Affinage

CHRNB2

Neuronal acetylcholine receptor subunit beta-2 · UniProt P17787

Length
502 aa
Mass
57.0 kDa
Annotated
2026-06-09
32 papers in source corpus 7 papers cited in narrative 6 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 3/4 claims corpus-supported (75%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CHRNB2 encodes the β2 subunit of the neuronal nicotinic acetylcholine receptor, where it assembles into α4β2 receptors that conduct acetylcholine-gated whole-cell currents (PMID:32536355). Multiple missense mutations clustered in the transmembrane domains act through a common gain-of-function mechanism: V287M in M2 and I312M in M3 each markedly increase receptor sensitivity to acetylcholine, and the Thr26Met variant elevates whole-cell α4β2 currents without altering reversal potential or the concentration–response relationship (PMID:11104662, PMID:15964197, PMID:18534914, PMID:32536355). These gain-of-function changes underlie autosomal dominant nocturnal frontal lobe epilepsy and associated memory deficits (PMID:11104662, PMID:15964197, PMID:18534914). Independently of its receptor role in neurons, CHRNB2 functions in cancer cells through acetylcholine-independent mechanisms: in gastric cancer it promotes proliferation, survival, and metastasis-associated functions and interfaces with PI3K-AKT and JAK-STAT signaling (PMID:34331011), while in pancreatic cancer it suppresses migration, invasion, and EMT by downregulating the β-catenin pathway, with upstream regulators including SOX6, SRY, SOX17, and TCF7L2 (PMID:36344976).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 1998 Low

    Establishing the genomic organization and chromosomal location of CHRNB2 was the prerequisite for systematic mutational analysis of this receptor subunit gene.

    Evidence Genomic sequencing and chromosomal mapping to chromosome 1

    PMID:9921897

    Open questions at the time
    • No functional experiment on the protein
    • Does not address subunit assembly or physiology
  2. 2000 High

    It was unknown how a CHRNB2 mutation could cause epilepsy; functional expression showed the M2 V287M mutation increases acetylcholine sensitivity ~10-fold, establishing a gain-of-function mechanism.

    Evidence Xenopus oocyte expression with electrophysiological recording of mutant receptor

    PMID:11104662

    Open questions at the time
    • Single mutation tested in a heterologous system
    • Does not establish in vivo circuit consequences
  3. 2005 Medium

    Whether gain-of-function generalized beyond one residue was open; the M3 I312M mutation also markedly increased acetylcholine sensitivity and linked the receptor change to ADNFLE with memory deficits.

    Evidence Functional characterization of mutant receptor; mutation identified in patient/twin cohort, replicated in an independent family

    PMID:15964197 PMID:18534914

    Open questions at the time
    • Functional assay details inferred from prior framework
    • Mechanism linking receptor hyperactivity to memory phenotype not defined
  4. 2020 Medium

    It was unclear whether an N-terminal variant outside the channel-lining helices alters function; Thr26Met raised whole-cell α4β2 currents without changing reversal potential or response shape, extending gain-of-function to a non-transmembrane variant.

    Evidence Functional expression of mutant α4β2 receptors in human cell lines with whole-cell current recording

    PMID:32536355

    Open questions at the time
    • Single study, single lab
    • Biophysical basis of increased current not resolved
  5. 2021 Medium

    Beyond neuronal signaling, a role in cancer was untested; loss- and gain-of-function in gastric cancer showed CHRNB2 modulates proliferation, survival, and metastasis-associated functions and interfaces with PI3K-AKT and JAK-STAT signaling.

    Evidence CRISPR knockout, RNAi knockdown, overexpression in gastric cancer lines; in vitro assays; mouse xenograft; pathway analysis

    PMID:34331011

    Open questions at the time
    • Single lab
    • Direct molecular link between CHRNB2 and PI3K-AKT/JAK-STAT not mechanistically defined
  6. 2022 Medium

    Whether CHRNB2's cancer role depends on its ligand-gated channel activity was open; in pancreatic cancer it suppressed migration, invasion, and EMT via acetylcholine-independent β-catenin downregulation with defined upstream regulators.

