CHRNB4

gene
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Summary

CHRNB4 (cholinergic receptor nicotinic beta 4 subunit, HGNC:1964) is a protein-coding gene on chromosome 15q25.1, encoding Neuronal acetylcholine receptor subunit beta-4 (P30926). 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 syna….

This gene is found within a conserved gene cluster and encodes one of the beta subunits of the nicotinic acetylcholine receptor (nAChRs) superfamily which form ligand-gated ion channels with a central pore that forms a cation channel. Neuronal nAChRs are pentameric structures that can be either homomeric or heteromeric, with heteromeric structures containing both alpha and beta subunits. Each subunit contains an extracellular amino terminus and four transmembrane domains. Nicotine is one of the agonists that binds to the receptor. Variants in this gene have been associated with nicotine dependence and lung cancer. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 1143 — RefSeq curated summary.

At a glance

  • Gene–disease (curated): lung cancer (Limited, GenCC)
  • GWAS associations: 65
  • Clinical variants (ClinVar): 67 total — 1 pathogenic, 2 likely-pathogenic
  • Phenotypes (HPO): 1
  • Druggable target: yes — 20 molecules with ChEMBL bioactivity
  • MANE Select transcript: NM_000750

Identifiers

Gene identifiers

FieldValue
HGNC IDHGNC:1964
Approved symbolCHRNB4
Namecholinergic receptor nicotinic beta 4 subunit
Location15q25.1
Locus typegene with protein product
StatusApproved
Ensembl geneENSG00000117971
Ensembl biotypeprotein_coding
OMIM118509
Entrez1143

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 4 protein_coding, 3 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000261751, ENST00000412074, ENST00000558216, ENST00000559849, ENST00000560511, ENST00000560868, ENST00000929174, ENST00000929175

RefSeq mRNA: 2 — MANE Select: NM_000750 NM_000750, NM_001256567

CCDS: CCDS10306, CCDS58392

Canonical transcript exons

ENST00000261751 — 6 exons

ExonStartEnd
ENSE000007940447863107678631185
ENSE000012626497862896778629945
ENSE000016645597862411178625291
ENSE000036951377863543978635587
ENSE000037010077863128878631332
ENSE000038434537864107978641210

Expression profiles

Bgee: expression breadth ubiquitous, 125 present calls, max score 82.37.

FANTOM5 (CAGE): breadth broad, TPM avg 0.6693 / max 115.2605, expressed in 209 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter IDTPM avgSamples expressed
1511240.3839142
1511230.2621105
1511250.02333

Top tissues by expression

232 total, by Bgee expression score (0-100, higher = more expressed):

TissueAnatomy IDExpression scoreQuality
primordial germ cell in gonadCL:0000670 ∩ UBERON:000099182.37gold quality
male germ line stem cell (sensu Vertebrata) in testisCL:0000089 ∩ UBERON:000047380.21gold quality
right testisUBERON:000453477.82gold quality
left testisUBERON:000453377.69gold quality
testisUBERON:000047375.27gold quality
buccal mucosa cellCL:000233674.67silver quality
adrenal tissueUBERON:001830373.03gold quality
ganglionic eminenceUBERON:000402371.36gold quality
cortical plateUBERON:000534366.58gold quality
muscle layer of sigmoid colonUBERON:003580560.81gold quality
ventricular zoneUBERON:000305358.67gold quality
sural nerveUBERON:001548858.33silver quality
right adrenal glandUBERON:000123357.67gold quality
adrenal glandUBERON:000236957.61gold quality
vermiform appendixUBERON:000115457.37gold quality
tendon of biceps brachiiUBERON:000818857.25gold quality
sigmoid colonUBERON:000115957.03gold quality
left adrenal gland cortexUBERON:003582556.52gold quality
metanephric glomerulusUBERON:000473655.97gold quality
left adrenal glandUBERON:000123455.62gold quality
adrenal cortexUBERON:000123554.98gold quality
lower esophagus mucosaUBERON:003583454.95gold quality
right adrenal gland cortexUBERON:003582754.51gold quality
esophagus mucosaUBERON:000246954.45gold quality
caecumUBERON:000115353.58gold quality
thymusUBERON:000237053.58silver quality
colonUBERON:000115552.34gold quality
lymph nodeUBERON:000002952.18gold quality
large intestineUBERON:000005951.92gold quality
colonic epitheliumUBERON:000039751.30gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

ExperimentMarker?Max mean expression
E-ANND-3yes5.21

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ASCL1, SOX10, SP1, SP3

miRNA regulators (miRDB)

41 targeting CHRNB4, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNAMax scoreAvg scoremiRNA target_count
HSA-MIR-4747-5P100.0067.902681
HSA-MIR-5196-5P100.0067.982761
HSA-MIR-453499.9966.581907
HSA-MIR-808299.9567.271170
HSA-MIR-6780A-5P99.8866.692776
HSA-MIR-4728-5P99.8569.394718
HSA-MIR-6785-5P99.8268.684428
HSA-MIR-1273H-5P99.7766.322471
HSA-MIR-430699.7270.503630
HSA-MIR-4699-3P99.7170.153142
HSA-MIR-30B-3P99.7065.762325
HSA-MIR-3689A-3P99.7065.732306
HSA-MIR-3689B-3P99.7065.712311
HSA-MIR-3689C99.7065.712311
HSA-MIR-6779-5P99.7065.762363
HSA-MIR-6762-3P99.6666.941188
HSA-MIR-182799.6368.573265
HSA-MIR-7106-5P99.5367.473574
HSA-MIR-127599.4767.902749
HSA-MIR-94099.3766.142064
HSA-MIR-428499.3665.251293
HSA-MIR-185-5P99.3568.602497
HSA-MIR-464499.3569.122514
HSA-MIR-1912-3P99.3267.40936
HSA-MIR-6808-5P99.3166.232150
HSA-MIR-6893-5P99.3166.252119
HSA-MIR-4667-3P99.2665.451608
HSA-MIR-797499.2465.481137
HSA-MIR-6799-5P99.1465.722093
HSA-MIR-1295B-5P99.0367.50810

Literature-anchored findings (GeneRIF, showing 40)

