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nicotinic acetylcholine receptor α1 subunit

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Target not currently curated in GtoImmuPdb

Target id: 462

Nomenclature: nicotinic acetylcholine receptor α1 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 4 482 2q31.1 CHRNA1 cholinergic receptor nicotinic alpha 1 subunit 11
Mouse 4 457 2 43.76 cM Chrna1 cholinergic receptor nicotinic alpha 1 subunit 8
Rat 4 457 3q23 Chrna1 cholinergic receptor nicotinic alpha 1 subunit 15
Previous and Unofficial Names Click here for help
acetylcholine receptor subunit alpha | Achr-1 | cholinergic receptor, nicotinic, alpha 1 (muscle) | cholinergic receptor, nicotinic alpha 1 | cholinergic receptor, nicotinic, alpha 1 | cholinergic receptor
Database Links Click here for help
Alphafold P02708 (Hs), P04756 (Mm), P25108 (Rn)
CATH/Gene3D 2.70.170.10
ChEMBL Target CHEMBL4808 (Hs), CHEMBL3038460 (Mm), CHEMBL3137264 (Mm), CHEMBL3885509 (Rn), CHEMBL4523658 (Rn)
DrugBank Target P02708 (Hs)
Ensembl Gene ENSG00000138435 (Hs), ENSMUSG00000027107 (Mm), ENSRNOG00000018286 (Rn)
Entrez Gene 1134 (Hs), 11435 (Mm), 79557 (Rn)
Human Protein Atlas ENSG00000138435 (Hs)
KEGG Gene hsa:1134 (Hs), mmu:11435 (Mm), rno:79557 (Rn)
OMIM 100690 (Hs)
Orphanet ORPHA119411 (Hs)
Pharos P02708 (Hs)
RefSeq Nucleotide NM_001039523 (Hs), NM_007389 (Mm), NM_024485 (Rn)
RefSeq Protein NP_001034612 (Hs), NP_031415 (Mm), NP_077811 (Rn)
UniProtKB P02708 (Hs), P04756 (Mm), P25108 (Rn)
Wikipedia CHRNA1 (Hs)
Functional Characteristics Click here for help
(α1)2βγδ: PCa/PNa = 0.16 - 0.2, Pf = 2.1 – 2.9%; (α1)2βδε: PCa/PNa = 0.65 – 1.38, Pf = 4.1 – 7.2%
Natural/Endogenous Ligands Click here for help
acetylcholine
Commonly used antagonists (Human)
(α1)2β1γδ and (α1)2β1δε: α-bungarotoxin > pancuronium > vecuronium > rocuronium > tubocurarine (IC50 = 43 - 82 nM)

Download all structure-activity data for this target as a CSV file go icon to follow link

Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
succinylcholine Small molecule or natural product Approved drug Primary target of this compound Ligand has a PDB structure Hs Full agonist - -
⤷ selective for (α1)2β1γδ
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 7.0 pIC50 6
⤷ pIC50 7.0 (IC50 9.7x10-8 M) [6]
Description: Antagonism of ACh activation of α1β1εδ nACh receptors expressed in Xenopus oocytes.
α-bungarotoxin Peptide Click here for species-specific activity table Hs Antagonist - -
⤷
[125I]α-bungarotoxin Peptide Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Antagonist - -
⤷
[3H]α-bungarotoxin Peptide Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Antagonist - -
⤷
α-conotoxin GI Peptide Hs Antagonist - -
⤷
waglerin-1 Peptide Hs Antagonist - -
⤷ selective for (α1)2β1δε
α-conotoxin MI Peptide Hs Antagonist - -
⤷
pancuronium Small molecule or natural product Approved drug Primary target of this compound Hs Antagonist - -
⤷
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
gallamine Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs - no ~6.0 pIC50 - no
⤷ pIC50 ~6.0 (IC50 ~1x10-6 M) (α1)2β1γδ and (α1)2β1δε
Not voltage dependent
mecamylamine Small molecule or natural product Approved drug Click here for species-specific activity table Hs - no ~5.8 pIC50 - no
⤷ pIC50 ~5.8 (IC50 ~1.5x10-6 M) (α1)2β1δε
Not voltage dependent
Tissue Distribution Comments
In vertebrates α1-subunit mRNA is generally expressed in skeletal muscle
Physiological Consequences of Altering Gene Expression Click here for help
Homozygous knockout mice die at birth. Kyphosis and carpoptosis phenotypes are apparent in embryonic mice. Increased motor axon branching and expanded innervation were also seen. Spontaneous miniature and nerve-evoked endplate potentials were absent in muscle.
Species:  Mouse
Tissue:  in vivo
Technique:  Gene knockout
References:  1
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Multiple pterygium syndrome, lethal type; LMPS
Description: A fetal akinesia deformation sequence (FADS) disorder
Synonyms: Lethal multiple pterygium syndrome [Orphanet: ORPHA33108]
OMIM: 253290
Orphanet: ORPHA33108
Comments:  Mutation in acetylcholine receptor subunits are associated with fetal akinesia deformation sequence (FADS) disorders including lethal multiple pterygium syndrome.
References:  9
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Frameshift: Duplication Human H24RfsX19 c.117-133 dup17 Homozygous duplication of 17 base pairs in in exon 2 of the gene causing a frameshift and premature stop codon. 9
Missense Human R234L 761G>T 9
Disease:  Myasthenia gravis
Description: Myasthenia gravis is an autoimmune disease caused by auto-antibody attack on nicotinic acetylcholine receptors at the neuro-muscular junction. This disrupts nerve-muscle communication and results in muscle weakness and fatigue. Treatment has historically been limited to nonselective, chronic immunosuppressive therapies which have long-term toxicities. More selective and targeted therapies are now being developed, including the monoclonal antibody eculizumab (approved) and an investigational CAR-T cell therapy that targets antibody-producing plasma cells (Descartes-08; Cartesian Therapeutics; Phase 1/2).
Disease Ontology: DOID:437
OMIM: 254200
Orphanet: ORPHA589
Role:  Target for autoantibodies
References:  7
Disease:  Myasthenic syndrome, congenital, 1A, slow-channel; CMS1A
Synonyms: Congenital myasthenic syndrome [Orphanet: ORPHA590] [Disease Ontology: DOID:3635]
Postsynaptic congenital myasthenic syndromes [Orphanet: ORPHA98913]
Disease Ontology: DOID:3635
OMIM: 601462
Orphanet: ORPHA98913, ORPHA590
References:  4-5
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Missense Human G153S 13
Missense Human V156M 2
Missense Human N217K 3
Missense Human V249F 10
Missense Human T254I 2
Missense Human S269I 2
Missense Human C418W 12
Disease:  Myasthenic syndrome, congenital, 1B, fast-channel; CMS1B
Synonyms: Congenital myasthenic syndrome [Disease Ontology: DOID:3635] [Orphanet: ORPHA590]
Postsynaptic congenital myasthenic syndromes [Orphanet: ORPHA98913]
Disease Ontology: DOID:3635
OMIM: 608930
Orphanet: ORPHA98913, ORPHA590
References:  4-5
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Missense Human F233V 14
Missense Human V285I 14
General Comments
The human α1 subunit exists as two variants that arise from alternative splicing. The long variant is tabulated above.

