\",\n      \"pmids\": [\"19020039\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"whether GABAergic attenuation is direct (presynaptic α4β2 on GABAergic terminals) or indirect not fully resolved\", \"relevance of specific mutation (S284L) versus other ADNFLE alleles not compared in same model\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Knock-in of the Chrna4 A529 allele in mice confirmed that the intracellular-loop polymorphism modulates nicotine pharmacology in vivo, altering hypothermia sensitivity, voluntary nicotine consumption, and reward-related behavior, linking receptor-level affinity changes to whole-animal addiction-relevant phenotypes.\",\n      \"evidence\": \"Knock-in mouse model with behavioral pharmacology and midbrain synaptosome 86Rb+ efflux\",\n      \"pmids\": [\"20061993\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"human translational relevance of A529T not established\", \"downstream signaling mediating behavioral differences not identified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Characterization of rare human coding variants (R336C, P451L, R487Q) showed they alter surface expression, interactome composition, and agonist responsiveness of α4β2 receptors, establishing that CHRNA4 variation outside M2 also produces functional consequences relevant to nicotine dependence risk.\",\n      \"evidence\": \"[3H]epibatidine binding, LC-MS/MS interactome profiling, Xenopus oocyte electrophysiology, HEK293 expression\",\n      \"pmids\": [\"24385388\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"interactome changes not validated by reciprocal pull-downs\", \"in vivo consequences of these rare variants not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Follow-up electrophysiology on the R336C variant demonstrated that it specifically reduces agonist sensitivity after chronic nicotine exposure, suggesting this variant alters receptor desensitization or upregulation dynamics rather than baseline function.\",\n      \"evidence\": \"Electrophysiology of α4β2 channels carrying R336C with nicotine pre-incubation\",\n      \"pmids\": [\"26952864\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"molecular mechanism of altered upregulation not resolved\", \"single variant tested in isolation\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Discovery of functional CHRNA4 expression in hepatocytes established a non-neuronal role: acetylcholine or nicotine activates hepatocyte α4-containing nAChRs to drive calcium influx and downstream inflammatory signaling that promotes MASH, and liver-specific Chrna4 deletion protects against diet-induced steatohepatitis.\",\n      \"evidence\": \"Liver-specific Chrna4 knockout mice, calcium imaging, inflammatory pathway readouts, dietary MASH model, human liver expression correlation\",\n      \"pmids\": [\"38056431\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"precise stoichiometry and partner subunits of hepatocyte nAChR not defined\", \"whether hepatocyte CHRNA4 contributes to other liver diseases unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"METTL3-mediated m6A methylation of Chrna4 mRNA was identified as a post-transcriptional regulatory mechanism controlling α4 subunit expression in hippocampal neurons, with functional consequences for synaptic transmission and spatial memory.\",\n      \"evidence\": \"MeRIP-seq, METTL3 shRNA knockdown and pharmacological inhibition, electrophysiology, and behavioral testing in BPA-exposed rats\",\n      \"pmids\": [\"37495067\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"whether m6A regulation of CHRNA4 operates under physiological (non-BPA) conditions unknown\", \"reader protein mediating Chrna4 mRNA decay not identified\", \"single-lab finding\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis for how intracellular-loop and non-M2 variants allosterically modulate channel gating, the subunit composition of hepatocyte nAChRs containing α4, and the physiological regulators of CHRNA4 m6A modification remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"no high-resolution structure of disease-mutant α4β2 receptors\", \"hepatocyte nAChR stoichiometry undefined\", \"m6A regulation of CHRNA4 not confirmed outside BPA exposure context\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 2, 3, 4, 7, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2, 7, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 2, 3, 5, 6]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 5, 9]}\n    ],\n    \"complexes\": [\n      \"α4β2 nicotinic acetylcholine receptor\"\n    ],\n    \"partners\": [\n      \"CHRNB2\",\n      \"METTL3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}