P43681 (ACHA4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Neuronal acetylcholine receptor subunit alpha-4

Gene names

Name:	CHRNA4
Synonyms:	NACRA4

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	627 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane.
Subunit structure	Neuronal AChR is composed of two different types of subunits: alpha and beta. Alpha-4 subunit can be combined to beta-2 or beta-4 to give rise to functional receptors. Interacts with RIC3; which is required for proper folding and assembly. Ref.9
Subcellular location	Cell junction › synapse › postsynaptic cell membrane; Multi-pass membrane protein. Cell membrane; Multi-pass membrane protein.
Involvement in disease	Defects in CHRNA4 are the cause of nocturnal frontal lobe epilepsy type 1 (ENFL1) [MIM:600513]; also symbolized ADNFLE. ENFL1 is an autosomal dominant epilepsy characterized by nocturnal seizures with hyperkinetic automatisms and poorly organized stereotyped movements. Ref.10 Ref.11 Ref.12
Sequence similarities	Belongs to the ligand-gated ion channel (TC 1.A.9) family. Acetylcholine receptor (TC 1.A.9.1) subfamily. Alpha-4/CHRNA4 sub-subfamily. [View classification]

Ontologies

Keywords
Biological process	Ion transport Transport
Cellular component	Cell junction Cell membrane Membrane Postsynaptic cell membrane Synapse
Coding sequence diversity	Polymorphism
Disease	Disease mutation Epilepsy
Domain	Signal Transmembrane Transmembrane helix
Molecular function	Ionic channel Ligand-gated ion channel Receptor
PTM	Disulfide bond Glycoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological process	B cell activation Inferred from sequence or structural similarity. Source: UniProtKB DNA repair Inferred from mutant phenotype. Source: UniProtKB behavioral response to nicotine Inferred from mutant phenotype. Source: UniProtKB calcium ion transport Inferred from sequence or structural similarity. Source: UniProtKB cognition Inferred from mutant phenotype Ref.12. Source: UniProtKB membrane depolarization Inferred from sequence or structural similarity. Source: UniProtKB regulation of action potential Inferred from sequence or structural similarity. Source: UniProtKB regulation of dopamine secretion Inferred from sequence or structural similarity. Source: UniProtKB regulation of inhibitory postsynaptic membrane potential Inferred from sequence or structural similarity. Source: UniProtKB response to hypoxia Inferred from direct assay. Source: UniProtKB response to oxidative stress Inferred from mutant phenotype. Source: UniProtKB sensory perception of pain Inferred from sequence or structural similarity. Source: UniProtKB synaptic transmission, cholinergic Inferred from sequence or structural similarity. Source: UniProtKB
Cellular component	acetylcholine-gated channel complex Inferred from direct assay Ref.3. Source: UniProtKB cell junction Inferred from electronic annotation. Source: UniProtKB-KW dendrite Inferred from sequence or structural similarity. Source: UniProtKB external side of plasma membrane Inferred from sequence or structural similarity. Source: UniProtKB membrane fraction Inferred from sequence or structural similarity. Source: UniProtKB neuronal cell body Inferred from sequence or structural similarity. Source: UniProtKB postsynaptic membrane Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	acetylcholine binding Inferred by curator Ref.3. Source: UniProtKB acetylcholine receptor activity Inferred from direct assay Ref.3. Source: UniProtKB acetylcholine-activated cation-selective channel activity Inferred from direct assay Ref.3. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Signal peptide	1 – 28	28	Potential
	Chain	29 – 627	599	Neuronal acetylcholine receptor subunit alpha-4		PRO_0000000351
Regions
	Topological domain	29 – 242	214	Extracellular Potential
	Transmembrane	243 – 267	25	Helical; Potential
	Transmembrane	275 – 293	19	Helical; Potential
	Transmembrane	309 – 330	22	Helical; Potential
	Topological domain	331 – 600	270	Cytoplasmic Potential
	Transmembrane	601 – 619	19	Helical; Potential
Amino acid modifications
	Glycosylation	57	1	N-linked (GlcNAc...) Potential
	Glycosylation	107	1	N-linked (GlcNAc...) Potential
	Glycosylation	174	1	N-linked (GlcNAc...) Potential
	Disulfide bond	161 ↔ 175		By similarity
	Disulfide bond	225 ↔ 226		Associated with receptor activation By similarity
Natural variations
	Natural variant	280	1	S → F in ENFL1. Ref.10		VAR_000295
	Natural variant	280	1	S → L in ENFL1. Ref.11 Ref.12		VAR_017531
	Natural variant	387	1	E → G. Ref.5 Corresponds to variant rs45604738 [ dbSNP | Ensembl ].		VAR_023402
	Natural variant	517	1	S → L. Ref.5 Corresponds to variant rs45622132 [ dbSNP | Ensembl ].		VAR_023403
Experimental info
	Sequence conflict	4	1	G → E in AAH96290. Ref.7