  • CHRNB4 subunit is expressed in the soma of the majority of pyramidal cells, with fairly consistent immunoreactivity observed throughout the different regions of the hippocampus. (PMID:12663058)
  • absence of differences in the pharmacological profile of nicotinic receptor alpha3beta4 argues against role for incorporated beta3 subunit in formation of agonist binding sites while changes in channel kinetics suggest important effect on receptor gating (PMID:12912995)
  • The receptors containing the R136W and M467V mutations (or variants) had a higher sensitivity to acetylcholine and lower EC50 than the wild-type. (PMID:15742216)
  • In the 2,827 long-term smokers examined, common susceptibility and protective haplotypes at the CHRNA5-A3-B4 locus were associated with nicotine dependence severity. (PMID:18618000)
  • Correlated SNPs in the cholinergic nicotinic receptor gene cluster CHRNA5-CHRNA3-CHRNB4, in a case-control study of cocaine dependence composed of 504 European-American and 583 African-Americans. (PMID:18759969)
  • CHRNB4 seem to exert no relevant influence on smoking cessation probability in heavy smokers in the general population. (PMID:18996504)
  • Two distinct variant groups in the CHRNA5-CHRNA3-CHRNB4 gene cluster are strongly associated with heavy smoking. The snp rs16969968 alters the coding sequence of these genes. (PMID:19029397)
  • Genetic variant in the CHRNA5-CHRNA3-CHRNB4 gene cluster is associated with smoking cessation during pregnancy. (PMID:19429911)
  • Missense mutation of CHRNB4, CHRNB3 and CHRNA4 are associated with sporadic amyotrophic lateral sclerosis. (PMID:19628475)
  • Genetic variation at CHRNA5/CHRNA3/CHRNB4 cluster influences blood nicotine level. (PMID:19628476)
  • These results indicate that variants within CHRNA3 and among CHRNA5, CHRNA3, and CHRNB4 contribute significantly to the etiology of ND through gene-gene interactions. (PMID:19859904)
  • Data suggest that interactions between alpha3beta4 nAChRs and P2X2 receptors may modulate transmission at enteric synapses that use ATP and acetylcholine as co-transmitters. (PMID:20426799)
  • The data of this study supported the importance of variants in the CHRNA5/A3/B4 gene cluster as mediators of the genetic risk for substance dependence. (PMID:20485328)
  • Variation in the nicotinic acetylcholine receptor gene cluster CHRNA5-CHRNA3-CHRNB4 influences cognitive flexibility differently in African Americans and European Americans. (PMID:20631687)
  • This review focuses on the clustered nicotinic acetylcholine receptor genes CHRNalpha5/alpha3/beta4 and evaluates their role in nicotine addiction and lung cancer. (PMID:20685379)
  • associations of variants in the CHRNA5/A3/B4 cluster with smoking initiation, smoking quantity and smoking cessation (PMID:20808433)
  • evidence that CHRNA5-CHRNA3-CHRNB4 gene cluster variants,particularly CHRNA5 variant rs16969968, could be associated with cognitive performance possibly mediating in part risk for developing nicotine dependence (PMID:20886544)
  • functional properties of nAChRs containing beta4R349C subunit; mutation caused reduction in potency of ACh and nicotine, decreased density of whole-cell current evoked by maximal transmitter concentrations, altered kinetics of ACh-evoked whole-cell currents (PMID:21107856)
  • CHRNA5-CHRNA3-CHRNB4 is involved in the transition toward heavy smoking in mid-adulthood and in smoking persistence. (PMID:21168125)
  • Single nucleotide polymorphism (SNP) CHRNB4 on chromosome 15 is not associated with Parkinson’s disease risk in the overall anaylsis or after stratifying on smoking status. (PMID:21228559)
  • Variant A of the rs1051730 SNP of CHRNA5-A3-B4 gene cluster was significantly associated with smoking quantity in 2 Italian populations, Val Borbera and Cilento, no association was found in Carlantino population. (PMID:21248747)
  • neuronal nicotinic acetylcholine receptors alpha4beta4 and alpha7 show differential agonist binding modes (PMID:21343288)
  • Single Nucleotide Polymorphisms in CHRNB4 is associated with smoking persistence in African Americans. (PMID:21436384)
  • The A2A receptor reduces the desensitization of alpha3beta4 nAChR through the action of protein kinase A. Mutations disrupting the sequence 385RAES388 abolish PKA-induced changes in nAChR function. (PMID:21486776)
  • Nicotinic acetylcholine receptor polymorphisms are associated with additional increased risk of lung cancer, bladder cancer, and chronic obstructive pulmonary disease after adjustment for smoking. (PMID:21646606)
  • Variation in CHRNA5-A3-B4 was independently and additively associated with increased smoking, nicotine dependence, and lung cancer risk. (PMID:21747048)
  • alpha6beta4* nAChRs are expressed and contribute to exocytosis in human chromaffin cells of the adrenal gland, the main source of adrenaline under stressful situations. (PMID:21917987)
  • Overexpression of alpha3/alpha5/beta4 nicotinic acetylcholine receptor subunits produces changes in two specific aspects of executive functioning–working memory and response inhibition–that may be related to nicotine dependence vulnerability. (PMID:22024278)
  • This study examines whether the CHRNA5/CHRNA3/CHRNB4 locus is correlated also with externalizing behaviors in three independent longitudinally assessed adolescent samples (PMID:22042234)
  • Missense variants at conserved residues in CHRNB4 are associated with lower risk for nicotine dependence in African Americans and European Americans. (PMID:22042774)
  • vivo evidence of the involvement of the CHRNA5, CHRNA3 and CHRNB4 genomic cluster in nicotine addiction (PMID:22101982)
  • Single nucleotide polymorphisma in CHRNB4 showed suggestive association with the comorbidity of depression and nicotine dependence. (PMID:22241830)
  • The genetic risks of nicotine dependence associated with the CHRNA5-A3-B4 subunit genes are specific, and not shared among commonly comorbid psychiatric disorders (PMID:22336398)
  • Collectively, the presence of alpha7 and beta4 nAChRs in PDLSCs supports a key role of Nicotinic acetylcholine receptor (nAChRs) in the modulation of nicotine-induced apoptosis (PMID:22382680)
  • study provides evidence for a general role of the CHRNA5/A3/B4 gene cluster in substance use initiation that is not limited to nicotine and alcohol. (PMID:22382757)
  • Quantitative trait disequilibrium test (QTDT) significant association was detected between age at onset of daily smoking and variants located upstream of CHRNB4. (PMID:22438940)
  • transgenic mice with human alpha 5, alpha 3, beta 4 subunit genes drank less ethanol than wild-type in a two-bottle (ethanol vs. water) preference test; results suggest a complex role for this receptor subunit gene cluster in the modulation of ethanol’s as well as nicotine’s effects (PMID:22459873)
  • Compared with etomidate, carboetomidate’s higher hydrophobicity is associated with greater inhibition of alpha4/beta2 neuronal nicotinic acetylcholine receptors. (PMID:22543065)
  • epigenetic deregulation of nicotinic acetylcholine receptor subunit (nAChR) genes which in the case of CHRNB4 is strongly associated with genetic lung cancer susceptibility variants and a functional impact on tumorigenic potential (PMID:22945651)
  • 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. (PMID:22956269)

Cross-species orthologs

3 orthologs

OrganismSymbolGene ID
danio_reriochrnb4ENSDARG00000101677
mus_musculusChrnb4ENSMUSG00000035200
rattus_norvegicusChrnb4ENSRNOG00000014427

Paralogs (45): GABRA3 (ENSG00000011677), GABRA1 (ENSG00000022355), CHRNA3 (ENSG00000080644), GABRP (ENSG00000094755), CHRNA4 (ENSG00000101204), GLRA2 (ENSG00000101958), GABRE (ENSG00000102287), CHRNE (ENSG00000108556), GABRA4 (ENSG00000109158), GLRB (ENSG00000109738), GABRR2 (ENSG00000111886), GABRG2 (ENSG00000113327), CHRNA2 (ENSG00000120903), CHRNA10 (ENSG00000129749), CHRND (ENSG00000135902), CHRNA1 (ENSG00000138435), GLRA3 (ENSG00000145451), GABRA6 (ENSG00000145863), GABRB2 (ENSG00000145864), GLRA1 (ENSG00000145888), GABRR1 (ENSG00000146276), CHRNB3 (ENSG00000147432), CHRNA6 (ENSG00000147434), HTR3B (ENSG00000149305), GABRA2 (ENSG00000151834), CHRNB2 (ENSG00000160716), GABRG1 (ENSG00000163285), GABRB1 (ENSG00000163288), GABRB3 (ENSG00000166206), CHRFAM7A (ENSG00000166664), HTR3A (ENSG00000166736), CHRNA5 (ENSG00000169684), CHRNB1 (ENSG00000170175), CHRNA9 (ENSG00000174343), CHRNA7 (ENSG00000175344), HTR3C (ENSG00000178084), GABRG3 (ENSG00000182256), GABRR3 (ENSG00000183185), HTR3E (ENSG00000186038), HTR3D (ENSG00000186090)

Protein

Protein identifiers

Neuronal acetylcholine receptor subunit beta-4P30926 (reviewed: P30926)

All UniProt accessions (2): P30926, H3BU02

UniProt curated annotations — full annotation on UniProt →

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. CHRNB4 forms heteropentameric neuronal acetylcholine receptors with CHRNA2, CHRNA3 and CHRNA4, as well as CHRNA5 and CHRNB3 as accesory subunits. CHRNA3:CHRNB4 being predominant in neurons of the autonomic ganglia, it is known as ganglionic nicotinic receptor. CHRNA3:CHRNB4 or CHRNA3:CHRNA5:CHRNB4 play also an important role in the habenulo-interpeduncular tract, modulating the mesolimbic dopamine system and affecting reward circuits and addiction. Hypothalamic CHRNA3:CHRNB4 nAChR activation by nicotine leads to activation of POMC neurons and a decrease in food intake.

Subunit / interactions. Neuronal AChR is composed of two different types of subunits: alpha and beta. CHRNB4/Beta-4 subunit can be combined to CHRNA2/alpha-2, CHRNA3/alpha-3 or CHRNA4/alpha-4, CHRNA5/alpha-5 and CHRNB3/beta-3 to give rise to functional receptors. Forms stoichiometries such as (CHRNA3)2:(CHRNB4)3 or (CHRNA3:CHRNB4)2:CHRNB3. Interacts with RIC3; which is required for proper folding and assembly. Interacts with LYPD6.

Subcellular location. Synaptic cell membrane. Cell membrane.

Activity regulation. Activated by a myriad of ligands such as acetylcholine, cytisine, nicotine, choline and epibatidine. The heteropentamer CHRNA3:CHRNB4 activity is blocked by the alpha-conotoxin ImI and AuIB.

Similarity. Belongs to the ligand-gated ion channel (TC 1.A.9) family. Acetylcholine receptor (TC 1.A.9.1) subfamily. Beta-4/CHRNB4 sub-subfamily.

