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nicotinic acetylcholine receptor α3 subunit

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Target id: 464

Nomenclature: nicotinic acetylcholine receptor α3 subunit

Family: Nicotinic acetylcholine receptors (nACh)

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 4 505 15q25.1 CHRNA3 cholinergic receptor nicotinic alpha 3 subunit 5
Mouse 4 499 9 B Chrna3 cholinergic receptor, nicotinic, alpha polypeptide 3 3
Rat 4 499 8q24 Chrna3 cholinergic receptor nicotinic alpha 3 subunit 4
Previous and Unofficial Names Click here for help
neuronal acetylcholine receptor subunit alpha-3 | Acra3 | cholinergic receptor, nicotinic, alpha 3 (neuronal) | cholinergic receptor, nicotinic alpha 3 | cholinergic receptor
Database Links Click here for help
Alphafold P32297 (Hs), Q8R4G9 (Mm), P04757 (Rn)
CATH/Gene3D 2.70.170.10
ChEMBL Target CHEMBL3068 (Hs), CHEMBL3885609 (Mm), CHEMBL3137276 (Rn), CHEMBL1907587 (Rn), CHEMBL3137275 (Rn), CHEMBL4106146 (Rn), CHEMBL1907593 (Rn)
DrugBank Target P32297 (Hs)
Ensembl Gene ENSG00000080644 (Hs), ENSMUSG00000032303 (Mm), ENSRNOG00000013829 (Rn)
Entrez Gene 1136 (Hs), 110834 (Mm), 25101 (Rn)
Human Protein Atlas ENSG00000080644 (Hs)
KEGG Gene hsa:1136 (Hs), mmu:110834 (Mm), rno:25101 (Rn)
OMIM 118503 (Hs)
Pharos P32297 (Hs)
RefSeq Nucleotide NM_000743 (Hs), NM_145129 (Mm), NM_052805 (Rn)
RefSeq Protein NP_000734 (Hs), NP_660111 (Mm), NP_434692 (Rn)
UniProtKB P32297 (Hs), Q8R4G9 (Mm), P04757 (Rn)
Wikipedia CHRNA3 (Hs)
Functional Characteristics Click here for help
α3β2: PCa/PNa = 1.5; α3β4: PCa/PNa = 0.78 - 1.1, Pf = 2.7 – 4.6%
Natural/Endogenous Ligands Click here for help
acetylcholine
Commonly used antagonists (Human)
α3β2: DHβE (KB = 1.6 μM, IC50 = 2.0 μM), tubocurarine (KB = 2.4 μM); α3β4: DHβE (KB = 19 μM, IC50 = 26 μM), tubocurarine (KB = 2.2 μM)

