Affinage

CHRNA5

Neuronal acetylcholine receptor subunit alpha-5 · UniProt P30532

Length
468 aa
Mass
53.1 kDa
Annotated
2026-06-09
100 papers in source corpus 22 papers cited in narrative 22 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CHRNA5 encodes the α5 subunit of neuronal nicotinic acetylcholine receptors, which incorporates into heteromeric receptors to shape cholinergic and nicotine-driven signaling across distinct neural circuits and to modulate proliferative signaling in epithelial and cancer cells (PMID:29954848, PMID:32817066). In the prefrontal cortex, α5 is essential for the rapid onset of postsynaptic nicotinic excitation in layer VI corticothalamic neurons and protects these responses from desensitization, an effect allosterically restored by the α-α site agonist NS9283 (PMID:32817066); α5 incorporation into α4β2* receptors in this circuit also determines the direction of developmental nicotine teratogenesis on neuronal morphology and currents (PMID:24055499). In the interpeduncular nucleus, Chrna5-expressing GABAergic neurons projecting to mesopontine raphe and tegmentum mediate the aversive valence of nicotine (PMID:29954848). The common coding variant rs16969968 (D398N) is a central functional determinant: it reduces aversive subjective responses to intravenous nicotine in humans (PMID:25948103), increases nicotine and alcohol self-administration and relapse in knock-in rodents with altered IPN reactivity (PMID:30293722, PMID:31288250), and confers increased excitatory responses with rapid desensitization in human iPSC-derived neurons (PMID:27698409). CHRNA5 expression is governed by 5' promoter haplotypes and cis-regulatory variants acting through SP1 binding, ASCL1 transcription, and DNA methylation, with low-expression haplotypes tracking nicotine-dependence and lung-cancer risk (PMID:20124469, PMID:20733116, PMID:21858091, PMID:26220977). In cancer, CHRNA5 functions as a positive regulator of proliferation, migration, invasion, and drug resistance through MEK/ERK signaling and a physical interaction with CES1 in head and neck carcinoma (PMID:39472448), YAP-dependent proliferation and stemness in hepatocellular carcinoma (PMID:35214008), and an AKT/JWA/SP1/CD44 axis in lung cancer (PMID:37224781), whereas in non-transformed bronchial cells it acts as a negative regulator of nicotine-induced motility (PMID:21586512).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2001 Medium

    Establishing the genomic architecture of CHRNA5 was the prerequisite for any regulatory or variant analysis, defining its exon-intron structure and its tail-to-tail 3'-UTR overlap with CHRNA3 within the clustered locus.

    Evidence Genomic sequencing and exon-intron structure analysis with polymorphism identification across the CHRNA5/A3/B4 cluster

    PMID:11721883

    Open questions at the time
    • Did not assign function to the identified polymorphisms
    • No expression or receptor-assembly data
  2. 2010 High

    Two studies addressed how CHRNA5 transcription is controlled, showing the clustered subunit genes are coordinately driven by ASCL1 in SCLC and that 5' promoter haplotypes set CHRNA5 mRNA levels in lung tissue.

    Evidence siRNA knockdown of ASCL1 with qRT-PCR in lung cancer lines; qRT-PCR on human lung tissue plus luciferase reporter assays across four lung cancer cell lines

    PMID:20124469 PMID:20733116

    Open questions at the time
    • ASCL1 knockdown effect shown for CHRNA3/B4, not direct CHRNA5 transcription
    • Did not identify the specific causal promoter nucleotides
    • No link to receptor function
  3. 2011 Medium

    Reporter-based dissection of promoter variants identified loss of an SP1 site and a distal repressor element as cis-regulatory mechanisms, mapping how risk alleles lower CHRNA5 expression.

    Evidence Luciferase reporter assays in neuroblastoma cells with allelic expression imbalance analysis in post-mortem brain

    PMID:21858091

    Open questions at the time
    • SP1 binding inferred from sequence, not directly demonstrated
    • Reporter assays in heterologous cells may not reflect endogenous chromatin
  4. 2011 Medium

    Functional studies in epithelial cells revealed an unexpected role for CHRNA5 as a brake on nicotine-induced motility, distinguishing its behavior in normal bronchial cells from its later pro-tumorigenic roles.

    Evidence siRNA knockdown and α-conotoxin MII inhibition with motility, invasion, and calcium influx assays in bronchial and lung cancer cells

    PMID:21586512

    Open questions at the time
    • Mechanism linking α5 loss to CHRNA7-dependent motility unresolved
    • Single lab; effects on adhesion molecules correlative
  5. 2011 High

    Gain-of-function overexpression of the human gene cluster in mice established that altered subunit dosage changes nicotine sensitivity, habenular/VTA circuit activation, and self-administration.

    Evidence BAC transgenic overexpression with radioligand binding, c-Fos imaging, and nicotine self-administration

    PMID:22101982

    Open questions at the time
    • Cluster overexpression cannot isolate CHRNA5-specific contribution
    • Did not test the rs16969968 variant
  6. 2013 Medium

    Quantitative allele-specific expression in human brain demonstrated that cis-regulatory variants act directly on CHRNA5 transcript levels in the cortex, extending the regulatory mechanism from lung/cancer cells to relevant neural tissue.