Isoforms (2)

UniProt IDNamesCanonical?
P30926-11yes
P30926-22

RefSeq proteins (2): NP_000741, NP_001243496 (=MANE)

Domains & families (InterPro)

IDNameType
IPR002394Nicotinic_acetylcholine_rcptFamily
IPR006029Neurotrans-gated_channel_TMDomain
IPR006201Neur_channelFamily
IPR006202Neur_chan_lig-bdDomain
IPR018000Neurotransmitter_ion_chnl_CSConserved_site
IPR036719Neuro-gated_channel_TM_sfHomologous_superfamily
IPR036734Neur_chan_lig-bd_sfHomologous_superfamily
IPR038050Neuro_actylchol_recHomologous_superfamily

Pfam: PF02931, PF02932

Catalyzed reactions (Rhea), 3 shown:

  • K(+)(in) = K(+)(out) (RHEA:29463)
  • Ca(2+)(in) = Ca(2+)(out) (RHEA:29671)
  • Na(+)(in) = Na(+)(out) (RHEA:34963)

UniProt features (59 total): strand 15, helix 8, turn 7, topological domain 5, glycosylation site 4, sequence variant 4, transmembrane region 4, site 2, splice variant 2, sequence conflict 2, signal peptide 1, chain 1, region of interest 1, binding site 1, disulfide bond 1, mutagenesis site 1

Structure

Experimental structures (PDB)

4 structures.

PDBMethodResolution (Å)
8ZRNELECTRON MICROSCOPY3.25
8ZRPELECTRON MICROSCOPY3.32
6PV7ELECTRON MICROSCOPY3.34
6PV8ELECTRON MICROSCOPY3.87

Predicted structure (AlphaFold)

ModelpLDDTFraction very-high
AF-P30926-F182.080.62

Antibody-complex structures (SAbDab): 26PV7, 6PV8

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (2): 82 (key residue that facilitates effective access of the conotoxin buia to the channel binding site); 134 (key residue for a low dissociation (k(off)) from the conotoxin buia)

Ligand- & substrate-binding residues (1): 262

Disulfide bonds (1): 153–167

Glycosylation sites (4): 36, 93, 138, 166

Mutagenesis-validated functional residues (1):

PositionPhenotype
272increases potency of agonists.

Function

Pathways and Gene Ontology

Reactome pathways

12 pathways

IDPathway
R-HSA-629587Highly sodium permeable postsynaptic acetylcholine nicotinic receptors
R-HSA-629594Highly calcium permeable postsynaptic nicotinic acetylcholine receptors
R-HSA-629597Highly calcium permeable nicotinic acetylcholine receptors
R-HSA-6798695Neutrophil degranulation
R-HSA-112314Neurotransmitter receptors and postsynaptic signal transmission
R-HSA-112315Transmission across Chemical Synapses
R-HSA-112316Neuronal System
R-HSA-168249Innate Immune System
R-HSA-168256Immune System
R-HSA-181431Acetylcholine binding and downstream events
R-HSA-622323Presynaptic nicotinic acetylcholine receptors
R-HSA-622327Postsynaptic nicotinic acetylcholine receptors

MSigDB gene sets: 196 (showing top): GOBP_EXCRETION, MODULE_92, GOBP_MEMBRANE_DEPOLARIZATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, REACTOME_INNATE_IMMUNE_SYSTEM, MODULE_274, GOBP_BEHAVIOR, GOCC_SECRETORY_GRANULE, GOBP_ADULT_BEHAVIOR, MODULE_64, GOBP_SYNAPTIC_TRANSMISSION_CHOLINERGIC, GOBP_REGULATION_OF_SMOOTH_MUSCLE_CONTRACTION, GOBP_NEUROTRANSMITTER_TRANSPORT, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, MORF_RAD51L3

GO Biological Process (18): monoatomic ion transport (GO:0006811), smooth muscle contraction (GO:0006939), regulation of smooth muscle contraction (GO:0006940), signal transduction (GO:0007165), synaptic transmission, cholinergic (GO:0007271), locomotory behavior (GO:0007626), neuronal action potential (GO:0019228), monoatomic ion transmembrane transport (GO:0034220), behavioral response to nicotine (GO:0035095), regulation of neurotransmitter secretion (GO:0046928), membrane depolarization (GO:0051899), positive regulation of transmission of nerve impulse (GO:0051971), synaptic transmission involved in micturition (GO:0060084), acetylcholine receptor signaling pathway (GO:0095500), response to nicotine (GO:0035094), regulation of membrane potential (GO:0042391), regulation of postsynaptic membrane potential (GO:0060078), excitatory postsynaptic potential (GO:0060079)

GO Molecular Function (8): ligand-gated monoatomic ion channel activity (GO:0015276), acetylcholine receptor activity (GO:0015464), acetylcholine-gated monoatomic cation-selective channel activity (GO:0022848), transmembrane signaling receptor activity (GO:0004888), monoatomic ion channel activity (GO:0005216), extracellular ligand-gated monoatomic ion channel activity (GO:0005230), protein binding (GO:0005515), transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential (GO:1904315)

GO Cellular Component (13): plasma membrane (GO:0005886), acetylcholine-gated channel complex (GO:0005892), membrane (GO:0016020), specific granule membrane (GO:0035579), neuron projection (GO:0043005), synapse (GO:0045202), tertiary granule membrane (GO:0070821), neurotransmitter receptor complex (GO:0098878), cholinergic synapse (GO:0098981), postsynaptic specialization membrane (GO:0099634), cation channel complex (GO:0034703), postsynaptic membrane (GO:0045211), synaptic membrane (GO:0097060)

Reactome top-level categories

Rollup of top-8 pathways:

CategoryPathways
Presynaptic nicotinic acetylcholine receptors2
Postsynaptic nicotinic acetylcholine receptors2
Acetylcholine binding and downstream events2
Innate Immune System1
Transmission across Chemical Synapses1
Neuronal System1
Immune System1
Neurotransmitter receptors and postsynaptic signal transmission1

GO top-level categories

Rollup of top GO terms by namespace:

CategoryTerms
transmission of nerve impulse2
regulation of membrane potential2
regulation of postsynaptic membrane potential2
postsynaptic neurotransmitter receptor activity2
monoatomic ion channel complex2
plasma membrane signaling receptor complex2
secretory granule membrane2
synapse2
synaptic membrane2
transport1
muscle contraction1
regulation of muscle contraction1
smooth muscle contraction1
cell communication1
cellular process1
signaling1
regulation of cellular process1
cellular response to stimulus1
chemical synaptic transmission1
behavior1
action potential1
monoatomic ion transport1
transmembrane transport1
adult behavior1
response to nicotine1
neurotransmitter secretion1
modulation of chemical synaptic transmission1
regulation of neurotransmitter transport1
regulation of secretion by cell1
positive regulation of cell communication1
positive regulation of nervous system process1
regulation of transmission of nerve impulse1
neuromuscular synaptic transmission1
micturition1
acetylcholine receptor activity1
postsynaptic signal transduction1
cellular response to acetylcholine1
response to chemical1
monoatomic ion transmembrane transport1
regulation of biological quality1

Protein interactions and networks

STRING

816 interactions, top by confidence (×1000):

Protein AProtein BPartner UniProtScore
CHRNB4PSMA4P25789938
CHRNB4CHRNA3P32297822
CHRNB4RIC3Q7Z5B4755
CHRNB4HYKKA2RU49700
CHRNB4DEGS2Q6QHC5608
CHRNB4IGBP1P78318606
CHRNB4CYP2A6P00190603
CHRNB4IREB2P48200577
CHRNB4GABBR2O75899568
CHRNB4NMUR2Q9GZQ4559
CHRNB4SLC6A4P31645557
CHRNB4CHRM2P08172557
CHRNB4SLC17A6Q9P2U8538
CHRNB4DRD1P21728526
CHRNB4HTR2AP28223514

IntAct

9 interactions, top by confidence:

ABTypeScore
CHRNB4MEOX2psi-mi:“MI:0915”(physical association)0.560
LYPD6CHRNB2psi-mi:“MI:0914”(association)0.350
LYNX1CHRNB2psi-mi:“MI:0914”(association)0.350
HCN1USP27Xpsi-mi:“MI:0914”(association)0.350
CHRNB4GPR89Apsi-mi:“MI:0914”(association)0.350
CHRNB4MEOX2psi-mi:“MI:0915”(physical association)0.000

BioGRID (69): CHRNB4 (Affinity Capture-RNA), CHRNB4 (Affinity Capture-MS), CHRNB4 (Two-hybrid), CHRNB4 (Affinity Capture-MS), SQSTM1 (Affinity Capture-MS), ABHD14A (Affinity Capture-MS), RHBDD3 (Affinity Capture-MS), UBA52 (Affinity Capture-MS), BNIP1 (Affinity Capture-MS), HS6ST2 (Affinity Capture-MS), ANO6 (Affinity Capture-MS), RNF215 (Affinity Capture-MS), SPPL2B (Affinity Capture-MS), DNAJB9 (Affinity Capture-MS), PLD6 (Affinity Capture-MS)

ESM2 similar proteins: A8WQK3, O16926, P02708, P02709, P02710, P02711, P02712, P02718, P04755, P04756, P04757, P05377, P09478, P09479, P09481, P09484, P09628, P12389, P12392, P17644, P18845, P19370, P20420, P22456, P23414, P25108, P25162, P26152, P26153, P30926, P32297, P43143, P48180, P48181, P49579, P49581, P91766, Q07263, Q15825, Q23022

Diamond homologs: A8WQK3, O16926, O70174, P02708, P02709, P02710, P02711, P02712, P02713, P02716, P02717, P04755, P04756, P04757, P04758, P04759, P05377, P09478, P09479, P09480, P09481, P09482, P09483, P09484, P09628, P09690, P11230, P12389, P12390, P12391, P12392, P13908, P17644, P17787, P18257, P18845, P19370, P20420, P22456, P22770

SIGNOR signaling

2 interactions.