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Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
[125I]epibatidine Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Full agonist 9.6 – 11.1 pKd
⤷ pKd 11.1 (Kd 7x10-12 M) α3β2
pKd 9.6 (Kd 2.3x10-10 M) α3β4
[3H]epibatidine Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Full agonist 9.6 – 11.1 pKd
⤷ pKd 11.1 (Kd 7x10-12 M) α3β2
pKd 9.6 (Kd 2.3x10-10 M) α3β4
[125I]epibatidine Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Rn Full agonist 9.5 – 10.9 pKd
⤷ pKd 10.5 – 10.9 (Kd 3.4x10-11 – 1.4x10-11 M) α3β2
pKd 9.5 – 9.5 (Kd 3.04x10-10 – 2.9x10-10 M) α3β4
[3H]epibatidine Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Rn Full agonist 9.5 – 10.9 pKd
⤷ pKd 10.5 – 10.9 (Kd 3.4x10-11 – 1.4x10-11 M) α3β2
pKd 9.5 – 9.5 (Kd 3.04x10-10 – 2.9x10-10 M) α3β4
varenicline Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Agonist 7.4 pKi 13
⤷ pKi 7.4 (Ki 3.96x10-8 M) α3β4 [13]
nicotine Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Agonist 5.8 pKi 13
⤷ pKi 5.8 (Ki 1.744x10-6 M) α3β4 [13]
[3H]cytisine Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Full agonist - -
⤷
View species-specific agonist tables
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
atracurium Small molecule or natural product Approved drug Click here for species-specific activity table Immunopharmacology Ligand Hs Antagonist 7.9 – 9.1 pIC50 9
⤷ pIC50 7.9 – 9.1 (IC50 1.16x10-8 – 9x10-10 M) [9]
Description: Antagonism of ACh activation of human α3β2 or α3β4 nACh receptors expressed in Xenopus oocytes, at different ACh concentrations.
α-conotoxin MII Peptide Click here for species-specific activity table Hs Antagonist - -
⤷ α3β2
α-conotoxin AuIB Peptide Hs Antagonist - -
⤷ α3β4
α-conotoxin PnIA Peptide Click here for species-specific activity table Hs Antagonist - -
⤷ α3β2
α-conotoxin-GIC Peptide Click here for species-specific activity table Hs Antagonist - -
⤷ α3β2
α-conotoxin TxIA Peptide Click here for species-specific activity table Hs Antagonist - -
⤷ α3β2
Channel Blockers
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Use-dependent Value Parameter Concentration range (M) Voltage-dependent (mV) Reference
mecamylamine Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Hs - no 5.1 – 6.4 pIC50 - no
⤷ pIC50 6.4 (IC50 3.9x10-7 M) α3β4
Not voltage dependent
pIC50 5.1 (IC50 7.6x10-6 M) α3β2
Not voltage dependent
hexamethonium Small molecule or natural product Click here for species-specific activity table Hs - no - - - no
⤷ α3β4
Not voltage dependent
α3β2
Not voltage dependent
A-867744 Small molecule or natural product Click here for species-specific activity table Hs - no - - - no 10
⤷ α3β4 [10]
Not voltage dependent
NS1738 Small molecule or natural product Click here for species-specific activity table Hs - no - - - no 20
⤷ α3β4 [20]
Not voltage dependent
Tissue Distribution Click here for help
Brain:-
High levels of α3-subunit mRNA are expressed in the medial habenula. Expression has also been detected in substantia nigra pars compacta and ventral tegmental area (similar patterns seen in rat)
Expression level:  High
Species:  Mouse
Technique:  in situ hybridisation
References:  6
Brain:-
Intense expression in the medial habenula with lower levels of expression in cortical layer IV, substantia nigra pars compacta, ventral tegmental area and in several hindbrain nuclei. Significant hybridization was also noted in the superficial layers of the superior colliculus and in inferior colliculus In contrast to rat brain, little hybridization was observed in thalamus.
Expression level:  High
Species:  Mouse
Technique:  in situ hybridisation
References:  12
Brain:-
Deletion of the α3 nAChR subunit gene in knockout mice decreases the levels of A85380-resistant [125I]-epibatidine binding in the medial habenula–fasciculus retroflexus–interpenduncular nucleus tract, the dorsal cortex of the inferior colliculus, and the medial vestibular and prepositus hypoglossal nuclei.
Species:  Mouse
Technique:  Radioligand binding
References:  23
Olfactory bulbs, including the mitral cell layer and the accessory olfactory bulb.
Species:  Mouse
Technique:  in situ hybridisation
References:  22
Brain:-
Intense expression in the medial habenula with less pronounced expression in the substantia nigra pars compacta and ventral tegmental area. In addition, hybridization was detected in olfactory bulb, cortical layer IV, basal lateral amygdala, interpeduncular nucleus, locus coeruleus, and several hindbrain nuclei, including motor nuclei such as motor nucleus V, facial nerve VII and nucleus ambiguous. Labeling was also observed in several thalamic areas.
Expression level:  High
Species:  Rat
Technique:  in situ hybridisation
References:  21
Sympathetic and parasympathetic nervous system
Species:  Rat
Technique:  RT-PCR and in situ hybridization.
References:  11,14-15
Tissue Distribution Comments
In situ hybridization of rhesus monkey (Macaca mulatta) brain shows that expression appears to be restricted primarily to the medial habenula with minor expression in the hippocampus [7].
Physiological Consequences of Altering Gene Expression Click here for help
Knockout mice have extensive autonomic dysfunctions. Phenotypic effects include bladder enlargement, dribbling urination, bladder infection, urinary stones and dilated ocular pupils. Mice survive to birth but have impaired growth and increased perinatal mortality.
Species:  Mouse
Tissue:  in vivo
Technique:  Knockout (homologous recombination)
References:  24
Heterozygous α3 mice are less sensitive to nicotine-induced seizures.
Species:  Mouse
Tissue:  in vivo
Technique:  Knockout
References:  18
Administration of α3 antisense RNA into cerebral ventricles for seven days reduced α3 mRNA levels in both thalamus and medial habenula. Hypothermia elicited by epibatidine administration was unaffected, but sensitivity to seizures elicited by epibatidine was significantly reduced.
Species:  Rat
Tissue:  Brain (cerebral ventricles)
Technique:  Antisense knockdown
References:  1
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Nicotine dependence, susceptibility to
Disease Ontology: DOID:0050742
OMIM: 612052
Role:  Single nucleotide polymorphisms in this gene are associated with susceptibility to nicotine dependence and lung cancer.
References:  8,17,19
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Single nucleotide polymorphism Human - Genome-wide association studies have found the SNP rs1051730 to be associated with nicotine dependence. This is a common variant in the nicotinic acetylcholine receptor gene cluster on chromosome 15q24 2,19
Disease:  Sporadic amyotrophic lateral sclerosis
Synonyms: SALS
Disease Ontology: DOID:332
OMIM: 105400
References:  16
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Missense Human R385H c.1154G>A Exon 5. M3-M4 intracellular loop 16
Missense Human S388F c.1163C>T Exon 5 16