    Evidence Allele-specific gene expression in post-mortem frontal cortex from two ancestral populations

    PMID:24303001

    Open questions at the time
    • 10 correlated variants could not be resolved to a single causal site
    • No functional receptor readout
  7. 2013 High

    A genetic-knockout developmental study showed that α5 incorporation into prefrontal α4β2* receptors dictates the direction of nicotine teratogenesis, providing a circuit-level mechanism for α5-dependent vulnerability.

    Evidence Developmental nicotine exposure in wildtype and Chrna5 knockout mice with patch-clamp electrophysiology and morphometry of layer VI neurons

    PMID:24055499

    Open questions at the time
    • Molecular basis of the morphological reversal in knockouts not defined
    • Single lab
  8. 2015 High

    Two studies tied the rs16969968 risk allele and a methylation-controlling SNP to human phenotype, showing the N398 allele blunts nicotine aversion and that lower CHRNA5 methylation/expression increases dependence risk.

    Evidence Intravenous nicotine challenge in humans of two ancestries; cis-meQTL across four brain regions and haplotype association in five cohorts (N=11,096)

    PMID:25948103 PMID:26220977

    Open questions at the time
    • Receptor-level mechanism of blunted aversion not addressed in the human challenge study
    • Causal direction between methylation and expression inferred from association
  9. 2016 High

    Human iPSC-derived neurons provided a cell-autonomous readout, showing the N398 allele increases nicotine-evoked excitatory currents but accelerates desensitization, connecting genotype to receptor biophysics in human cells.

    Evidence Whole-cell electrophysiology in iPSC-derived dopaminergic and glutamatergic neurons from D398 versus N398 donors

    PMID:27698409

    Open questions at the time
    • Donor lines not isogenic
    • Single lab; receptor subunit composition not directly resolved
  10. 2018 High

    Circuit-resolving studies localized α5 function to GABAergic IPN neurons mediating nicotine aversion and showed the human risk variant alters IPN reactivity and increases nicotine self-administration and relapse in knock-in rats.

    Evidence Chrna5-null electrophysiology, Chrna5Cre BAC transgenics, optogenetics and circuit tracing in mice; zinc-finger-nuclease knock-in rats with self-administration, reinstatement, and IPN electrophysiology

    PMID:29954848 PMID:30293722

    Open questions at the time
    • Downstream targets of the IPN-to-raphe/tegmentum projection not mapped
    • Priming requirement for aversion mechanistically unexplained
  11. 2018 Medium

    A gene-environment knock-in study showed D398N interacts with developmental nicotine exposure to set later nicotine intake and striatal dopamine release, demonstrating allele-dependent reprogramming.

    Evidence Two-bottle choice consumption and striatal synaptosome dopamine-release assays in D398N knock-in mice with developmental exposure

    PMID:29573323

    Open questions at the time
    • Molecular mediator of the divergent dopamine response unknown
    • Single lab
  12. 2019 High

    Subsequent work refined the cortical role, identifying Chrna5+ acetylcholine super-responder neurons of subplate identity defined by lynx prototoxin gene expression, and extended the variant's behavioral reach to alcohol and food relapse.

    Evidence Chrna5Cre opto-physiology with single-cell RNA-seq and pharmacology; α5SNP knock-in rats with alcohol/food reinstatement and c-Fos imaging

    PMID:31288250 PMID:36798433

    Open questions at the time
    • Functional necessity of lynx prototoxins for α5 regulation not directly tested
    • Insula c-Fos correlation does not establish causality
  13. 2020 High

    Optogenetic interrogation defined the kinetic role of α5 in prefrontal layer VI: it confers rapid-onset nicotinic excitation and desensitization resistance, with pharmacological rescue pinpointing the α-α binding site.

    Evidence Optogenetics plus ex vivo electrophysiology in two independent Chrna5 knockout transgenic lines with NS9283 rescue

    PMID:32817066

    Open questions at the time
    • In vivo behavioral consequence of altered kinetics not tested
    • Receptor stoichiometry underlying the kinetic effect inferred pharmacologically
  14. 2024 Medium

    A series of cancer studies established CHRNA5 as a nicotine-activated positive regulator of tumor cell proliferation, invasion, stemness, and drug resistance through distinct downstream pathways across tumor types and an inflammatory tissue.

    Evidence RNAi/overexpression with proliferation, migration, cell-cycle and xenograft assays plus co-IP/docking (HNSC, CES1/MEK-ERK; HCC, YAP; lung, AKT/JWA/SP1/CD44; breast, RB/CHEK1) and Chrna5 knockout in an imiquimod psoriasis model

    PMID:30543688 PMID:35214008 PMID:35513071 PMID:37224781 PMID:39472448

    Open questions at the time
    • Whether tumor effects require canonical ion-channel activity of α5 is unresolved
    • CES1 co-IP not reciprocally validated; pathways delineated largely in single labs
    • Reconciliation with the negative-regulator role in bronchial cells unaddressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the receptor-level kinetic and desensitization phenotypes conferred by α5 and the D398N variant translate into the specific behavioral and circuit-level changes, and how the same subunit acts as a motility brake in normal epithelium yet a pro-tumorigenic signaling node in cancer, remain unresolved.
  • No unifying mechanism linking ion-channel function to the cancer signaling pathways
  • Stoichiometry and partner-subunit dependence of α5 across tissues not systematically resolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-112316 Neuronal System 2
Partners
CES1CHRNA3CHRNA4CHRNB2CHRNB4
Complex memberships
α3β4α5 nicotinic acetylcholine receptorα4β2α5 nicotinic acetylcholine receptor

