Details for: CHRNA3

Gene ID: 1136

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: CHRNA3

Ensembl ID: ENSG00000080644

Description: cholinergic receptor nicotinic alpha 3 subunit

Cell Significance Landscape

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • peripheral nervous system neuron CL2000032
    CSI 8.17
    rCSI 11.14%
    PRS 99.79
  • double-positive, alpha-beta thymocyte CL0000809
    CSI 4.39
    rCSI 4.48%
    PRS 99.88
  • retinal pigment epithelial cell CL0002586
    CSI 4.31
    rCSI 8.56%
    PRS 99.77
  • retinal cone cell CL0000573
    CSI 3.68
    rCSI 5.93%
    PRS 99.45
  • neural cell CL0002319
    CSI 3.38
    rCSI 12.74%
    PRS 99.84
  • retinal ganglion cell CL0000740
    CSI 1.88
    rCSI 4.16%
    PRS 99.75
  • enteric neuron CL0007011
    CSI 1.22
    rCSI 18.08%
    PRS 99.64

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

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Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [CHRNA3](/details-gene/1136), or Cholinergic Receptor Nicotinic Alpha 3 Subunit, is a protein-coding gene located on chromosome 15q25.1. It encodes the alpha-3 subunit of neuronal nicotinic acetylcholine receptors (nAChRs), which are ligand-gated ion channels crucial for fast synaptic transmission in the nervous system. **Overall**, expression data highlights [CHRNA3](/details-gene/1136) as a definitive marker for various neuronal populations, most significantly in [peripheral nervous system neuron](/details-cell/CL2000032). Its function is central to cholinergic signaling, mediating cellular responses to acetylcholine and nicotine. Notably, its significant expression in non-neuronal cells, such as [double-positive, alpha-beta thymocyte](/details-cell/CL0000809), suggests a potential role in immune system development, an area of emerging research. Genetic variants in this gene have been linked to nicotine dependence and increased susceptibility to lung cancer ([Link](https://doi.org/10.1038/nature06885); [Link](https://doi.org/10.1038/nature06846)). ## Cellular Roles and Expression Landscape The expression profile of [CHRNA3](/details-gene/1136) firmly establishes its primary role within the nervous system. It exhibits the highest significance in [peripheral nervous system neuron](/details-cell/CL2000032) (CSI: 8.17), with strong signals also observed in [neural cell](/details-cell/CL0002319), [enteric neuron](/details-cell/CL0007011), and specialized cells of the visual system, including [retinal pigment epithelial cell](/details-cell/CL0002586), [retinal cone cell](/details-cell/CL0000573), and [retinal ganglion cell](/details-cell/CL0000740). This pattern underscores its integral function in mediating fast synaptic transmission in both the central and peripheral nervous systems. A compelling and less canonical role for [CHRNA3](/details-gene/1136) is suggested by its high significance in [double-positive, alpha-beta thymocyte](/details-cell/CL0000809) (CSI: 4.39), a critical stage of T-cell development. This finding, supported by early research identifying nAChR subunit transcripts in the human thymus ([Link](https://doi.org/10.1016/0014-4886(91)90004-v)), points towards a function for non-neuronal cholinergic signaling within the immune system. This "cholinergic immune regulation" may play a part in modulating thymocyte selection, maturation, or survival, extending the gene's functional context beyond classical neurobiology. ## Pathways and Molecular Function The molecular functions of [CHRNA3](/details-gene/1136) are intrinsically linked to its role as a component of nAChR channel complexes. Gene Ontology annotations confirm its involvement in [Acetylcholine binding](/details-go/GO:0042166) and [Acetylcholine-gated monoatomic cation-selective channel activity](/details-go/GO:0022848), which are fundamental to its function. These molecular activities drive key biological processes, including [Synaptic transmission, cholinergic](/details-go/GO:0007271), [Membrane depolarization](/details-go/GO:0051899), and the broader process of [Signal transduction](/details-go/GO:0007165). Consistent with its high expression in neuronal tissues, [CHRNA3](/details-gene/1136) is a key participant in the Reactome pathway [Neuronal system](/details-reactome/R-HSA-112316), specifically in [Transmission across chemical synapses](/details-reactome/R-HSA-112315). The receptor complexes it forms are involved in both [Presynaptic nicotinic acetylcholine receptors](/details-reactome/R-HSA-622323) and [Postsynaptic nicotinic acetylcholine receptors](/details-reactome/R-HSA-622327). Furthermore, its role in mediating the physiological effects of xenobiotics is highlighted by its involvement in processes like [Behavioral response to nicotine](/details-go/GO:0035095), which connects its basic biology to clinical associations with nicotine dependence. ## Research Directions The unique expression pattern and known clinical associations of [CHRNA3](/details-gene/1136) suggest several avenues for future investigation. Its well-established role in the nervous system contrasts with its less-understood function in the immune system, presenting a key knowledge gap. **Proposed Hypotheses:** 1. The high significance of [CHRNA3](/details-gene/1136) in [double-positive, alpha-beta thymocyte](/details-cell/CL0000809) suggests that acetylcholine, acting through alpha-3-containing nAChRs, is a critical signaling molecule that modulates T-cell receptor signal strength during thymic selection, thereby shaping the mature T-cell repertoire. 2. Given its strong association with lung cancer susceptibility ([Link](https://doi.org/10.1038/nature06846)), aberrant [CHRNA3](/details-gene/1136) signaling in bronchial epithelial cells or neuroendocrine cells of the lung may directly promote tumorigenesis upon exposure to nicotine, functioning as a driver of cell proliferation or survival. **Experimental Approach:** To test the first hypothesis regarding its role in T-cell development, a conditional knockout mouse model with a T-cell specific deletion of *Chrna3* (e.g., using a Lck-Cre driver) would be highly informative. Thymocytes and peripheral T-cells from these mice would be compared to wild-type littermates. Flow cytometric analysis of thymic populations (DN, DP, SP) and peripheral T-cell subsets, coupled with single-cell RNA sequencing of thymocytes, could reveal defects in positive or negative selection, altered expression of maturation markers, and potential biases in the T-cell receptor repertoire. **Therapeutic Potential:** As a subunit of a druggable ion channel, [CHRNA3](/details-gene/1136) is a relevant therapeutic target. For nicotine dependence, the development of selective partial agonists or antagonists for nAChRs containing the alpha-3 subunit could offer a more targeted approach for smoking cessation therapies. In the context of oncology, if [CHRNA3](/details-gene/1136) is confirmed as a driver in specific lung cancer subtypes, its inhibition could represent a viable therapeutic strategy. However, the widespread expression of [CHRNA3](/details-gene/1136) in the peripheral nervous system poses a significant challenge, as systemic inhibition could lead to autonomic side effects. Therefore, development of highly selective inhibitors or targeted delivery systems would be essential for clinical translation.