References

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1. An MC, Lin W, Yang J, Dominguez B, Padgett D, Sugiura Y, Aryal P, Gould TW, Oppenheim RW, Hester ME et al.. (2010) Acetylcholine negatively regulates development of the neuromuscular junction through distinct cellular mechanisms. Proc Natl Acad Sci USA, 107 (23): 10702-7. [PMID:20498043]

2. Croxen R, Newland C, Beeson D, Oosterhuis H, Chauplannaz G, Vincent A, Newsom-Davis J. (1997) Mutations in different functional domains of the human muscle acetylcholine receptor alpha subunit in patients with the slow-channel congenital myasthenic syndrome. Hum Mol Genet, 6 (5): 767-74. [PMID:9158151]

3. Engel AG, Ohno K, Milone M, Wang HL, Nakano S, Bouzat C, Pruitt 2nd JN, Hutchinson DO, Brengman JM, Bren N et al.. (1996) New mutations in acetylcholine receptor subunit genes reveal heterogeneity in the slow-channel congenital myasthenic syndrome. Hum Mol Genet, 5 (9): 1217-27. [PMID:8872460]

4. Engel AG, Ohno K, Sine SM. (2003) Sleuthing molecular targets for neurological diseases at the neuromuscular junction. Nat Rev Neurosci, 4 (5): 339-52. [PMID:12728262]

5. Engel AG, Shen XM, Selcen D, Sine SM. (2010) What have we learned from the congenital myasthenic syndromes. J Mol Neurosci, 40 (1-2): 143-53. [PMID:19688192]

6. 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]

7. Lindstrom JM. (2000) Acetylcholine receptors and myasthenia. Muscle Nerve, 23 (4): 453-77. [PMID:10716755]

8. Merlie JP, Sebbane R, Gardner S, Lindstrom J. (1983) cDNA clone for the alpha subunit of the acetylcholine receptor from the mouse muscle cell line BC3H-1. Proc Natl Acad Sci USA, 80 (12): 3845-9. [PMID:6344089]

9. Michalk A, Stricker S, Becker J, Rupps R, Pantzar T, Miertus J, Botta G, Naretto VG, Janetzki C, Yaqoob N et al.. (2008) Acetylcholine receptor pathway mutations explain various fetal akinesia deformation sequence disorders. Am J Hum Genet, 82 (2): 464-76. [PMID:18252226]

10. Milone M, Wang HL, Ohno K, Fukudome T, Pruitt JN, Bren N, Sine SM, Engel AG. (1997) Slow-channel myasthenic syndrome caused by enhanced activation, desensitization, and agonist binding affinity attributable to mutation in the M2 domain of the acetylcholine receptor alpha subunit. J Neurosci, 17 (15): 5651-65. [PMID:9221765]

11. Noda M, Furutani Y, Takahashi H, Toyosato M, Tanabe T, Shimizu S, Kikyotani S, Kayano T, Hirose T, Inayama S et al.. (1983) Cloning and sequence analysis of calf cDNA and human genomic DNA encoding alpha-subunit precursor of muscle acetylcholine receptor. Nature, 305 (5937): 818-23. [PMID:6688857]

12. Shen XM, Deymeer F, Sine SM, Engel AG. (2006) Slow-channel mutation in acetylcholine receptor alphaM4 domain and its efficient knockdown. Ann Neurol, 60 (1): 128-36. [PMID:16685696]

13. Sine SM, Ohno K, Bouzat C, Auerbach A, Milone M, Pruitt JN, Engel AG. (1995) Mutation of the acetylcholine receptor alpha subunit causes a slow-channel myasthenic syndrome by enhancing agonist binding affinity. Neuron, 15 (1): 229-39. [PMID:7619526]

14. Wang HL, Milone M, Ohno K, Shen XM, Tsujino A, Batocchi AP, Tonali P, Brengman J, Engel AG, Sine SM. (1999) Acetylcholine receptor M3 domain: stereochemical and volume contributions to channel gating. Nat Neurosci, 2 (3): 226-33. [PMID:10195214]

15. Witzemann V, Stein E, Barg B, Konno T, Koenen M, Kues W, Criado M, Hofmann M, Sakmann B. (1990) Primary structure and functional expression of the alpha-, beta-, gamma-, delta- and epsilon-subunits of the acetylcholine receptor from rat muscle. Eur J Biochem, 194 (2): 437-48. [PMID:1702709]

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