References

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1. Adams MR, Nikkel AL, Donnelly-Roberts DL, Watt AT, Johnston JF, Cowsert LM, Butler M, Kroeger PE, Frost L, Curzon P et al.. (2004) In vitro and in vivo effects of an alpha3 neuronal nicotinic acetylcholine receptor antisense oligonucleotide. Brain Res Mol Brain Res, 129 (1-2): 67-79. [PMID:15469883]

2. Amos CI, Wu X, Broderick P, Gorlov IP, Gu J, Eisen T, Dong Q, Zhang Q, Gu X, Vijayakrishnan J et al.. (2008) Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1. Nat Genet, 40 (5): 616-22. [PMID:18385676]

3. Bessis A, Simon-Chazottes D, Devillers-Thiéry A, Guénet JL, Changeux JP. (1990) Chromosomal localization of the mouse genes coding for alpha 2, alpha 3, alpha 4 and beta 2 subunits of neuronal nicotinic acetylcholine receptor. FEBS Lett, 264 (1): 48-52. [PMID:2338144]

4. Boulter J, Evans K, Goldman D, Martin G, Treco D, Heinemann S, Patrick J. (1986) Isolation of a cDNA clone coding for a possible neural nicotinic acetylcholine receptor alpha-subunit. Nature, 319 (6052): 368-74. [PMID:3753746]

5. Fornasari D, Chini B, Tarroni P, Clementi F. (1990) Molecular cloning of human neuronal nicotinic receptor alpha 3-subunit. Neurosci Lett, 111 (3): 351-6. [PMID:2336208]

6. Goldman D, Simmons D, Swanson LW, Patrick J, Heinemann S. (1986) Mapping of brain areas expressing RNA homologous to two different acetylcholine receptor alpha-subunit cDNAs. Proc Natl Acad Sci USA, 83 (11): 4076-80. [PMID:3012549]

7. Han ZY, Le Novère N, Zoli M, Hill JA, Champtiaux N, Changeux JP. (2000) Localization of nAChR subunit mRNAs in the brain of Macaca mulatta. Eur J Neurosci, 12 (10): 3664-74. [PMID:11029636]

8. Improgo MR, Scofield MD, Tapper AR, Gardner PD. (2010) The nicotinic acetylcholine receptor CHRNA5/A3/B4 gene cluster: dual role in nicotine addiction and lung cancer. Prog Neurobiol, 92 (2): 212-26. [PMID:20685379]

9. Jonsson M, Gurley D, Dabrowski M, Larsson O, Johnson EC, Eriksson LI. (2006) Distinct pharmacologic properties of neuromuscular blocking agents on human neuronal nicotinic acetylcholine receptors: a possible explanation for the train-of-four fade. Anesthesiology, 105 (3): 521-33. [PMID:16931985]

10. Malysz J, Grønlien JH, Anderson DJ, Håkerud M, Thorin-Hagene K, Ween H, Wetterstrand C, Briggs CA, Faghih R, Bunnelle WH et al.. (2009) In vitro pharmacological characterization of a novel allosteric modulator of alpha 7 neuronal acetylcholine receptor, 4-(5-(4-chlorophenyl)-2-methyl-3-propionyl-1H-pyrrol-1-yl)benzenesulfonamide (A-867744), exhibiting unique pharmacological profile. J Pharmacol Exp Ther, 330 (1): 257-67. [PMID:19389923]

11. Mandelzys A, Pié B, Deneris ES, Cooper E. (1994) The developmental increase in ACh current densities on rat sympathetic neurons correlates with changes in nicotinic ACh receptor alpha-subunit gene expression and occurs independent of innervation. J Neurosci, 14 (4): 2357-64. [PMID:8158273]