    Evidence siRNA knockdown and overexpression in pancreatic cancer lines; Transwell assays; Western blot for β-catenin and EMT markers

    PMID:36344976

    Open questions at the time
    • Acetylcholine-independent mechanism not structurally explained
    • Apparently opposite directionality versus gastric cancer not reconciled

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a neuronal acetylcholine receptor subunit exerts ligand-independent, tissue-specific effects on cancer signaling pathways remains unresolved.
  • No structural or biochemical basis for acetylcholine-independent activity
  • Opposite proliferative effects across cancer types not mechanistically explained

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Localization
GO:0005886 plasma membrane 1
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 2
Partners
CHRNA4
Complex memberships
α4β2 nicotinic acetylcholine receptor

Evidence

Reading pass · 6 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 The CHRNB2 V287M missense mutation within the M2 transmembrane domain causes an approximately 10-fold increase in acetylcholine sensitivity of the nicotinic acetylcholine receptor, as demonstrated by functional expression in Xenopus oocytes. Xenopus oocyte expression system, electrophysiological functional assay of mutant receptor American journal of human genetics High 11104662
2005 The CHRNB2 I312M mutation in transmembrane region M3 markedly increases receptor sensitivity to acetylcholine, establishing gain-of-function as the mechanism underlying ADNFLE and associated memory deficits. Functional electrophysiological characterization of mutant receptor (implied from prior Xenopus oocyte framework cited in abstract context); mutation identified in patient/twin cohort Neurobiology of disease Medium 15964197 18534914
2020 The CHRNB2 Thr26Met variant leads to significantly higher whole-cell nicotinic currents when expressed as α4β2 receptors in human cell lines, in both homo- and heterozygous conditions, without major changes in current reversal potential or the shape of the concentration-response relation. Functional expression of mutant α4β2 receptors in human cell lines; whole-cell current recording The Canadian journal of neurological sciences Medium 32536355
2021 CHRNB2 knockdown attenuates gastric cancer cell proliferation, while forced overexpression increases proliferation; CHRNB2 knockout significantly affects cell survival and metastasis-associated functions. Pathway analysis revealed that CHRNB2 interferes with PI3K-AKT and JAK-STAT signaling. Gene knockout (genome editing), RNA interference knockdown, ectopic overexpression in gastric cancer cell lines; in vitro proliferation assays; mouse xenograft in vivo model; pathway analysis Oncogene Medium 34331011
2022 CHRNB2 inhibits migration and invasion of pancreatic cancer cells via an acetylcholine-independent mechanism by downregulating the β-catenin pathway, with upstream regulators including SOX6, SRY, SOX17, and TCF7L2; CHRNB2 also suppresses EMT. siRNA knockdown and ectopic overexpression in pancreatic cancer cell lines; Transwell migration/invasion assays; Western blot for β-catenin pathway components and EMT markers Cancer cell international Medium 36344976
1998 The CHRNB2 gene is localized to chromosome 1 and its genomic structure (intron-exon organization) was determined, providing the framework for mutational analyses of this nicotinic receptor subunit gene. Genomic sequencing and chromosomal mapping Human genetics Low 9921897