Evidence

Reading pass · 22 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 CHRNA5 acts as a negative regulator of nicotine signaling in bronchial cells: siRNA-mediated silencing of CHRNA5, or pharmacological inhibition with α-conotoxin MII, increased cell motility, invasiveness, and calcium influx in both non-transformed bronchial cells and lung cancer cell lines, mimicking the effect of nicotine. These effects were blocked by inhibiting CHRNA7 (α7 nAChR). Silencing CHRNA5 also decreased expression of cell adhesion molecules P120 and ZO-1 in lung cancer cells and reduced DeltaNp63α expression in squamous cell carcinoma lines. siRNA knockdown, pharmacological inhibition (α-conotoxin MII), in vitro motility/invasion assays, calcium influx measurement, western blot for adhesion molecules Carcinogenesis Medium 21586512
2010 ASCL1 transcription factor regulates expression of the CHRNA5/A3/B4 gene cluster in small-cell lung carcinoma (SCLC): knockdown of ASCL1 in SCLC cells significantly decreased expression of the α3 and β4 nAChR subunit genes without affecting other highly expressed nAChR genes, and without effect in non-SCLC lines. The clustered nAChR genes (CHRNA5, CHRNA3, CHRNB4) are coordinately overexpressed in SCLC and contain putative ASCL1 binding sites in their promoters. Quantitative RT-PCR in lung cancer cell lines and patient samples; siRNA knockdown of ASCL1; in silico promoter analysis Molecular cancer research : MCR Medium 20124469
2010 Promoter haplotypes of CHRNA5 significantly regulate its mRNA transcript levels in human lung tissue. The delTTC promoter haplotype was associated with the highest CHRNA5 transcript levels, while the insTGG haplotype (linked to risk alleles for nicotine dependence, lung cancer, and COPD) was associated with the lowest transcript levels. Luciferase reporter assays in human lung cancer cell lines confirmed that 5' promoter haplotypes significantly altered CHRNA5 promoter activity, while 3'-UTR variants did not. Quantitative RT-PCR on human lung tissue from 68 patients; luciferase reporter assays in four human lung cancer cell lines (A549, H460, H520, H596) Journal of the National Cancer Institute High 20733116
2011 CHRNA5 promoter variants affect allelic expression: luciferase reporter assays showed that deletion at rs3841324 combined with variation at rs503464 decreased CHRNA5 promoter-derived activity, potentially by loss of an SP-1 binding site. Variations within the CHRNA5 5'UTR (rs55853698 and rs55781567) also altered luciferase expression. A distal promoter region was found to strongly repress CHRNA5 transcription. Luciferase reporter assays in BE(2)-C neuroblastoma cells; allelic expression imbalance (AEI) analysis in post-mortem brain tissue; heterologous promoter constructs PloS one Medium 21858091
2013 Cis-regulatory variants in the CHRNA5-CHRNA3-CHRNB4 region exert a direct cis-regulatory effect on CHRNA5 transcript levels in human frontal cortex. Quantitative allele-specific expression analysis in African-American (n=49) and European-American (n=111) brain samples identified 10 highly correlated variants in a 9 kb region as potential functional variants modifying CHRNA5 mRNA expression levels. Quantitative allele-specific gene expression (ASE) in post-mortem human frontal cortex from subjects of African and European ancestry PloS one Medium 24303001
2015 The intronic CHRNB4 SNP rs11636753 is associated with CHRNA5 DNA methylation levels in multiple human brain regions (prefrontal cortex, frontal cortex, temporal cortex, pons). The rs11636753 major (G) allele was associated with lower CHRNA5 DNA methylation, lower CHRNA5 mRNA expression, and increased nicotine dependence risk. Haplotype analysis showed rs11636753-G and rs16969968-A alleles together increased nicotine dependence risk more than either alone, connecting methylation differences to mRNA expression and dependence risk. cis-meQTL analysis using SNP genotypes and DNA methylation in post-mortem brain (BrainCloud and Brain QTL cohorts, N=240); expression analysis; haplotype association in five independent cohorts (N=11,096) Human molecular genetics High 26220977
2018 In the mouse interpeduncular nucleus (IPN), α5-null (Chrna5 knockout) mice show markedly reduced electrophysiological responses to nicotinic acetylcholine receptor stimulation. Chrna5-expressing IPN neurons are GABAergic and project to mesopontine raphe and tegmentum. Optogenetic stimulation of Chrna5-expressing IPN neurons is aversive, but only after priming by recent prior stimulation or nicotine exposure. The Chrna5Cre transgenic mice revealed that Chrna5 transcription is regulated independently from the Chrna3/b4 genes transcribed on the opposite strand. Electrophysiology in α5-null mice; BAC recombineering to generate Chrna5Cre transgenic mice; optogenetics; reporter-based circuit tracing; immunohistochemistry The Journal of neuroscience High 29954848