Sequences

	Sequence		Length	Mass (Da)
	P43681 [UniParc]. Last modified February 1, 1996. Version 2. Checksum: B3A0C0151E5A2AA8	FASTA	627	69,957
	10 20 30 40 50 60 MELGGPGAPR LLPPLLLLLG TGLLRASSHV ETRAHAEERL LKKLFSGYNK WSRPVANISD 70 80 90 100 110 120 VVLVRFGLSI AQLIDVDEKN QMMTTNVWVK QEWHDYKLRW DPADYENVTS IRIPSELIWR 130 140 150 160 170 180 PDIVLYNNAD GDFAVTHLTK AHLFHDGRVQ WTPPAIYKSS CSIDVTFFPF DQQNCTMKFG 190 200 210 220 230 240 SWTYDKAKID LVNMHSRVDQ LDFWESGEWV IVDAVGTYNT RKYECCAEIY PDITYAFVIR 250 260 270 280 290 300 RLPLFYTINL IIPCLLISCL TVLVFYLPSE CGEKITLCIS VLLSLTVFLL LITEIIPSTS 310 320 330 340 350 360 LVIPLIGEYL LFTMIFVTLS IVITVFVLNV HHRSPRTHTM PTWVRRVFLD IVPRLLLMKR 370 380 390 400 410 420 PSVVKDNCRR LIESMHKMAS APRFWPEPEG EPPATSGTQS LHPPSPSFCV PLDVPAEPGP 430 440 450 460 470 480 SCKSPSDQLP PQQPLEAEKA SPHPSPGPCR PPHGTQAPGL AKARSLSVQH MSSPGEAVEG 490 500 510 520 530 540 GVRCRSRSIQ YCVPRDDAAP EADGQAAGAL ASRNTHSAEL PPPDQPSPCK CTCKKEPSSV 550 560 570 580 590 600 SPSATVKTRS TKAPPPHLPL SPALTRAVEG VQYIADHLKA EDTDFSVKED WKYVAMVIDR 610 620 IFLWMFIIVC LLGTVGLFLP PWLAGMI

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Cloning and transient expression of genes encoding the human alpha-4 and beta-2 neuronal nicotinic acetylcholine receptor (nAChR) subunits." Monteggia L.M., Gopalakrishnan M., Touma E., Idler K.B., Nash N., Arneric S.P., Sullivan J.P., Giordano T. Gene 155:189-193(1995) [PubMed: 7721089] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Brain.
[2]	"Exon-intron structure of the human neuronal nicotinic acetylcholine receptor alpha 4 subunit (CHRNA4)." Steinlein O.K., Weiland S., Stood J., Propping P. Genomics 32:289-294(1996) [PubMed: 8833159] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]	"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." Elliott K.J., Ellis S.B., Berckhan K.J., Urrutia A., Chavez-Noriega L.E., Johnson E.C., Velicelebi G., Harpold M.M. J. Mol. Neurosci. 7:217-228(1996) [PubMed: 8906617] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Hippocampus.
[4]	"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." Groot Kormelink P.J., Luyten W.H.M.L. FEBS Lett. 400:309-314(1997) [PubMed: 9009220] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[5]	NIEHS SNPs program Submitted (JUN-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS GLY-387 AND LEU-517.
[6]	"The DNA sequence and comparative analysis of human chromosome 20." Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R., Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L., Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M., Beasley O.P., Bird C.P., Blakey S.E. , Bridgeman A.M., Brown A.J., Buck D., Burrill W.D., Butler A.P., Carder C., Carter N.P., Chapman J.C., Clamp M., Clark G., Clark L.N., Clark S.Y., Clee C.M., Clegg S., Cobley V.E., Collier R.E., Connor R.E., Corby N.R., Coulson A., Coville G.J., Deadman R., Dhami P.D., Dunn M., Ellington A.G., Frankland J.A., Fraser A., French L., Garner P., Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E., Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J., Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D., Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S., Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D., Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A., Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T., Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I., Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H., Rice C.M., Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S., Skuce C.D., Smith M.L., Soderlund C., Steward C.A., Sulston J.E., Swann R.M., Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A., Tracey A., Tromans A.C., Vaudin M., Wall M., Wallis J.M., Whitehead S.L., Whittaker P., Willey D.L., Williams L., Williams S.A., Wilming L., Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S., Rogers J. Nature 414:865-871(2001) [PubMed: 11780052] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[7]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[8]	"Molecular cloning of human neuronal nicotinic acetylcholine receptor 4-like subunit." Mamalaki A., Remoundos M., Tzartos S. Submitted (MAY-1995) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 26-627. Tissue: Brain.
[9]	"RIC-3 enhances functional expression of multiple nicotinic acetylcholine receptor subtypes in mammalian cells." Lansdell S.J., Gee V.J., Harkness P.C., Doward A.I., Baker E.R., Gibb A.J., Millar N.S. Mol. Pharmacol. 68:1431-1438(2005) [PubMed: 16120769] [Abstract] Cited for: INTERACTION WITH RIC3.
[10]	"A missense mutation in the neuronal nicotinic acetylcholine receptor alpha-4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy." Steinlein O.K., Mulley J.C., Propping P., Wallace R.H., Phillips H.A., Sutherland G.R., Scheffer I.E., Berkovic S.F. Nat. Genet. 11:201-203(1995) [PubMed: 7550350] [Abstract] Cited for: VARIANT ENFL1 PHE-280.
[11]	"A novel mutation of CHRNA4 responsible for autosomal dominant nocturnal frontal lobe epilepsy." Hirose S., Iwata H., Akiyoshi H., Kobayashi K., Ito M., Wada K., Kaneko S., Mitsudome A. Neurology 53:1749-1753(1999) [PubMed: 10563623] [Abstract] Cited for: VARIANT ENFL1 LEU-280.
[12]	"A Korean kindred with autosomal dominant nocturnal frontal lobe epilepsy and mental retardation." Cho Y.-W., Motamedi G.K., Laufenberg I., Sohn S.-I., Lim J.-G., Lee H., Yi S.-D., Lee J.-H., Kim D.-K., Reba R., Gaillard W.D., Theodore W.H., Lesser R.P., Steinlein O.K. Arch. Neurol. 60:1625-1632(2003) [PubMed: 14623738] [Abstract] Cited for: VARIANT ENFL1 LEU-280.
+	Additional computationally mapped references.