Source papers

Stage 0 corpus · 32 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 CHRNB2 is the second acetylcholine receptor subunit associated with autosomal dominant nocturnal frontal lobe epilepsy. American journal of human genetics 233 11104662
2007 Association of the neuronal nicotinic receptor beta2 subunit gene (CHRNB2) with subjective responses to alcohol and nicotine. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 96 17226798
2005 The CHRNB2 mutation I312M is associated with epilepsy and distinct memory deficits. Neurobiology of disease 76 15964197
2000 Haplotypes of four novel single nucleotide polymorphisms in the nicotinic acetylcholine receptor beta2-subunit (CHRNB2) gene show no association with smoking initiation or nicotine dependence. American journal of medical genetics 65 11054772
2008 Gene-gene interactions among CHRNA4, CHRNB2, BDNF, and NTRK2 in nicotine dependence. Biological psychiatry 52 18534558
2002 Genetic and functional analysis of single nucleotide polymorphisms in the beta2-neuronal nicotinic acetylcholine receptor gene (CHRNB2). Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco 45 11906688
2004 Candidate gene association studies of the alpha 4 (CHRNA4) and beta 2 (CHRNB2) neuronal nicotinic acetylcholine receptor subunit genes in Alzheimer's disease. Neuroscience letters 38 15026168
2009 Nicotinic acetylcholine receptor beta2 subunit (CHRNB2) gene and short-term ability to quit smoking in response to nicotine patch. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 34 19755656
2007 Autosomal dominant nocturnal frontal lobe epilepsy with a mutation in the CHRNB2 gene. Epilepsia 32 17900292
1998 The structures of the human neuronal nicotinic acetylcholine receptor beta2- and alpha3-subunit genes (CHRNB2 and CHRNA3). Human genetics 28 9921897
2015 Generalized epilepsy in a family with basal ganglia calcifications and mutations in SLC20A2 and CHRNB2. European journal of medical genetics 25 26475232
2021 Blockade of CHRNB2 signaling with a therapeutic monoclonal antibody attenuates the aggressiveness of gastric cancer cells. Oncogene 20 34331011
2008 Autosomal dominant nocturnal frontal lobe epilepsy and mild memory impairment associated with CHRNB2 mutation I312M in the neuronal nicotinic acetylcholine receptor. Epilepsy & behavior : E&B 20 18534914
2018 Association and cis-mQTL analysis of variants in CHRNA3-A5, CHRNA7, CHRNB2, and CHRNB4 in relation to nicotine dependence in a Chinese Han population. Translational psychiatry 18 29666375
2011 The identification of a novel mutation of nicotinic acetylcholine receptor gene CHRNB2 in a Chinese patient: Its possible implication in non-familial nocturnal frontal lobe epilepsy. Epilepsy research 18 21497487
2021 Long Non-coding RNAs Gabarapl2 and Chrnb2 Positively Regulate Inflammatory Signaling in a Mouse Model of Dry Eye. Frontiers in medicine 16 34957168
2022 CHRNB2 represses pancreatic cancer migration and invasion via inhibiting β-catenin pathway. Cancer cell international 14 36344976
2023 Rare coding variants in CHRNB2 reduce the likelihood of smoking. Nature genetics 12 37308787
2020 Variants in CHRNB2 and CHRNA4 Identified in Patients with Insular Epilepsy. The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques 11 32536355
2012 Possible association of nicotinic acetylcholine receptor gene (CHRNA4 and CHRNB2) polymorphisms with nicotine dependence in Japanese males: an exploratory study. Pharmacopsychiatry 11 23037950
2002 Mutational analysis of nicotinic acetylcholine receptor beta2 subunit gene (CHRNB2) in a representative cohort of Italian probands affected by autosomal dominant nocturnal frontal lobe epilepsy. Epilepsia 11 11952766
2008 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. Journal of neural transmission (Vienna, Austria : 1996) 10 18762859
2015 Mutational analysis of CHRNB2, CHRNA2 and CHRNA4 genes in Chinese population with autosomal dominant nocturnal frontal lobe epilepsy. International journal of clinical and experimental medicine 9 26309560
2012 Hippocampal sclerosis worsens autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) phenotype related to CHRNB2 mutation. European journal of neurology 8 22897520
1999 Mutation screening of the CHRNA4 and CHRNB2 nicotinic cholinergic receptor genes in Alzheimer's disease. Neuroreport 8 10549797
2022 Increased Risky Choice and Reduced CHRNB2 Expression in Adult Male Rats Exposed to Nicotine Vapor. International journal of molecular sciences 5 35163155
2012 A case of autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) coexisting with pervasive developmental disorder harboring SCN1A mutation in addition to CHRNB2 mutation. Epilepsy & behavior : E&B 5 23032131
2015 The possible role of maternal bonding style and CHRNB2 gene polymorphisms in nicotine dependence and related depressive phenotype. Progress in neuro-psychopharmacology & biological psychiatry 4 25640319
2024 Clinical, molecular, physiologic, and therapeutic feature of patients with CHRNA4 and CHRNB2 deficiency: A systematic review. Journal of neurochemistry 3 39193833
2023 Two novel variants of the STXBP1 and CHRNB2 genes identified in a Chinese boy with refractory seizures and developmental delay. Psychiatric genetics 2 37706497
2011 [Mutational analysis of CHRNB2 and CHRNA2 genes in southern Chinese population with autosomal dominant nocturnal frontal lobe epilepsy]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 2 21287502
2023 Familial Epilepsy Associated With Concurrent CHRNB2 Mutation and RBFOX1 Exon Deletion: A Case Report. Cureus 1 37033539

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