2018 Transgenic rats expressing the human CHRNA5 risk polymorphism (rs16969968, D398N, α5SNP) self-administer more nicotine at high doses and exhibit higher nicotine-induced reinstatement of nicotine seeking than wild-type rats. IPN neurons of α5SNP rats showed altered reactivity to nicotine electrophysiologically, linking the IPN circuit to the higher relapse phenotype. Zinc finger nuclease-generated knock-in rats; intravenous nicotine self-administration; reinstatement paradigm; ex vivo electrophysiology of IPN neurons Current biology : CB High 30293722
2011 Transgenic mice overexpressing the human CHRNA5/A3/B4 genomic cluster showed increased functional α3β4-nAChRs in brain regions where these subunits are normally expressed, increased sensitivity to pharmacological effects of nicotine, higher activation of the medial habenula and reduced activation of dopaminergic VTA neurons after acute nicotine, and increased acquisition of nicotine self-administration with a differential response in a progressive ratio test. BAC transgenic mouse overexpression; radioligand binding for α3β4-nAChRs; pharmacological nicotine challenge; c-Fos immunostaining; nicotine self-administration; progressive ratio test Amino acids High 22101982
2016 iPSC-derived human dopaminergic and glutamatergic neurons carrying the CHRNA5 N398 risk allele (rs16969968) showed increased excitatory postsynaptic current responses to nicotine compared to D398 neurons. N398 glutamatergic neurons responded to lower nicotine doses (0.1 μM) with greater frequency and amplitude but also exhibited rapid desensitization, consistent with prior functional characterizations of the N398-associated receptor. iPSC differentiation to dopaminergic and glutamatergic neurons from homozygous D398 or N398 donors; whole-cell electrophysiology; gene expression profiling Scientific reports High 27698409
2020 Chrna5 is essential for the rapid onset of postsynaptic cholinergic responses in prefrontal cortex layer VI corticothalamic neurons: optogenetic stimulation of cholinergic afferents in Chrna5 knockout mice showed slowed and delayed nicotinic excitation compared to wild-type. Chrna5 also protects nicotinic responses against desensitization under sustained stimulation conditions. An agonist for the α-α nicotinic binding site (NS9283) allosterically restored the rapid-onset kinetics without triggering desensitization. Optogenetics combined with ex vivo electrophysiology in compound-transgenic Chrna5 knockout and wild-type mice; two independent optogenetic mouse lines; pharmacological rescue with NS9283 The Journal of neuroscience High 32817066
2013 Chrna5 genotype determines the lasting effects of developmental in vivo nicotine exposure on prefrontal cortex layer VI neuron morphology and nAChR currents: in wildtype mice, developmental nicotine exposure produced an immature morphological phenotype (apical dendrite morphology) and reduced nAChR currents persisting into adulthood; in α5(-/-) mice, developmental nicotine tended to normalize adult morphology and nAChR currents. Thus α5 subunit incorporation into α4β2* nAChRs in prefrontal layer VI mediates the direction of nicotine teratogenesis. In vivo developmental nicotine exposure in wildtype and Chrna5 knockout mice; patch-clamp electrophysiology; morphometric analysis of prefrontal layer VI neurons Neuropharmacology High 24055499
2019 Chrna5-expressing neurons in the prefrontal cortex include a distinct population of acetylcholine super-responders with subplate identity. Single-cell transcriptomics revealed that Chrna5+ super-responders uniquely express GPI-anchored lynx prototoxin genes (Lypd1, Ly6g6e, Lypd6b), predicting distinct regulation of nicotinic receptors. Pharmacological manipulation of lynx regulation was developed from transcriptomic predictions. Complex transgenic Chrna5Cre mice; opto-physiological experiments; single-cell RNA sequencing; pharmacological manipulation iScience High 36798433
2019 Transgenic rats expressing the human CHRNA5 α5SNP (rs16969968) consumed more alcohol and exhibited increased relapse to alcohol seeking after abstinence. Higher relapse to alcohol was associated with altered neuronal activity in the insula (measured by c-Fos immunostaining). Relapse to food seeking was also increased in α5SNP transgenic rats, and nicotine treatment reduced relapse in both transgenic and control rats. Transgenic knock-in rats (α5SNP); alcohol self-administration; reinstatement paradigm; c-Fos immunostaining; food seeking assay; nicotine treatment Neuropsychopharmacology High 31288250
2001 The genomic structure of CHRNA5 was determined: the gene contains multiple exons, and its 3'-UTR region partially overlaps in a tail-to-tail configuration with the 3'-UTR of CHRNA3 due to two previously unknown introns in CHRNA3. Four novel intragenic polymorphisms were identified and characterized in the CHRNA5/A3/B4 cluster. Genomic sequencing; exon-intron structure analysis; polymorphism identification Journal of human genetics Medium 11721883