AEffectBMechanism
CHRNB4“form complex”“Neuronal nicotinic acetylcholine receptor complex, alpha3-alpha5-beta4”binding
CHRNB4“form complex”“Neuronal nicotinic acetylcholine receptor complex, alpha3-alpha6-beta4”binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

67 variants total. Per-class counts are floors (≥ shown; pagination cap):

ClassificationCount (floor)
Pathogenic1
Likely pathogenic2
Uncertain significance43
Likely benign8
Benign8

Top pathogenic / likely-pathogenic (3)

Variant IDHGVSClassification
3336651NM_000750.5(CHRNB4):c.1411G>C (p.Val471Leu)Pathogenic
1344512NM_000750.5(CHRNB4):c.178C>T (p.Leu60Phe)Likely pathogenic
1344513NM_000750.5(CHRNB4):c.658G>A (p.Val220Met)Likely pathogenic

SpliceAI

1209 predictions. Top by Δscore:

VariantEffectΔscore
15:78628374:T:TAdonor_gain1.0000
15:78628375:C:Adonor_gain1.0000
15:78628965:A:ACdonor_gain1.0000
15:78628966:C:CCdonor_gain1.0000
15:78628966:CA:Cdonor_gain1.0000
15:78628966:CACT:Cdonor_gain1.0000
15:78629957:C:CTacceptor_gain1.0000
15:78631070:ACTCA:Adonor_loss1.0000
15:78631073:CA:Cdonor_loss1.0000
15:78631074:A:ACdonor_gain1.0000
15:78631075:C:CCdonor_gain1.0000
15:78631075:CTT:Cdonor_gain1.0000
15:78631075:CTTG:Cdonor_gain1.0000
15:78631181:CATTC:Cacceptor_gain1.0000
15:78631183:TTC:Tacceptor_gain1.0000
15:78631184:TC:Tacceptor_gain1.0000
15:78631185:CC:Cacceptor_gain1.0000
15:78631185:CCTGG:Cacceptor_loss1.0000
15:78631186:C:CCacceptor_gain1.0000
15:78631186:CTGG:Cacceptor_loss1.0000
15:78631187:T:Aacceptor_loss1.0000
15:78635438:CCACG:Cdonor_gain1.0000
15:78628356:AAAG:Adonor_gain0.9900
15:78628959:CAACT:Cdonor_loss0.9900
15:78628960:AACTT:Adonor_loss0.9900
15:78628961:ACTTA:Adonor_loss0.9900
15:78628962:CTTAC:Cdonor_loss0.9900
15:78628963:TT:Tdonor_loss0.9900
15:78628964:TACA:Tdonor_loss0.9900
15:78628965:A:Cdonor_loss0.9900

AlphaMissense

3279 scored. Top likely-pathogenic:

VariantProtein changeam_pathogenicity
15:78629702:C:AW201C0.999
15:78629702:C:GW201C0.999
15:78631104:A:GW111R0.999
15:78631104:A:TW111R0.999
15:78631182:A:GW85R0.999
15:78631182:A:TW85R0.999
15:78629704:A:GW201R0.998
15:78629704:A:TW201R0.998
15:78629793:A:GF171S0.998
15:78631102:C:AW111C0.998
15:78631102:C:GW111C0.998
15:78631159:C:AW92C0.998
15:78631159:C:GW92C0.998
15:78631180:C:AW85C0.998
15:78631180:C:GW85C0.998
15:78629617:G:TR230S0.997
15:78629790:C:GR172P0.997
15:78629799:A:GL169P0.997
15:78629852:G:CS151R0.997
15:78629852:G:TS151R0.997
15:78629854:T:GS151R0.997
15:78631161:A:GW92R0.997
15:78631161:A:TW92R0.997
15:78631166:A:GL90P0.997
15:78629804:G:CC167W0.996
15:78629866:C:GA147P0.996
15:78629889:C:AG139V0.996
15:78629901:A:TV135D0.996
15:78631097:G:TP113H0.996
15:78631176:C:GD87H0.996

dbSNP variants (sampled 300 via entrez): RS1000166231 (15:78650209 A>G), RS1000219662 (15:78634982 G>T), RS1000253384 (15:78638577 G>A), RS1000268528 (15:78656282 A>G), RS1000270355 (15:78635268 A>C), RS1000301146 (15:78656524 C>T), RS1000431036 (15:78661635 C>G,T), RS1000550482 (15:78636292 G>A,C), RS1000603007 (15:78636706 C>A), RS1000699238 (15:78624159 C>G,T), RS1000825099 (15:78634055 T>C), RS1000855837 (15:78661697 CCA>C), RS1000855914 (15:78662103 C>A), RS1001021909 (15:78628566 G>C), RS1001074098 (15:78653062 A>C,G,T)

Disease associations

OMIM: gene MIM:118509 | disease phenotypes: MIM:606963

GenCC curated gene-disease

DiseaseClassificationInheritance
lung cancerLimitedAutosomal dominant

Mondo (5): frontotemporal dementia (MONDO:0017276), lung adenocarcinoma (MONDO:0005061), chronic obstructive pulmonary disease (MONDO:0005002), amyotrophic lateral sclerosis (MONDO:0004976), lung cancer (MONDO:0008903)

Orphanet (3): Frontotemporal dementia (Orphanet:282), Amyotrophic lateral sclerosis (Orphanet:803), NON RARE IN EUROPE: Adenocarcinoma of the lung (Orphanet:415268)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPOTerm
HP:0007354Amyotrophic lateral sclerosis

GWAS associations

65 associations (top):

StudyTraitp-value
GCST000170_1Lung cancer5.000000e-20
GCST000171_1Nicotine dependence6.000000e-20
GCST000233_1Lung cancer1.000000e-08
GCST001102_3Sudden cardiac arrest4.000000e-07
GCST002539_77Schizophrenia2.000000e-13
GCST002584_1Exhaled carbon monoxide levels2.000000e-09
GCST003025_22Attention function in attention deficit hyperactive disorder6.000000e-06
GCST003185_2Nicotine dependence4.000000e-17
GCST003262_17Post bronchodilator FEV14.000000e-09
GCST003262_22Post bronchodilator FEV17.000000e-07
GCST003262_229Post bronchodilator FEV13.000000e-13
GCST003262_407Post bronchodilator FEV12.000000e-11
GCST003262_409Post bronchodilator FEV11.000000e-10
GCST003262_51Post bronchodilator FEV17.000000e-09
GCST003262_673Post bronchodilator FEV18.000000e-09
GCST003262_739Post bronchodilator FEV16.000000e-08
GCST003262_743Post bronchodilator FEV12.000000e-07
GCST003262_757Post bronchodilator FEV17.000000e-08
GCST003262_772Post bronchodilator FEV14.000000e-13
GCST003262_800Post bronchodilator FEV15.000000e-09
GCST003262_822Post bronchodilator FEV13.000000e-10
GCST003262_916Post bronchodilator FEV12.000000e-14
GCST003262_919Post bronchodilator FEV12.000000e-08
GCST003262_957Post bronchodilator FEV13.000000e-09
GCST003262_975Post bronchodilator FEV11.000000e-07
GCST003264_1111Post bronchodilator FEV1/FVC ratio9.000000e-08
GCST003264_1115Post bronchodilator FEV1/FVC ratio2.000000e-07
GCST003264_1152Post bronchodilator FEV1/FVC ratio3.000000e-09
GCST003264_1235Post bronchodilator FEV1/FVC ratio1.000000e-07
GCST003264_1307Post bronchodilator FEV1/FVC ratio8.000000e-14

EFO canonical traits (10, from GWAS)

EFO IDTrait name
EFO:0004278sudden cardiac arrest
EFO:0004318smoking behavior
EFO:0006520carbon monoxide exhalation measurement
EFO:0007636attention function measurement
EFO:0004314forced expiratory volume
EFO:0004713FEV/FVC ratio
EFO:0004340body mass index
EFO:0009369diffusing capacity of the lung for carbon monoxide
EFO:0007874gut microbiome measurement
EFO:0006527smoking status measurement

MeSH disease descriptors (3)