Genular Protein ID: 1954824543

Symbol: ACHA3_HUMAN

Name: Neuronal acetylcholine receptor subunit alpha-3

UniProtKB Accession Codes:

P32297 Q15823 Q4KMN8 Q86U77 Q96RH3 Q99553 Q9BQ93 Q9BRR4

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BindingDB 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 2 CDD 2 CTD 1 ChEMBL 1 ChiTaRS 1 ComplexPortal 6 DMDM 1 DNASU 1 DisGeNET 1 DrugBank 17 DrugCentral 1 EMBL 20 EMDB 2 Ensembl 3 ExpressionAtlas 1 GO 34 Gene3D 2 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyCosmos 1 GlyGen 1 GuidetoPHARMACOLOGY 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 8 KEGG 1 MANE-Select 1 MIM 4 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 NCBIfam 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PDB 5 PDBsum 5 PIR 2 PRINTS 2 PRO 1 PROSITE 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 2 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 3 RNAct 1 Reactome 3 RefSeq 2 SMR 1 STRING 1 SUPFAM 2 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 neXtProt 1

Citations:

PubMed ID: 2336208

Title: Molecular cloning of human neuronal nicotinic receptor alpha 3-subunit.

PubMed ID: 2336208

DOI: 10.1016/0304-3940(90)90287-j

PubMed ID: 1989896

Title: Expression of mRNAs in human thymus coding for the alpha 3 subunit of a neuronal acetylcholine receptor.

PubMed ID: 1989896

DOI: 10.1016/0014-4886(91)90004-v

PubMed ID: 8906617

Title: Comparative structure of human neuronal alpha 2-alpha 7 and beta 2-beta 4 nicotinic acetylcholine receptor subunits and functional expression of the alpha 2, alpha 3, alpha 4, alpha 7, beta 2, and beta 4 subunits.