2015 The CHRNA5 rs16969968 A (N398) risk allele in humans was associated with significantly lower ratings of aversive effects of intravenous nicotine (P<5×10⁻⁸), with marked specificity over pleasurable and stimulatory effects. The risk allele was also associated with greater improvement on the Stroop cognitive control task following nicotine administration. This effect was replicated in both European-American and African-American subjects. Intravenous nicotine challenge in human subjects (n=192); subjective ratings of nicotine effects; Stroop cognitive task; genotype-stratified analysis Neuropsychopharmacology High 25948103
2018 The CHRNA5 D398N variant interacts with developmental nicotine exposure in mice: offspring of dams exposed to nicotine during development showed genotype-dependent differences in nicotine intake at weaning; N Nic (N398 + developmental nicotine) offspring consumed the most nicotine at the highest concentration, while D Nic (D398 + developmental nicotine) offspring consumed the least. Nicotine-stimulated dopamine release from striatal synaptosomes was increased in D Nic offspring but decreased in N Nic offspring relative to genotype-matched controls. Two-bottle choice nicotine consumption test; synaptosome nicotine-stimulated dopamine release assay; developmental nicotine exposure paradigm; D398N knock-in mice Genes, brain, and behavior Medium 29573323
2024 Nicotine activates CHRNA5 in head and neck squamous cell carcinoma (HNSC) cells to promote proliferation, migration, and invasion. CHRNA5 knockdown reduced these effects, while nicotine reversed them. CHRNA5 activation by nicotine regulates CES1 expression and downstream MEK/ERK signaling: CHRNA5 knockdown decreased p-MEK/MEK, p-ERK/ERK, and CES1 protein levels. Co-immunoprecipitation and molecular docking confirmed a physical interaction between CHRNA5 and CES1. Tumor formation was reduced in nude mice using sh-CHRNA5 Cal27 cells. CCK-8 proliferation assay; wound healing and Transwell migration/invasion assays; siRNA knockdown and overexpression; immunofluorescence; co-immunoprecipitation; molecular docking; western blot for MEK/ERK; transcriptomics/pathway enrichment; in vivo tumor formation assay; IHC in patient tissues Cell death & disease Medium 39472448
2022 CHRNA5 regulates YAP activity in hepatocellular carcinoma (HCC): both in vitro and in vivo assays showed CHRNA5 modulates HCC proliferation through YAP. CHRNA5 also promotes HCC stemness by upregulating Nanog, Sox2, and OCT4, and enhances metastasis by regulating EMT-associated genes. CHRNA5 knockdown or overexpression modulated sorafenib sensitivity in HCC cells. In vitro cell proliferation, migration, invasion assays; YAP activity measurement; stemness gene expression analysis; EMT marker analysis; in vivo xenograft; drug sensitivity assay Pharmaceutics Medium 35214008
2022 CHRNA5 promotes psoriasis-like inflammation: Chrna5 knockout mice showed significantly reduced severity in an imiquimod-induced psoriasis model. Mechanistically, Chrna5 knockout regulated inflammation through the MAPK kinase kinase-1/c-Jun N-terminal kinase–MAPK/NF-κB pathway. Single-cell sequencing revealed that after Chrna5 knockout, the keratinocyte subpopulation was reduced and Jak/STAT signaling was downregulated. Silencing CHRNA5 in human keratinocytes inhibited proliferation and migration. Chrna5 knockout mice; imiquimod-induced psoriasis model; single-cell RNA sequencing; western blot for MAPK/NF-κB pathway; siRNA knockdown in human keratinocytes; proliferation and migration assays The Journal of investigative dermatology Medium 35513071
2018 CHRNA5 siRNA knockdown in MCF7 breast cancer cells reduced cell viability and DNA synthesis, indicating G1 cell cycle arrest, and increased apoptotic sub-G1 population. Mechanistically, CHRNA5 depletion decreased phosphorylated RB (Ser807/811), increased the BAX/BCL2 ratio, and reduced total and phosphorylated CHEK1 (Ser345). Co-exposure to topoisomerase inhibitors with CHRNA5 siRNA enhanced chemosensitivity, potentially due to reduced DNA damage response. siRNA knockdown; cell viability (CCK-8 equivalent); flow cytometry cell cycle analysis; western blot for RB, BAX, BCL2, CHEK1; gene expression microarray; topoisomerase inhibitor co-treatment PloS one Medium 30543688
2023 Nicotine downregulates JWA expression via the CHRNA5-mediated AKT pathway in lung cancer cells: CHRNA5 knockdown reduced AKT signaling, leading to lower JWA expression, which in turn enhanced CD44 expression through inhibition of SP1 ubiquitination-mediated degradation, promoting lung cancer cell stemness (colony and spheroid formation) and progression. This pathway was validated in vivo, with JAC4 inhibiting nicotine-triggered tumor progression through the JWA/SP1/CD44 axis. GSEA; siRNA knockdown; western blot for AKT, p-AKT, SP1, CD44; ubiquitination assay; colony and spheroid formation assays; in vivo tumor xenograft Ecotoxicology and environmental safety Medium 37224781