DescriptorNameTree numbers
D000690Amyotrophic Lateral SclerosisC10.228.854.139; C10.574.562.250; C10.574.950.050; C10.668.467.250; C18.452.845.800.050
D057180Frontotemporal DementiaC10.228.140.380.266.299; C10.574.950.300.299; C18.452.845.800.300.299; F03.615.400.380.299
D029424Pulmonary Disease, Chronic ObstructiveC08.381.495.389; C23.550.291.500.875

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (11): CHEMBL1907591 (PROTEIN COMPLEX), CHEMBL1907594 (PROTEIN COMPLEX), CHEMBL2109230 (PROTEIN COMPLEX), CHEMBL2111384 (PROTEIN COMPLEX GROUP), CHEMBL2221346 (PROTEIN COMPLEX GROUP), CHEMBL3038459 (PROTEIN COMPLEX), CHEMBL3137273 (PROTEIN COMPLEX), CHEMBL3137285 (PROTEIN COMPLEX), CHEMBL3885595 (PROTEIN COMPLEX), CHEMBL4524133 (PROTEIN COMPLEX GROUP)

Molecules with ChEMBL bioactivity

20 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 426,191 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

MoleculeNamePhasePatents
CHEMBL1076903VARENICLINE45,807
CHEMBL3NICOTINE4184,969
CHEMBL894BUPROPION436,982
CHEMBL267936MECAMYLAMINE45,623
CHEMBL46ONDANSETRON441,386
CHEMBL56564TROPISETRON419,312
CHEMBL667ACETYLCHOLINE4124,626
CHEMBL2103881DEXMECAMYLAMINE318
CHEMBL497939CYTISINICLINE32,766
CHEMBL111659ALTINICLINE2129
CHEMBL1172928RADAFAXINE21,079
CHEMBL1230982ANABASEINE2139
CHEMBL1257065STILONIUM IODIDE2751
CHEMBL132966RIVANICLINE2911
CHEMBL134713GTS-212269
CHEMBL2179529AZD1446278
CHEMBL238465SOFINICLINE2153
CHEMBL430497TEBANICLINE21,155
CHEMBL60704818-METHOXYCORONARIDINE26
CHEMBL504652TC-2216132

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

5 annotations.

VariantTypeLevelDrugsPhenotypes
rs10851907Metabolism/PK3cotinineTobacco Use Disorder
rs1948Toxicity3nicotineTobacco Use Disorder
rs2869950Toxicity3nicotineTobacco Use Disorder
rs3813567Toxicity3nicotineTobacco Use Disorder
rs7178270Toxicity3nicotineTobacco Use Disorder

PharmGKB variants

6 variants.

VariantGenesLevelScore#Clin annotsDrugs
rs3813567CHRNB432.001nicotine
rs10851907CHRNB430.001cotinine
rs2869950CHRNB4, FAM13A30.001nicotine
rs1948CHRNB433.001nicotine
rs7178270CHRNB433.001nicotine
rs950776CHRNB40.000

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: lgic — Nicotinic acetylcholine receptors (nACh)

Binding affinities (BindingDB)

7 measured of 9 human assays (10 total across all organisms); most potent 7 below. Values come from heterogeneous assays and are not directly comparable.

LigandMeasureValue
CHEMBL4453542KI2.5 nM
CHEMBL4450133KI6.7 nM
CHEMBL4440403KI20 nM
CHEMBL4535466KI138 nM
CHEMBL4463888KI631 nM
18-methoxycoronaridineKI700 nM
CHEMBL4468230KI1630 nM

ChEMBL bioactivities

1230 potent at pChembl≥5 of 1586 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChemblTypeValueUnitMolecule
10.14Ki0.072nMEPIBATIDINE
10.04Ki0.091nMEPIBATIDINE
9.90Ki0.126nMCHEMBL1209244
9.83Ki0.149nMCHEMBL1209243
9.82Ki0.15nMEPIBATIDINE
9.82Ki0.15nM(-)-EPIBATIDINE
9.80Ki0.16nMCHEMBL220476
9.80IC500.16nMCHEMBL1269126
9.80Ki0.158nMCHEMBL1209187
9.80EC500.16nMCHEMBL1209244
9.73Ki0.186nMCHEMBL1209124
9.72Ki0.191nMEPIBATIDINE
9.70Ki0.2nMCHEMBL462846
9.70IC500.2nMCHEMBL4869892
9.66Ki0.22nMEPIBATIDINE
9.64Ki0.23nMEPIBATIDINE
9.62IC500.24nMCHEMBL4860756
9.61Ki0.243nMCHEMBL1209187
9.55IC500.28nMCHEMBL4876825
9.52Kd0.3nMEPIBATIDINE
9.52IC500.3nMCHEMBL412032
9.52Kd0.3nM(-)-EPIBATIDINE
9.46IC500.35nMCHEMBL4462550
9.43IC500.37nMCHEMBL4454232
9.42Ki0.382nMCHEMBL1209186
9.39IC500.41nMCHEMBL4878931
9.34IC500.46nMCHEMBL4556075
9.34Ki0.457nMEPIBATIDINE
9.29IC500.51nMCHEMBL566208
9.28Ki0.527nMHOMOEPIBATIDINE
9.26IC500.55nMCHEMBL4443845
9.24IC500.57nMCHEMBL4585225
9.24IC500.58nMCHEMBL566886
9.21IC500.62nMCHEMBL566050
9.19IC500.65nMCHEMBL4463134
9.19IC500.65nMCHEMBL565844
9.16Ki0.684nMCHEMBL4163848
9.15IC500.7nMCHEMBL569465
9.13Ki0.748nMCHEMBL1209124
9.12IC500.75nMCHEMBL429557
9.10Ki0.799nMCHEMBL4170527
9.09Ki0.818nMCHEMBL4163257
9.07Ki0.856nMCHEMBL1209126
9.05Ki0.882nMCHEMBL1209072
9.04IC500.92nMCHEMBL4531333
9.03Ki0.944nMCHEMBL363973
9.03Ki0.925nMHOMOEPIBATIDINE
9.03IC500.93nMCHEMBL425006
9.02IC500.95nMCHEMBL4440025
9.02Ki0.957nMCHEMBL1209184

PubChem BioAssay actives

1157 with measured affinity, of 2985 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

