CHRNA3: Cholinergic Receptor Nicotinic Alpha 3 Subunit
Genetic insights into nicotine dependence, lung cancer susceptibility, and autonomic nervous system function
Gene Information Card
| Symbol | CHRNA3 |
|---|---|
| Full Name | Cholinergic Receptor Nicotinic Alpha 3 Subunit |
| Gene Type | protein-coding |
| Chromosomal Location | 15q25.1 |
| NCBI Gene ID | 1136 ncbi.nlm.nih.gov/gene/1136 |
| Ensembl ID | ENSG00000180644 |
| UniProt ID | P32297 |
| OMIM ID | 118503 |
| HGNC ID | 1957 |
| Aliases | NACHRA3, CHRNA3, LNCR2 |
Description
CHRNA3 encodes the alpha-3 subunit of the neuronal nicotinic acetylcholine receptor (nAChR), a pentameric ligand-gated ion channel that mediates fast synaptic transmission in the central and peripheral nervous systems. The alpha-3 subunit is essential for ganglionic neurotransmission in autonomic ganglia and modulates dopamine release in reward pathways. Genetic variants in CHRNA3 are strongly associated with nicotine dependence, smoking quantity, and increased risk for lung cancer and chronic obstructive pulmonary disease (COPD). The gene is part of the CHRNA5-CHRNA3-CHRNB4 cluster on chromosome 15q25.1.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Nicotine dependence | Altered receptor function due to CHRNA3 variants (e.g., rs1051730) affects nicotine binding and reward signaling, increasing addiction risk. | GWAS meta-analysis (Thorgeirsson et al., 2008, Nature) and multiple replication studies. |
| Lung cancer | CHRNA3 variants (rs1051730, rs16969968) are associated with increased lung cancer risk, partly mediated through smoking behavior but also through direct effects on lung tissue. | Case-control studies (Amos et al., 2008, Nat Genet; Hung et al., 2008, Nature). |
| Chronic obstructive pulmonary disease (COPD) | CHRNA3 polymorphisms contribute to COPD susceptibility via altered inflammatory responses and smoking behavior. | Genome-wide association studies (Pillai et al., 2009, PLoS Genet). |
| Autonomic nervous system dysfunction | Mutations in CHRNA3 can impair ganglionic transmission, leading to autonomic failure, including impaired heart rate regulation. | Rare variant studies and functional assays (Wang et al., 2002, J Biol Chem). |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Brain (cerebellum, frontal cortex) | 3.2 | Medium |
| Lung | 1.8 | Low |
| Adrenal gland | 5.6 | High |
| Autonomic ganglia | 8.1 | High |
| Placenta | 0.9 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| SH-SY5Y (neuroblastoma) | 4.5 | Endogenous expression; used in nAChR studies |
| HEK293 (embryonic kidney) | 0.2 | Low; often used for heterologous expression |
| A549 (lung carcinoma) | 1.1 | Moderate; relevant for lung cancer research |
| IMR-32 (neuroblastoma) | 6.0 | High; model for neuronal nAChR |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| rs1051730 (c.645G>A, p.Arg215His) | SNP (missense) | 0.35 (European) | Reduced receptor function; associated with nicotine dependence and lung cancer |
| rs16969968 (c.1192G>A, p.Asp398Asn) | SNP (missense) | 0.37 (European) | Altered agonist sensitivity; linked to smoking behavior |
| c.1A>G (p.Met1Val) | Missense | <0.01 | Loss of start codon; rare, likely pathogenic in autonomic dysfunction |
Mutation functional classification
Loss of Function (LOF)
rs1051730 (p.Arg215His) reduces channel conductance and calcium permeability, leading to decreased nAChR activity.
Gain of Function (GOF)
No well-characterized gain-of-function mutations reported in CHRNA3.
Dominant Negative (DN)
Heterozygous missense mutations in the transmembrane domain may exert dominant-negative effects on receptor assembly, though evidence is limited.
View complete mutation data：
Gene Ontology (GO)
| • transmembrane signaling receptor activity (GO:0004888) | • extracellular ligand-gated ion channel activity (GO:0005230) |
| • nicotinic acetylcholine-gated receptor complex (GO:0005892) | • ion transport (GO:0006811) |
| • chemical synaptic transmission (GO:0007268) | • regulation of dopamine secretion (GO:0014059) |
| • postsynaptic membrane (GO:0045211) |
Pathways
• Nicotine addiction (KEGG: hsa05033)
• Neuroactive ligand-receptor interaction (KEGG: hsa04080)
• Acetylcholine binding and downstream events (Reactome: R-HSA-629587)
Protein Summary
The CHRNA3 protein (UniProt P32297) is a 505-amino acid integral membrane protein with four transmembrane domains (M1-M4), a large extracellular N-terminal domain containing the acetylcholine-binding site, and a cytoplasmic loop between M3 and M4 that modulates receptor trafficking and phosphorylation. It assembles as a pentamer with other nAChR subunits (e.g., beta-2, beta-4, alpha-5) to form functional ion channels. The alpha-3 subunit is critical for fast cholinergic transmission in autonomic ganglia and contributes to nicotine's reinforcing effects in the brain. Post-translational modifications include N-glycosylation at Asn46 and Asn110, which are essential for receptor assembly and surface expression.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| CHRNA3 Knockout HEK293 Cell Line | EDJ-KQ3236 | Human | 1136 | Details Get a Quote |
| CHRNA3 Knockout A-549 Cell Line | EDJ-KQ24747 | Human | 1136 | Details Get a Quote |
| CHRNA3 Knockout HCT 116 Cell Line | EDJ-KQ24748 | Human | 1136 | Details Get a Quote |
| CHRNA3 Knockout HeLa Cell Line | EDJ-KQ52902 | Human | 1136 | Details Get a Quote |