12. Marks MJ, Pauly JR, Gross SD, Deneris ES, Hermans-Borgmeyer I, Heinemann SF, Collins AC. (1992) Nicotine binding and nicotinic receptor subunit RNA after chronic nicotine treatment. J Neurosci, 12 (7): 2765-84. [PMID:1613557]

13. Nirogi R, Mohammed AR, Shinde AK, Ravella SR, Bogaraju N, Subramanian R, Mekala VR, Palacharla RC, Muddana N, Thentu JB et al.. (2020) Discovery and Development of 3-(6-Chloropyridine-3-yloxymethyl)-2-azabicyclo[3.1.0]hexane Hydrochloride (SUVN-911): A Novel, Potent, Selective, and Orally Active Neuronal Nicotinic Acetylcholine α4β2 Receptor Antagonist for the Treatment of Depression. J Med Chem, 63 (6): 2833-2853. [PMID:32026697]

14. Poth K, Nutter TJ, Cuevas J, Parker MJ, Adams DJ, Luetje CW. (1997) Heterogeneity of nicotinic receptor class and subunit mRNA expression among individual parasympathetic neurons from rat intracardiac ganglia. J Neurosci, 17 (2): 586-96. [PMID:8987781]

15. Rust G, Burgunder JM, Lauterburg TE, Cachelin AB. (1994) Expression of neuronal nicotinic acetylcholine receptor subunit genes in the rat autonomic nervous system. Eur J Neurosci, 6 (3): 478-85. [PMID:8019684]

16. Sabatelli M, Eusebi F, Al-Chalabi A, Conte A, Madia F, Luigetti M, Mancuso I, Limatola C, Trettel F, Sobrero F et al.. (2009) Rare missense variants of neuronal nicotinic acetylcholine receptor altering receptor function are associated with sporadic amyotrophic lateral sclerosis. Hum Mol Genet, 18 (20): 3997-4006. [PMID:19628475]

17. Saccone SF, Hinrichs AL, Saccone NL, Chase GA, Konvicka K, Madden PA, Breslau N, Johnson EO, Hatsukami D, Pomerleau O et al.. (2007) Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3713 SNPs. Hum Mol Genet, 16 (1): 36-49. [PMID:17135278]

18. Salas R, Cook KD, Bassetto L, De Biasi M. (2004) The alpha3 and beta4 nicotinic acetylcholine receptor subunits are necessary for nicotine-induced seizures and hypolocomotion in mice. Neuropharmacology, 47 (3): 401-7. [PMID:15275829]

19. Thorgeirsson TE, Geller F, Sulem P, Rafnar T, Wiste A, Magnusson KP, Manolescu A, Thorleifsson G, Stefansson H, Ingason A et al.. (2008) A variant associated with nicotine dependence, lung cancer and peripheral arterial disease. Nature, 452 (7187): 638-42. [PMID:18385739]

20. Timmermann DB, Grønlien JH, Kohlhaas KL, Nielsen EØ, Dam E, Jørgensen TD, Ahring PK, Peters D, Holst D, Christensen JK et al.. (2007) An allosteric modulator of the alpha7 nicotinic acetylcholine receptor possessing cognition-enhancing properties in vivo. J Pharmacol Exp Ther, 323 (1): 294-307. [PMID:17625074]

21. Wada E, Wada K, Boulter J, Deneris E, Heinemann S, Patrick J, Swanson LW. (1989) Distribution of alpha 2, alpha 3, alpha 4, and beta 2 neuronal nicotinic receptor subunit mRNAs in the central nervous system: a hybridization histochemical study in the rat. J Comp Neurol, 284 (2): 314-35. [PMID:2754038]

22. Whiteaker P, Jimenez M, McIntosh JM, Collins AC, Marks MJ. (2000) Identification of a novel nicotinic binding site in mouse brain using [(125)I]-epibatidine. Br J Pharmacol, 131 (4): 729-39. [PMID:11030722]

23. Whiteaker P, Peterson CG, Xu W, McIntosh JM, Paylor R, Beaudet AL, Collins AC, Marks MJ. (2002) Involvement of the alpha3 subunit in central nicotinic binding populations. J Neurosci, 22 (7): 2522-9. [PMID:11923417]

24. Xu W, Gelber S, Orr-Urtreger A, Armstrong D, Lewis RA, Ou CN, Patrick J, Role L, De Biasi M, Beaudet AL. (1999) Megacystis, mydriasis, and ion channel defect in mice lacking the alpha3 neuronal nicotinic acetylcholine receptor. Proc Natl Acad Sci USA, 96 (10): 5746-51. [PMID:10318955]

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