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 The CHRNA5-CHRNA3-CHRNB4 nicotinic receptor subunit gene cluster affects risk for nicotine dependence in African-Americans and in European-Americans. Cancer research 218 19706762
2008 A candidate gene approach identifies the CHRNA5-A3-B4 region as a risk factor for age-dependent nicotine addiction. PLoS genetics 216 18618000
2008 The CHRNA5-A3 region on chromosome 15q24-25.1 is a risk factor both for nicotine dependence and for lung cancer. Journal of the National Cancer Institute 184 18957677
2008 Genetic variation in the CHRNA5 gene affects mRNA levels and is associated with risk for alcohol dependence. Molecular psychiatry 180 18414406
2011 Relationship between CYP2A6 and CHRNA5-CHRNA3-CHRNB4 variation and smoking behaviors and lung cancer risk. Journal of the National Cancer Institute 152 21747048
2007 The CHRNA5/A3/B4 gene cluster variability as an important determinant of early alcohol and tobacco initiation in young adults. Biological psychiatry 146 18163978
2009 A common genetic variant in the 15q24 nicotinic acetylcholine receptor gene cluster (CHRNA5-CHRNA3-CHRNB4) is associated with a reduced ability of women to quit smoking in pregnancy. Human molecular genetics 121 19429911
2008 Association of a single nucleotide polymorphism in neuronal acetylcholine receptor subunit alpha 5 (CHRNA5) with smoking status and with 'pleasurable buzz' during early experimentation with smoking. Addiction (Abingdon, England) 118 18783506
2008 A risk allele for nicotine dependence in CHRNA5 is a protective allele for cocaine dependence. Biological psychiatry 117 18519132
2012 Interplay of genetic risk factors (CHRNA5-CHRNA3-CHRNB4) and cessation treatments in smoking cessation success. The American journal of psychiatry 115 22648373
2011 Genetic variation at CHRNA5-CHRNA3-CHRNB4 interacts with smoking status to influence body mass index. International journal of epidemiology 94 21593077
2011 Association of the CHRNA5-A3-B4 gene cluster with heaviness of smoking: a meta-analysis. Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco 94 22071378
2009 Association of serum cotinine level with a cluster of three nicotinic acetylcholine receptor genes (CHRNA3/CHRNA5/CHRNB4) on chromosome 15. Human molecular genetics 91 19628476
2012 Higher FKBP5, COMT, CHRNA5, and CRHR1 allele burdens are associated with PTSD and interact with trauma exposure: implications for neuropsychiatric research and treatment. Neuropsychiatric disease and treatment 79 22536069
2011 Markers in the 15q24 nicotinic receptor subunit gene cluster (CHRNA5-A3-B4) predict severity of nicotine addiction and response to smoking cessation therapy. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 74 21268243
2011 The CHRNA5-A3-B4 gene cluster in nicotine addiction. Molecular psychiatry 70 21968931
2010 The nicotinic acetylcholine receptor CHRNA5/A3/B4 gene cluster: dual role in nicotine addiction and lung cancer. Progress in neurobiology 70 20685379
2010 Associations of variants in CHRNA5/A3/B4 gene cluster with smoking behaviors in a Korean population. PloS one 70 20808433
2015 A CHRNA5 Smoking Risk Variant Decreases the Aversive Effects of Nicotine in Humans. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 67 25948103
2010 Mediating effects of smoking and chronic obstructive pulmonary disease on the relation between the CHRNA5-A3 genetic locus and lung cancer risk. Cancer 63 20564069
2016 The CHRNA5-A3-B4 Gene Cluster and Smoking: From Discovery to Therapeutics. Trends in neurosciences 62 27871728
2015 CHRNA5 risk variant predicts delayed smoking cessation and earlier lung cancer diagnosis--a meta-analysis. Journal of the National Cancer Institute 62 25873736
2010 TTC12-ANKK1-DRD2 and CHRNA5-CHRNA3-CHRNB4 influence different pathways leading to smoking behavior from adolescence to mid-adulthood. Biological psychiatry 62 21168125
2012 Genetic variation in the 15q25 nicotinic acetylcholine receptor gene cluster (CHRNA5-CHRNA3-CHRNB4) interacts with maternal self-reported smoking status during pregnancy to influence birth weight. Human molecular genetics 59 22956269
2011 A CHRNA5 allele related to nicotine addiction and schizophrenia. Genes, brain, and behavior 55 21418140
2012 From men to mice: CHRNA5/CHRNA3, smoking behavior and disease. Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco 54 22544838
2010 Risk gene variants for nicotine dependence in the CHRNA5-CHRNA3-CHRNB4 cluster are associated with cognitive performance. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 52 20886544
2010 Association and interaction analysis of variants in CHRNA5/CHRNA3/CHRNB4 gene cluster with nicotine dependence in African and European Americans. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 51 19859904
2012 Analysis of detailed phenotype profiles reveals CHRNA5-CHRNA3-CHRNB4 gene cluster association with several nicotine dependence traits. Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco 50 22241830
2014 Stratification by smoking status reveals an association of CHRNA5-A3-B4 genotype with body mass index in never smokers. PLoS genetics 49 25474695
2014 Contribution of Variants in CHRNA5/A3/B4 Gene Cluster on Chromosome 15 to Tobacco Smoking: From Genetic Association to Mechanism. Molecular neurobiology 47 25471942
2010 From smoking to lung cancer: the CHRNA5/A3/B4 connection. Oncogene 45 20581870
2011 CHRNA5 as negative regulator of nicotine signaling in normal and cancer bronchial cells: effects on motility, migration and p63 expression. Carcinogenesis 43 21586512