Web resources

GeneReviews

NIEHS-SNPs

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

L35901 mRNA. Translation: AAA64743.1.
X89741 , X89742, X89743, X89744, X89745, X89746 Genomic DNA. Translation: CAA61893.1.
U62433 mRNA. Translation: AAB40111.1.
Y08421 mRNA. Translation: CAA69698.1.
DQ093071 Genomic DNA. Translation: AAY88737.1.
AL121827 Genomic DNA. No translation available.
BC096290 mRNA. Translation: AAH96290.1.
X87629 mRNA. Translation: CAA60959.1.

IPI

IPI00020036.

PIR

JC4021.

RefSeq

NP_000735.1. NM_000744.5.

UniGene

Hs.10734.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2GVT	model	-	A/C	38-241	[»]

ProteinModelPortal

P43681.

SMR

P43681. Positions 34-363, 593-621.

ModBase

Search...

Protein-protein interaction databases

STRING

P43681.

PTM databases

PhosphoSite

P43681.

Polymorphism databases

DMDM

1351848.

Proteomic databases

PRIDE

P43681.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000370263; ENSP00000359285; ENSG00000101204.

GeneID

1137.

KEGG

hsa:1137.

UCSC

uc002yes.2. human.

Organism-specific databases

CTD

1137.

GeneCards

GC20M061974.

H-InvDB

HIX0040627.

HGNC

HGNC:1958. CHRNA4.

HPA

CAB034064.

MIM

118504. gene.
600513. phenotype.

neXtProt

NX_P43681.

Orphanet

98784. Nocturnal frontal lobe epilepsy.

PharmGKB

PA26490.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG09528.

HOGENOM

HBG387619.

HOVERGEN

HBG003756.

InParanoid

P43681.

OMA

VQHMSSP.

OrthoDB

EOG480HWN.

PhylomeDB

P43681.

Enzyme and pathway databases

Reactome

REACT_13685. Neuronal System.

Gene expression databases

ArrayExpress

P43681.

Bgee

P43681.

CleanEx

HS_CHRNA4.

Genevestigator

P43681.

GermOnline

ENSG00000101204. Homo sapiens.

Family and domain databases

InterPro

IPR006202. Neur_chan_lig-bd.
IPR006201. Neur_channel.
IPR006029. Neurotrans-gated_channel_TM.
IPR018000. Neurotransmitter_ion_chnl_CS.
IPR002394. Nicotinic_acetylcholine_rcpt.
[Graphical view]

Gene3D

G3DSA:2.70.170.10. Neur_chan_lig_bd. 1 hit.

KO

K04806.

PANTHER

PTHR18945. Neur_channel. 1 hit.

Pfam

PF02931. Neur_chan_LBD. 1 hit.
PF02932. Neur_chan_memb. 1 hit.
[Graphical view]

PRINTS

PR00254. NICOTINICR.
PR00252. NRIONCHANNEL.

SUPFAM

SSF90112. Neu_channel_TM. 1 hit.
SSF63712. Neur_chan_LBD. 1 hit.

TIGRFAMs

TIGR00860. LIC. 1 hit.

PROSITE

PS00236. NEUROTR_ION_CHANNEL. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

DrugBank

DB00184. Nicotine.
DB01273. Varenicline.

NextBio

4730.

SOURCE

Search...

Entry information

Entry name

ACHA4_HUMAN

Accession

Primary (citable) accession number: P43681
Secondary accession number(s): Q4JGR7, Q4VAQ6

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1995
Last sequence update:	February 1, 1996
Last modified:	January 25, 2012
This is version 125 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.