CompoundAssayTypeValueUnit
2-(6-chloro-3-pyridinyl)-7-azabicyclo[2.2.1]heptane1359525: Displacement of [3H]epibatidine from human alpha3beta4 nAChR expressed in HEK293 cell membraneski0.0001uM
N-[5-[2-[[(1R,5R,6S)-3-azabicyclo[3.2.1]octan-6-yl]oxy]phenyl]-3-pyridinyl]ethanesulfonamide;hydrochloride495033: Displacement of [3H]epibatidine from alpha3beta4 nicotinic receptor expressed in human HEK293 cellski0.0001uM
N-[5-[2-[[(1R,5R,6S)-3-azabicyclo[3.2.1]octan-6-yl]oxy]phenyl]-3-pyridinyl]propane-2-sulfonamide;hydrochloride495033: Displacement of [3H]epibatidine from alpha3beta4 nicotinic receptor expressed in human HEK293 cellski0.0001uM
(1R,2R,4S)-2-(6-chloro-3-pyridinyl)-7-azabicyclo[2.2.1]heptane1563867: Displacement of [3H]epibatidine from human alpha3beta4 nAChR transfected in HEK243 cell membraneki0.0001uM
3-[(1R,6R,9S,12S,15S,21S,24S,27S,30S,33R,36S,39S,45S,48S,53R)-53-[(2-aminoacetyl)amino]-24-(3-carbamimidamidopropyl)-6-carbamoyl-48-(hydroxymethyl)-21,30,45-tris(1H-imidazol-5-ylmethyl)-9-(2-methylpropyl)-8,11,14,20,23,26,29,32,35,38,44,47,50,52-tetradecaoxo-27,36-di(propan-2-yl)-3,4,55,56-tetrathia-7,10,13,19,22,25,28,31,34,37,43,46,49,51-tetradecazatetracyclo[31.17.7.015,19.039,43]heptapentacontan-12-yl]propanoic acid1753051: Inhibition of human alpha6/alpha3beta4 nAChR expressed in Xenopus laevis oocytes assessed as inhibition of acetylcholine-induced current response measured after 5 min by two-electrode voltage-clamp methodic500.0002uM
3-[(1R,6R,9S,12S,15S,21S,24S,27S,30S,33R,36S,39S,45S,48S,53R)-53-[(2-aminoacetyl)amino]-24,30-bis(2-amino-2-oxoethyl)-9-[(2S)-butan-2-yl]-6-carbamoyl-48-(hydroxymethyl)-21,45-bis(1H-imidazol-5-ylmethyl)-8,11,14,20,23,26,29,32,35,38,44,47,50,52-tetradecaoxo-27,36-di(propan-2-yl)-3,4,55,56-tetrathia-7,10,13,19,22,25,28,31,34,37,43,46,49,51-tetradecazatetracyclo[31.17.7.015,19.039,43]heptapentacontan-12-yl]propanoic acid1753051: Inhibition of human alpha6/alpha3beta4 nAChR expressed in Xenopus laevis oocytes assessed as inhibition of acetylcholine-induced current response measured after 5 min by two-electrode voltage-clamp methodic500.0002uM
7-(6-chloro-3-pyridinyl)-2-azabicyclo[2.2.1]heptane276250: Displacement of [3H]epibatidine from human recombinant alpha-3-beta-4 nAChR in HEK293 cells by SPA assayki0.0002uM
3-(6-chloro-3-pyridinyl)-3,6-diazabicyclo[3.1.1]heptane1252850: Displacement of [3H]-Epibatidine from human aplha3beta4 nAChR expressed in HEK293 cells pre-incubated for 5 mins followed by overnight incubation by radioligand liquid scintillation counter analysiski0.0002uM
(2S)-N-[3-[4-(3-aminopropylamino)butylamino]propyl]-3-cyclohexyl-2-[(2-naphthalen-1-ylacetyl)amino]propanamide1563140: Antagonist activity at alpha3beta4 nAChR (unknown origin) expressed in Xenopus laevis oocytes assessed as inhibition of Ach-induced channel activation at -100 mV holding potential treated for 1 min by two electrode voltage-clamp assayic500.0002uM
5-[2-[[(1R,5R,6S)-3-azabicyclo[3.2.1]octan-6-yl]oxy]phenyl]pyridin-3-ol;hydrochloride495033: Displacement of [3H]epibatidine from alpha3beta4 nicotinic receptor expressed in human HEK293 cellski0.0002uM
N-[5-[2-[[(1R,5R,6S)-3-azabicyclo[3.2.1]octan-6-yl]oxy]phenyl]-3-pyridinyl]methanesulfonamide;hydrochloride495033: Displacement of [3H]epibatidine from alpha3beta4 nicotinic receptor expressed in human HEK293 cellski0.0002uM
(2S)-N-[3-[4-(3-aminopropylamino)butylamino]propyl]-3-cyclohexyl-2-[[(E)-3-phenylprop-2-enoyl]amino]propanamide1563140: Antagonist activity at alpha3beta4 nAChR (unknown origin) expressed in Xenopus laevis oocytes assessed as inhibition of Ach-induced channel activation at -100 mV holding potential treated for 1 min by two electrode voltage-clamp assayic500.0003uM
3-[(1R,6R,9S,12S,15S,21S,24S,27S,30S,33R,36S,39S,45S,48S,53R)-53-[(2-aminoacetyl)amino]-30-(2-amino-2-oxoethyl)-24-(3-carbamimidamidopropyl)-6-carbamoyl-48-(hydroxymethyl)-21,45-bis(1H-imidazol-5-ylmethyl)-9-(2-methylpropyl)-8,11,14,20,23,26,29,32,35,38,44,47,50,52-tetradecaoxo-27,36-di(propan-2-yl)-3,4,55,56-tetrathia-7,10,13,19,22,25,28,31,34,37,43,46,49,51-tetradecazatetracyclo[31.17.7.015,19.039,43]heptapentacontan-12-yl]propanoic acid1753051: Inhibition of human alpha6/alpha3beta4 nAChR expressed in Xenopus laevis oocytes assessed as inhibition of acetylcholine-induced current response measured after 5 min by two-electrode voltage-clamp methodic500.0003uM
(3S)-3-[[(2S)-5-amino-2-[[(2S)-4-amino-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2R)-2-[[2-[(2-aminoacetyl)amino]acetyl]amino]-3-sulfanylpropanoyl]amino]-3-sulfanylpropanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-imidazol-4-yl)propanoyl]pyrrolidine-2-carbonyl]amino]propanoyl]amino]-3-sulfanylpropanoyl]amino]propanoyl]amino]propanoyl]amino]-4-oxobutanoyl]amino]-4-oxobutanoyl]amino]-5-oxopentanoyl]amino]-4-[[(2S)-1-[[(2R)-1-amino-1-oxo-3-sulfanylpropan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-4-oxobutanoic acid241633: Inhibitory concentration against Nicotinic acetylcholine receptor alpha3-beta4ic500.0003uM
N-[(2S)-1-[3-[4-(3-aminopropylamino)butylamino]propylamino]-3-cyclohexyl-1-oxopropan-2-yl]benzamide1563140: Antagonist activity at alpha3beta4 nAChR (unknown origin) expressed in Xenopus laevis oocytes assessed as inhibition of Ach-induced channel activation at -100 mV holding potential treated for 1 min by two electrode voltage-clamp assayic500.0004uM
3-[(1R,6R,9S,12S,15S,21S,24S,27S,30S,33R,36S,39S,45S,48S,53R)-53-[(2-aminoacetyl)amino]-9-[(2S)-butan-2-yl]-24-(3-carbamimidamidopropyl)-6-carbamoyl-48-(hydroxymethyl)-21,30,45-tris(1H-imidazol-5-ylmethyl)-8,11,14,20,23,26,29,32,35,38,44,47,50,52-tetradecaoxo-27,36-di(propan-2-yl)-3,4,55,56-tetrathia-7,10,13,19,22,25,28,31,34,37,43,46,49,51-tetradecazatetracyclo[31.17.7.015,19.039,43]heptapentacontan-12-yl]propanoic acid1753051: Inhibition of human alpha6/alpha3beta4 nAChR expressed in Xenopus laevis oocytes assessed as inhibition of acetylcholine-induced current response measured after 5 min by two-electrode voltage-clamp methodic500.0004uM
N-[3-[2-[[(1R,5R,6S)-3-azabicyclo[3.2.1]octan-6-yl]oxy]phenyl]-4-pyridinyl]methanesulfonamide;hydrochloride495033: Displacement of [3H]epibatidine from alpha3beta4 nicotinic receptor expressed in human HEK293 cellski0.0004uM
N-[(2S)-1-[3-[4-(3-aminopropylamino)butylamino]propylamino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]cyclohexanecarboxamide1563140: Antagonist activity at alpha3beta4 nAChR (unknown origin) expressed in Xenopus laevis oocytes assessed as inhibition of Ach-induced channel activation at -100 mV holding potential treated for 1 min by two electrode voltage-clamp assayic500.0005uM
6-(6-chloro-3-pyridinyl)-8-azabicyclo[3.2.1]octane276250: Displacement of [3H]epibatidine from human recombinant alpha-3-beta-4 nAChR in HEK293 cells by SPA assayki0.0005uM
2-(tert-butylamino)-1-(3,4-dichlorophenyl)butan-1-one459714: Antagonist activity at alpha3beta4 nAChR receptor in human SH-SY5Y cells assessed as inhibition of carbamylcholine-induced 86Rb+ efflux by liquid scintillation countingic500.0005uM
N-[(2S)-1-[3-[4-(3-aminopropylamino)butylamino]propylamino]-3-cyclohexyl-1-oxopropan-2-yl]cycloheptanecarboxamide1563140: Antagonist activity at alpha3beta4 nAChR (unknown origin) expressed in Xenopus laevis oocytes assessed as inhibition of Ach-induced channel activation at -100 mV holding potential treated for 1 min by two electrode voltage-clamp assayic500.0006uM
N-[(2S)-1-[3-[4-(3-aminopropylamino)butylamino]propylamino]-3-cyclohexyl-1-oxopropan-2-yl]cyclopentanecarboxamide1563140: Antagonist activity at alpha3beta4 nAChR (unknown origin) expressed in Xenopus laevis oocytes assessed as inhibition of Ach-induced channel activation at -100 mV holding potential treated for 1 min by two electrode voltage-clamp assayic500.0006uM