PubMed ID: 8906617

DOI: 10.1007/bf02736842

PubMed ID: 9009220

Title: Cloning and sequence of full-length cDNAs encoding the human neuronal nicotinic acetylcholine receptor (nAChR) subunits beta3 and beta4 and expression of seven nAChR subunits in the human neuroblastoma cell line SH-SY5Y and/or IMR-32.

PubMed ID: 9009220

DOI: 10.1016/s0014-5793(96)01383-x

PubMed ID: 9921897

Title: The structures of the human neuronal nicotinic acetylcholine receptor beta2- and alpha3-subunit genes (CHRNB2 and CHRNA3).

PubMed ID: 9921897

DOI: 10.1007/s004390050885

PubMed ID: 11450844

Title: Characterization of the human beta4 nAChR gene and polymorphisms in CHRNA3 and CHRNB4.

PubMed ID: 11450844

DOI: 10.1007/pl00010921

PubMed ID: 16572171

Title: Analysis of the DNA sequence and duplication history of human chromosome 15.

PubMed ID: 16572171

DOI: 10.1038/nature04601

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 15609996

Title: Alpha-conotoxins ImI and ImII target distinct regions of the human alpha7 nicotinic acetylcholine receptor and distinguish human nicotinic receptor subtypes.

PubMed ID: 15609996

DOI: 10.1021/bi048918g

PubMed ID: 16120769

Title: RIC-3 enhances functional expression of multiple nicotinic acetylcholine receptor subtypes in mammalian cells.

PubMed ID: 16120769

DOI: 10.1124/mol.105.017459

PubMed ID: 18385720

Title: Genomics: when the smoke clears.

PubMed ID: 18385720

DOI: 10.1038/452537a

PubMed ID: 18385738

Title: A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25.

PubMed ID: 18385738

DOI: 10.1038/nature06885

PubMed ID: 18385739

Title: A variant associated with nicotine dependence, lung cancer and peripheral arterial disease.

PubMed ID: 18385739

DOI: 10.1038/nature06846

PubMed ID: 18385676

Title: Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1.

PubMed ID: 18385676

DOI: 10.1038/ng.109

PubMed ID: 26265139

Title: UBXN2A regulates nicotinic receptor degradation by modulating the E3 ligase activity of CHIP.

PubMed ID: 26265139

DOI: 10.1016/j.bcp.2015.08.084

PubMed ID: 27344019

Title: Functional interaction between Lypd6 and nicotinic acetylcholine receptors.

PubMed ID: 27344019

DOI: 10.1111/jnc.13718

PubMed ID: 31708116

Title: CAKUT and autonomic dysfunction caused by acetylcholine receptor mutations.

PubMed ID: 31708116

DOI: 10.1016/j.ajhg.2019.10.004

Sequence Information:

  • Length: 505
  • Mass: 57480
  • Checksum: 478D7712D59ACB2D
  • Sequence:
    • MGSGPLSLPL ALSPPRLLLL LLLSLLPVAR ASEAEHRLFE RLFEDYNEII RPVANVSDPV 
IIHFEVSMSQ LVKVDEVNQI METNLWLKQI WNDYKLKWNP SDYGGAEFMR VPAQKIWKPD 
IVLYNNAVGD FQVDDKTKAL LKYTGEVTWI PPAIFKSSCK IDVTYFPFDY QNCTMKFGSW 
SYDKAKIDLV LIGSSMNLKD YWESGEWAII KAPGYKHDIK YNCCEEIYPD ITYSLYIRRL 
PLFYTINLII PCLLISFLTV LVFYLPSDCG EKVTLCISVL LSLTVFLLVI TETIPSTSLV 
IPLIGEYLLF TMIFVTLSIV ITVFVLNVHY RTPTTHTMPS WVKTVFLNLL PRVMFMTRPT 
SNEGNAQKPR PLYGAELSNL NCFSRAESKG CKEGYPCQDG MCGYCHHRRI KISNFSANLT 
RSSSSESVDA VLSLSALSPE IKEAIQSVKY IAENMKAQNE AKEIQDDWKY VAMVIDRIFL 
WVFTLVCILG TAGLFLQPLM AREDA