2011 Association between CHRNA5 genetic variation at rs16969968 and brain reactivity to smoking images in nicotine dependent women. Drug and alcohol dependence 41 21764527
2018 Relationship of common variants in CHRNA5 with early-onset schizophrenia and executive function. Schizophrenia research 40 30366711
2018 Chrna5-Expressing Neurons in the Interpeduncular Nucleus Mediate Aversion Primed by Prior Stimulation or Nicotine Exposure. The Journal of neuroscience : the official journal of the Society for Neuroscience 38 29954848
2018 A Human Polymorphism in CHRNA5 Is Linked to Relapse to Nicotine Seeking in Transgenic Rats. Current biology : CB 36 30293722
2010 Promoter polymorphisms and transcript levels of nicotinic receptor CHRNA5. Journal of the National Cancer Institute 36 20733116
2016 Genetic Risk Can Be Decreased: Quitting Smoking Decreases and Delays Lung Cancer for Smokers With High and Low CHRNA5 Risk Genotypes - A Meta-Analysis. EBioMedicine 35 27543155
2015 Lack of Associations of CHRNA5-A3-B4 Genetic Variants with Smoking Cessation Treatment Outcomes in Caucasian Smokers despite Associations with Baseline Smoking. PloS one 34 26010901
2016 Increased nicotine response in iPSC-derived human neurons carrying the CHRNA5 N398 allele. Scientific reports 31 27698409
2015 Rare, low frequency and common coding variants in CHRNA5 and their contribution to nicotine dependence in European and African Americans. Molecular psychiatry 31 26239294
2015 Genetic variation (CHRNA5), medication (combination nicotine replacement therapy vs. varenicline), and smoking cessation. Drug and alcohol dependence 30 26142345
2013 Distinct loci in the CHRNA5/CHRNA3/CHRNB4 gene cluster are associated with onset of regular smoking. Genetic epidemiology 29 24186853
2011 Overexpression of the CHRNA5/A3/B4 genomic cluster in mice increases the sensitivity to nicotine and modifies its reinforcing effects. Amino acids 29 22101982
2010 ASCL1 regulates the expression of the CHRNA5/A3/B4 lung cancer susceptibility locus. Molecular cancer research : MCR 28 20124469
2019 Low Smoking Exposure, the Adolescent Brain, and the Modulating Role of CHRNA5 Polymorphisms. Biological psychiatry. Cognitive neuroscience and neuroimaging 26 31072760
2015 A multiancestry study identifies novel genetic associations with CHRNA5 methylation in human brain and risk of nicotine dependence. Human molecular genetics 25 26220977
2011 Chromosome 15q25 (CHRNA3-CHRNA5) variation impacts indirectly on lung cancer risk. PloS one 25 21559498
2010 Variation in the nicotinic acetylcholine receptor gene cluster CHRNA5-CHRNA3-CHRNB4 and its interaction with recent tobacco use influence cognitive flexibility. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 25 20631687
2001 Characterization of the genomic structure of the human neuronal nicotinic acetylcholine receptor CHRNA5/A3/B4 gene cluster and identification of novel intragenic polymorphisms. Journal of human genetics 25 11721883
2019 Genome-Wide Variants Shared Between Smoking Quantity and Schizophrenia on 15q25 Are Associated With CHRNA5 Expression in the Brain. Schizophrenia bulletin 24 30202994
2016 The CHRNA5/CHRNA3/CHRNB4 Nicotinic Receptor Regulome: Genomic Architecture, Regulatory Variants, and Clinical Associations. Human mutation 24 27758088
2015 Gene variance in the nicotinic receptor cluster (CHRNA5-CHRNA3-CHRNB4) predicts death from cardiopulmonary disease and cancer in smokers. Journal of internal medicine 24 26689306
2014 DRD2/CHRNA5 interaction on prefrontal biology and physiology during working memory. PloS one 23 24819610
2013 Chrna5 genotype determines the long-lasting effects of developmental in vivo nicotine exposure on prefrontal attention circuitry. Neuropharmacology 23 24055499
2020 Genetic Variant in CHRNA5 and Response to Varenicline and Combination Nicotine Replacement in a Randomized Placebo-Controlled Trial. Clinical pharmacology and therapeutics 22 32602170
2013 Scrutiny of the CHRNA5-CHRNA3-CHRNB4 smoking behavior locus reveals a novel association with alcohol use in a Finnish population based study. International journal of molecular epidemiology and genetics 22 23875064
2011 Externalizing behaviors are associated with SNPs in the CHRNA5/CHRNA3/CHRNB4 gene cluster. Behavior genetics 22 22042234
2024 Nicotine-induced CHRNA5 activation modulates CES1 expression, impacting head and neck squamous cell carcinoma recurrence and metastasis via MEK/ERK pathway. Cell death & disease 21 39472448
2019 Profound alteration in reward processing due to a human polymorphism in CHRNA5: a role in alcohol dependence and feeding behavior. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 21 31288250
2012 The CHRNA5/A3/B4 gene cluster and tobacco, alcohol, cannabis, inhalants and other substance use initiation: replication and new findings using mixture analyses. Behavior genetics 21 22382757
2020 Genetic susceptibility to nicotine addiction: Advances and shortcomings in our understanding of the CHRNA5/A3/B4 gene cluster contribution. Neuropharmacology 20 32738310
2012 Method for evaluating multiple mediators: mediating effects of smoking and COPD on the association between the CHRNA5-A3 variant and lung cancer risk. PloS one 20 23077662
2020 Chrna5 is Essential for a Rapid and Protected Response to Optogenetic Release of Endogenous Acetylcholine in Prefrontal Cortex. The Journal of neuroscience : the official journal of the Society for Neuroscience 19 32817066