N-[(2S)-1-[3-[4-(3-aminopropylamino)butylamino]propylamino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]cyclopentanecarboxamide1563140: Antagonist activity at alpha3beta4 nAChR (unknown origin) expressed in Xenopus laevis oocytes assessed as inhibition of Ach-induced channel activation at -100 mV holding potential treated for 1 min by two electrode voltage-clamp assayic500.0006uM
2-(tert-butylamino)-1-(3-chlorophenyl)butan-1-one459714: Antagonist activity at alpha3beta4 nAChR receptor in human SH-SY5Y cells assessed as inhibition of carbamylcholine-induced 86Rb+ efflux by liquid scintillation countingic500.0006uM
2-(tert-butylamino)-1-(3-chloro-4-methylphenyl)propan-1-one459714: Antagonist activity at alpha3beta4 nAChR receptor in human SH-SY5Y cells assessed as inhibition of carbamylcholine-induced 86Rb+ efflux by liquid scintillation countingic500.0006uM
2-(tert-butylamino)-1-(3,4-dichlorophenyl)pentan-1-one459714: Antagonist activity at alpha3beta4 nAChR receptor in human SH-SY5Y cells assessed as inhibition of carbamylcholine-induced 86Rb+ efflux by liquid scintillation countingic500.0006uM
5-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-N-(4-nitrophenyl)pyridin-3-amine1359525: Displacement of [3H]epibatidine from human alpha3beta4 nAChR expressed in HEK293 cell membraneski0.0007uM
2-(tert-butylamino)-1-(3-chlorophenyl)pentan-1-one459714: Antagonist activity at alpha3beta4 nAChR receptor in human SH-SY5Y cells assessed as inhibition of carbamylcholine-induced 86Rb+ efflux by liquid scintillation countingic500.0007uM
5-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-N-phenylpyridin-3-amine1359525: Displacement of [3H]epibatidine from human alpha3beta4 nAChR expressed in HEK293 cell membraneski0.0008uM
5-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-N-[4-(trifluoromethyl)phenyl]pyridin-2-amine1359525: Displacement of [3H]epibatidine from human alpha3beta4 nAChR expressed in HEK293 cell membraneski0.0008uM
(3S)-3-[[(2S)-1-[(2S)-4-amino-2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S)-1-[(2S)-1-[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2R)-2-[(2-aminoacetyl)amino]-3-sulfanylpropanoyl]amino]-3-sulfanylpropanoyl]amino]-3-hydroxypropanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]pyrrolidine-2-carbonyl]pyrrolidine-2-carbonyl]amino]-3-sulfanylpropanoyl]amino]-3-phenylpropanoyl]amino]propanoyl]amino]-3-hydroxybutanoyl]amino]-4-oxobutanoyl]pyrrolidine-2-carbonyl]amino]-4-oxo-4-[[(2R)-1-oxo-3-sulfanylpropan-2-yl]amino]butanoic acid242203: Inhibitory concentration against Nicotinic acetylcholine receptor alpha2-beta4; Range is 0.3-1.5 nMic500.0008uM
5-(6-chloro-3-pyridinyl)-2-azabicyclo[2.2.1]heptane276250: Displacement of [3H]epibatidine from human recombinant alpha-3-beta-4 nAChR in HEK293 cells by SPA assayki0.0009uM
N-[(2S)-1-[3-[4-(3-aminopropylamino)butylamino]propylamino]-1-oxo-3-phenylpropan-2-yl]butanamide1563140: Antagonist activity at alpha3beta4 nAChR (unknown origin) expressed in Xenopus laevis oocytes assessed as inhibition of Ach-induced channel activation at -100 mV holding potential treated for 1 min by two electrode voltage-clamp assayic500.0009uM
(2S)-N-[3-[4-(3-aminopropylamino)butylamino]propyl]-2-[[2-(2-bicyclo[2.2.1]heptanyl)acetyl]amino]-3-cyclohexylpropanamide1563140: Antagonist activity at alpha3beta4 nAChR (unknown origin) expressed in Xenopus laevis oocytes assessed as inhibition of Ach-induced channel activation at -100 mV holding potential treated for 1 min by two electrode voltage-clamp assayic500.0009uM
N-[(2S)-1-[3-[[(1R,2R)-2-[(3-aminopropylamino)methyl]cyclopropyl]methylamino]propylamino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]butanamide1563140: Antagonist activity at alpha3beta4 nAChR (unknown origin) expressed in Xenopus laevis oocytes assessed as inhibition of Ach-induced channel activation at -100 mV holding potential treated for 1 min by two electrode voltage-clamp assayic500.0009uM
(1R,5R,6S)-6-[2-(4-methoxy-3-pyridinyl)phenoxy]-3-azabicyclo[3.2.1]octane;hydrochloride495033: Displacement of [3H]epibatidine from alpha3beta4 nicotinic receptor expressed in human HEK293 cellski0.0009uM
(1R,5R,6S)-6-[2-(4-fluoro-3-pyridinyl)phenoxy]-3-azabicyclo[3.2.1]octane;hydrochloride495033: Displacement of [3H]epibatidine from alpha3beta4 nicotinic receptor expressed in human HEK293 cellski0.0009uM
4-[[5-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-3-pyridinyl]amino]phenol1359525: Displacement of [3H]epibatidine from human alpha3beta4 nAChR expressed in HEK293 cell membraneski0.0010uM
5-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-N-[4-(trifluoromethyl)phenyl]pyridin-3-amine1359525: Displacement of [3H]epibatidine from human alpha3beta4 nAChR expressed in HEK293 cell membraneski0.0010uM
(1R,15R,17S,18S)-17-ethyl-7-methoxy-3,13-diazapentacyclo[13.3.1.02,10.04,9.013,18]nonadeca-2(10),4(9),5,7-tetraene1973135: Displacement of [3H]Ibogaine from human alpha3beta4 nAChRs expressed in HEK293 cells assessed as inhibition constant incubated for 2 hrs by scintillation counter analysiski0.0010uM
(3S)-3-amino-4-[(2S)-2-[[(2R)-1-[[(2R)-1-[[(2S)-1-[[(2S)-4-amino-1-[(2S)-2-[[(2S)-1-[[(2R)-1-[[(2S,3R)-1-[[(2S)-1-[[(2S)-1-[[(2S)-4-amino-1-[(2S)-2-[[(2S)-5-amino-1-[[(2S,3S)-1-[[(2R)-1-amino-1-oxo-3-sulfanylpropan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-1,5-dioxopentan-2-yl]carbamoyl]pyrrolidin-1-yl]-1,4-dioxobutan-2-yl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-1-oxo-3-sulfanylpropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]carbamoyl]pyrrolidin-1-yl]-1,4-dioxobutan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-1-oxo-3-sulfanylpropan-2-yl]amino]-1-oxo-3-sulfanylpropan-2-yl]carbamoyl]pyrrolidin-1-yl]-4-oxobutanoic acid242122: Inhibitory concentration against Nicotinic acetylcholine receptor alpha3-beta4; Range is 0.7-1 nMic500.0010uM
3-[2-[[(1R,5R,6S)-3-azabicyclo[3.2.1]octan-6-yl]oxy]phenyl]pyridin-4-amine;hydrochloride495033: Displacement of [3H]epibatidine from alpha3beta4 nicotinic receptor expressed in human HEK293 cellski0.0010uM
N-[(2S)-1-[3-[4-(3-aminopropylamino)butylamino]propylamino]-3-cyclohexyl-1-oxopropan-2-yl]cyclobutanecarboxamide1563140: Antagonist activity at alpha3beta4 nAChR (unknown origin) expressed in Xenopus laevis oocytes assessed as inhibition of Ach-induced channel activation at -100 mV holding potential treated for 1 min by two electrode voltage-clamp assayic500.0011uM
N-(4-chlorophenyl)-5-(3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-amine1359525: Displacement of [3H]epibatidine from human alpha3beta4 nAChR expressed in HEK293 cell membraneski0.0012uM
2-[tert-butyl(methyl)amino]-1-(3-chlorophenyl)propan-1-one459714: Antagonist activity at alpha3beta4 nAChR receptor in human SH-SY5Y cells assessed as inhibition of carbamylcholine-induced 86Rb+ efflux by liquid scintillation countingic500.0012uM
(1R,5R,6S)-6-(2-pyridin-3-ylphenoxy)-3-azabicyclo[3.2.1]octane;hydrochloride495033: Displacement of [3H]epibatidine from alpha3beta4 nicotinic receptor expressed in human HEK293 cellski0.0012uM
5-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-N-(4-fluorophenyl)pyridin-3-amine1359525: Displacement of [3H]epibatidine from human alpha3beta4 nAChR expressed in HEK293 cell membraneski0.0013uM
1-(3-bromophenyl)-2-(tert-butylamino)propan-1-one459714: Antagonist activity at alpha3beta4 nAChR receptor in human SH-SY5Y cells assessed as inhibition of carbamylcholine-induced 86Rb+ efflux by liquid scintillation countingic500.0013uM
N-[5-[2-[[(1S,5S,6R)-3-azabicyclo[3.2.1]octan-6-yl]oxy]phenyl]-3-pyridinyl]methanesulfonamide;hydrochloride495033: Displacement of [3H]epibatidine from alpha3beta4 nicotinic receptor expressed in human HEK293 cellski0.0013uM
5-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-N-(4-methylphenyl)pyridin-3-amine1359525: Displacement of [3H]epibatidine from human alpha3beta4 nAChR expressed in HEK293 cell membraneski0.0014uM

CTD chemical–gene interactions

58 total (human), top 30 by PubMed support.

ChemicalActions (top 5)PubMed papers
Acetylcholinedecreases reaction, increases activity, affects binding, affects reaction, increases reaction (+2 more)6
epibatidinedecreases reaction, increases activity, affects binding3
bisphenol Adecreases methylation, affects activity, affects binding, decreases reaction, increases reaction2
entinostatincreases expression, affects cotreatment2
Estradiolaffects cotreatment, increases expression, affects activity, affects binding, decreases reaction (+1 more)2
Nicotineaffects binding, increases activity2
Tubocurarineaffects binding, decreases reaction, increases activity2
triptolideaffects binding, decreases reaction, increases activity1
cytisineaffects binding, increases activity1
propionaldehydedecreases expression1
crotonyl alcoholincreases reaction, increases transport, affects binding, decreases reaction1
N’-nitrosonornicotineaffects binding1
decabromobiphenyl etherincreases expression1
tetrabromobisphenol Aincreases expression1
n-pentanoldecreases reaction, increases reaction, increases transport, affects binding1
coumarindecreases phosphorylation1
isobutyl alcoholaffects binding, affects reaction, increases reaction, increases transport1
tetrachlorodianincreases expression1
4-nonylphenoldecreases reaction, increases reaction, affects activity, affects binding1
2-butanolaffects reaction, increases reaction, increases transport, affects binding1
celastrolincreases activity, affects binding, decreases reaction1
4-octylphenolaffects activity, affects binding, decreases reaction1
imidaclopridaffects binding, increases activity1
CGP 52608affects binding, increases reaction1
cisatracuriumaffects binding, decreases reaction, increases activity1
4-((2-(1-methyl-2-pyrrolidinyl)ethyl)thio)phenol hydrochlorideaffects binding, increases activity1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamideaffects cotreatment, increases expression1
1,2-bis-N-cytisinylethaneaffects binding, increases reaction, increases localization1
2,2’,4,4’-tetrabromodiphenyl etherincreases expression1
dorsomorphinincreases expression, affects cotreatment1

ChEMBL screening assays

407 unique, capped per target: 309 binding, 96 functional, 2 admet

Representative assays (with source publication via chembl_document):

Assay IDTypeDescriptionSource paper
CHEMBL1020768BindingDisplacement of [3H]epibatidine from alpha4beta4 nAChR expressed in HEK293 cellsCarbamoylcholine analogs as nicotinic acetylcholine receptor agonists–structural modifications of 3-(dimethylamino)butyl dimethylcarbamate (DMABC). — Bioorg Med Chem Lett
CHEMBL1068091FunctionalAntagonist activity at human alpha4beta4 nAChR receptor expressed in human SH-SY5Y cells assessed as inhibition of carbamylcholine-induced 86Rb+ efflux by liquid scintillation countingSynthesis and biological evaluation of bupropion analogues as potential pharmacotherapies for smoking cessation. — J Med Chem
CHEMBL4603065ADMETInhibition of human alpha3beta4 nAChR assessed as increase in acetylcholine-induced normalized current at 2 uM (Rvb = 78.5 +/- 10 uM)Differentiating the Pharmacodynamics and Toxicology of Macrolide and Ketolide Antibiotics. — J Med Chem

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

CellosaurusNameCategorySex
CVCL_D1KFPrecisION hnAChR alpha3/beta4-HEKTransformed cell lineFemale

Clinical trials (associated diseases)

455 trials via MONDO — disease-level, not drug-specific.

TrialPhaseStatusTitle
NCT00158041PHASE4COMPLETEDSubcutaneous Amifostine Safety Study
NCT00277160PHASE4COMPLETEDA Study of Primary Prophylaxis With Neulasta (Pegfilgrastim) Versus Secondary Prophylaxis After Chemotherapy in Elderly Subjects (>/= 65 Years Old) With Cancer
NCT00365508PHASE4COMPLETEDCounseling and Nicotine Replacement Therapy in Helping Adult Smokers Quit Smoking
NCT00440960PHASE4COMPLETEDAnesthesia in Flexible Bronchoscopy for Lung Cancer Diagnostic
NCT00492843PHASE4TERMINATEDLoading Dose or Standard Dose of Intravenous Ibandronate in Treating Patients With Lung Cancer and Skeletal Metastasis
NCT00666978PHASE4COMPLETEDHealth Education Counseling With or Without Bupropion in Helping African Americans Stop Smoking
NCT00675168PHASE4UNKNOWNPositron Emission Tomography (PET)/Computed Tomography (CT) and Roentgen in Lung Cancer: Evaluation of Patients in General Practice
NCT00712647PHASE4COMPLETEDCarotene and Retinol Efficacy Trial
NCT00747773PHASE4COMPLETEDCryospray Ablation of Surgical Resection Specimens To Determine Safety And Histological Effect In The Lung
NCT01060137PHASE4COMPLETEDFentanyl Matrix in Lung Cancer Pain
NCT01381627PHASE4UNKNOWNSafety Evaluation of Dexmedetomidine for EBUS-TBNA
NCT01741506PHASE4COMPLETEDCoagulation Profile in Patients Undergoing Video Assisted Thorascopic Surgery (VATS) for Lung Cancer
NCT02246023PHASE4COMPLETEDFractionated Versus Target-controlled Propofol Administration in Bronchoscopy
NCT02275702PHASE4COMPLETEDRandomized Study of Preoperative Dexamethasone for Quality of Recovery in VATS Lung Resection Patients
NCT02346318PHASE4UNKNOWNThe Randomized Controlled Clinical Trial of Kushen Injection
NCT02476526PHASE4COMPLETEDSafety of Low Dose IV Contrast CT Scanning in Chronic Kidney Disease
NCT02490059PHASE4COMPLETEDUltrathin Bronchoscopy for Solitary Pulmonary Nodules
NCT02504801PHASE4UNKNOWNEfficacy of Nebulized Pulmicort Respules in Primary Lung Cancer Patients With COPD
NCT02869789PHASE4COMPLETEDAn Investigational Immuno-therapy Study for Safety of Nivolumab in Combination With Ipilimumab to Treat Advanced Cancers
NCT03302221PHASE4WITHDRAWNRegional Haemodynamic Changes in Radial Artery Assessment With Continuous Pulsed-wave Doppler Ultrasound
NCT03313544PHASE4UNKNOWNEvolution of the Heart Function When Monitoring Immunotherapies Anti-cancerous Inhibiting PD-1
NCT03394222PHASE4COMPLETEDEffect of Preoperative Budesonide Inhalation on Arterial Blood Oxygenation and Intrapulmonary Shunt During OLV
NCT03570645PHASE4COMPLETEDComparison of the Duration of Ropivacaine Combined With Dexmedetomidine or Dexamethasone on Paravertebral Block
NCT03571126PHASE4UNKNOWNOlanzapine for the Prevention and Treatment of Nausea and Vomiting Induced by Chemotherapy of Lung Cancer
NCT03642457PHASE4TERMINATEDEfficacy Between Serratus Plane Block And Local Infiltration In Vats
NCT04145570PHASE4COMPLETEDA Single-Dose,ComparativeBioavailability Study ofTwo Formulations ofErlotinib150mgTabletsunderFastingConditions
NCT04155008PHASE4TERMINATEDNutrition and Pharmacological Algorithm for Oncology Patients Study
NCT04613284PHASE4UNKNOWNRh-Endostatin Combined With CCRT(50 Gy) Followed by Durvalumab Maintenance for the Treatment of Specific Phase III NSCLC
NCT05463913PHASE4RECRUITINGLung Nodule Detection Using Ultra-long FOV PET/CT
NCT05521789PHASE4RECRUITINGErector Spinae Block for Thoracic Surgery
NCT05525338PHASE4RECRUITINGComparison of Standard Dose Alectinib to Alectinib in Adjusted Dose Based on Alectinib Bloodlevels
NCT05663242PHASE4RECRUITINGThe Effects of Using Different Anesthetics on the Prognosis of Primary Lung Tumors and Its Mechanism of Action
NCT05926336PHASE4RECRUITINGThe Effects of Using Different Anesthetics on the Prognosis of Primary Tumors and Its Mechanism of Action
NCT06105801PHASE4RECRUITINGEBUS-TBNA vs Transbronchial Mediastinal Cryobiopsy for Adequacy of Next Generation Sequencing
NCT06276933PHASE4NOT_YET_RECRUITINGA Study of Camrelizumab Combined With Chemotherapy ± Thalidomide in First-line Treatment of Patients With Advanced Non-small Cell Lung Cancer (NSCLC)
NCT06646471PHASE4RECRUITINGPROspective Master-protocol for Evaluation of Systemic THErapeutics in Elderly With Thoracic Malignancies
NCT07405086PHASE4RECRUITINGMorning Versus Afternoon Administration of Immunotherapy for the Treatment of Advanced or Metastatic Solid Tumors, The Knight SHIFT Study
NCT00376051PHASE4COMPLETEDSerotonergic Function and Behavioural and Psychological Symptoms of Frontotemporal Dementia
NCT00950430PHASE4ENROLLING_BY_INVITATIONImaging of Brain Amyloid Plaques in the Aging Population
NCT06093126PHASE4RECRUITINGLemborexant for Insomnia in a Patient With Dementia: An N-of-1 Trial