2012 Association of nicotine dependence susceptibility gene, CHRNA5, with Parkinson's disease age at onset: gene and smoking status interaction. Parkinsonism & related disorders 19 22884254
2011 Association of the nicotine metabolite ratio and CHRNA5/CHRNA3 polymorphisms with smoking rate among treatment-seeking smokers. Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco 19 21385908
2011 Single nucleotide polymorphisms in CHRNA5 rs16969968, CHRNA3 rs578776, and LOC123688 rs8034191 are associated with heaviness of smoking in women in Northeastern Ontario, Canada. Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco 19 21810735
2011 In vitro and ex vivo analysis of CHRNA3 and CHRNA5 haplotype expression. PloS one 19 21858091
2013 Cis-regulatory variants affect CHRNA5 mRNA expression in populations of African and European ancestry. PloS one 18 24303001
2012 Polymorphisms of CHRNA5-CHRNA3-CHRNB4 Gene Cluster and NSCLC Risk in Chinese Population. Translational oncology 17 23397474
2011 A twin association study of nicotine dependence with markers in the CHRNA3 and CHRNA5 genes. Behavior genetics 17 21748402
2023 Chrna5 and lynx prototoxins identify acetylcholine super-responder subplate neurons. iScience 16 36798433
2022 CHRNA5 Contributes to Hepatocellular Carcinoma Progression by Regulating YAP Activity. Pharmaceutics 16 35214008
2014 Interplay of genetic risk (CHRNA5) and environmental risk (partner smoking) on cigarette smoking reduction. Drug and alcohol dependence 16 25073833
2016 SNPs in NRXN1 and CHRNA5 are associated to smoking and regulation of GABAergic and glutamatergic pathways. Pharmacogenomics 15 27355804
2015 CHRNA5 polymorphisms and risk of lung cancer in Chinese Han smokers. American journal of cancer research 15 26693074
2013 CHRNA5-A3-B4 genetic variants alter nicotine intake and interact with tobacco use to influence body weight in Alaska Native tobacco users. Addiction (Abingdon, England) 15 23692359
2023 JWA inhibits nicotine-induced lung cancer stemness and progression through CHRNA5/AKT-mediated JWA/SP1/CD44 axis. Ecotoxicology and environmental safety 14 37224781
2018 Cholinergic Receptor Nicotinic Alpha 5 (CHRNA5) RNAi is associated with cell cycle inhibition, apoptosis, DNA damage response and drug sensitivity in breast cancer. PloS one 14 30543688
2014 CHRNA5 variant predicts smoking cessation in patients with acute myocardial infarction. Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco 14 24727484
2013 Examination of rare missense variants in the CHRNA5-A3-B4 gene cluster to level of response to alcohol in the San Diego Sibling Pair study. Alcoholism, clinical and experimental research 14 23458267
2013 Genomics and personalized medicine: CHRNA5-CHRNA3-CHRNB4 and smoking cessation treatment. Journal of food and drug analysis 14 25214750
2010 Low ethanol concentration alters CHRNA5 RNA levels during early human development. Reproductive toxicology (Elmsford, N.Y.) 14 20438829
2018 Combined genetic influence of the nicotinic receptor gene cluster CHRNA5/A3/B4 on nicotine dependence. BMC genomics 13 30453884
2013 Association of CHRNA5-A3-B4 variation with esophageal squamous cell carcinoma risk and smoking behaviors in a Chinese population. PloS one 13 23844051
2011 Association of a variant in the CHRNA5-A3-B4 gene cluster region to heavy smoking in the Italian population. European journal of human genetics : EJHG 13 21248747
2022 CHRNA5 Is Overexpressed in Patients with Psoriasis and Promotes Psoriasis-Like Inflammation in Mouse Models. The Journal of investigative dermatology 11 35513071
2020 Association of CHRNA5 Gene Variants with Crack Cocaine Addiction. Neuromolecular medicine 11 32152934
2018 The interaction of the Chrna5 D398N variant with developmental nicotine exposure. Genes, brain, and behavior 11 29573323
2014 A recall-by-genotype study of CHRNA5-A3-B4 genotype, cotinine and smoking topography: study protocol. BMC medical genetics 11 24451018
2014 CHRNA5 and CHRNA3 variants and level of neuroticism in young adult Mexican American men and women. Twin research and human genetics : the official journal of the International Society for Twin Studies 11 24588897
2013 Smoking status, snus use, and variation at the CHRNA5-CHRNA3-CHRNB4 locus in relation to obesity: the GLACIER study. American journal of epidemiology 11 23729684
2012 Nicotine dependence and comorbid psychiatric disorders: examination of specific genetic variants in the CHRNA5-A3-B4 nicotinic receptor genes. Drug and alcohol dependence 11 22336398
2012 Functional effect of polymorphisms in 15q25 locus on CHRNA5 mRNA, bulky DNA adducts and TP53 mutations. International journal of cancer 11 23011884
2021 The Cumulative Effect of Gene-Gene Interactions Between GSTM1, CHRNA3, CHRNA5 and SOD3 Gene Polymorphisms Combined with Smoking on COPD Risk. International journal of chronic obstructive pulmonary disease 10 34707353
2017 Study on polymorphisms in CHRNA5/CHRNA3/CHRNB4 gene cluster and the associated with the risk of non-small cell lung cancer. Oncotarget 10 29416783
2016 IREB2, CHRNA5, CHRNA3, FAM13A & hedgehog interacting protein genes polymorphisms & risk of chronic obstructive pulmonary disease in Tatar population from Russia. The Indian journal of medical research 10 28474623
2014 Identification of CHRNA5 rare variants in African-American heavy smokers. Psychiatric genetics 10 24682045
2012 The polymorphism of the CHRNA5 gene and the strength of nicotine addiction in lung cancer and COPD patients. European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation (ECP) 10 21955800

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