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α4

Family: Nicotinic acetylcholine receptors

Contents:
Gene and Protein Information
Previous and Unofficial Names
Database Links
Tissue Distribution
Physiological Consequences of Altering Gene Expression
Clinically-Relevant Mutations and Pathophysiology
References
Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 4 627 20q13.2-q13.3 CHRNA4 cholinergic receptor, nicotinic, alpha 4 (neuronal) 19
Mouse 4 629 2 H4 Chrna4 cholinergic receptor, nicotinic, alpha polypeptide 4 1
Rat 4 630 3q43 Chrna4 cholinergic receptor, nicotinic, alpha 4 (neuronal) 7
Previous and Unofficial Names
Neuronal, α-bungarotoxin-insensitive
EBN
EBN1
BFNC
cholinergic receptor, nicotinic, alpha polypeptide 4
acetylcholine receptor, nicotinic, alpha 4 (neuronal)
NARAC
Neuronal nicotinic acetylcholine receptor alpha 4 subunit
cholinergic receptor, nicotinic, alpha 4
cholinergic receptor, nicotinic, alpha 4 subunit
neuronal acetylcholine receptor subunit alpha-4
alpha4 nAChR
Acra-4
Acra4
a4 nicotinic receptor
alpha4-nAChR
Database Links
ChEMBL Target 10670 (Hs), 100148 (Mm), 12019 (Rn)
DrugBank Target 947 (Hs)
Ensembl ENSG00000101204 (Hs), ENSMUSG00000027577 (Mm), ENSRNOG00000011202 (Rn)
Entrez Gene 1137 (Hs), 11438 (Mm), 25590 (Rn)
GeneCards CHRNA4 (Hs)
GenitoUrinary Development Molecular Anatomy Project Chrna4 (Mm)
HomoloGene 592
Human Protein Reference Database 00333 (Hs)
InterPro P43681 (Hs), O70174 (Mm), P09483 (Rn)
KEGG Gene hsa:1137 (Hs), mmu:11438 (Mm), rno:25590 (Rn)
OMIM 118504 (Hs)
Orphanet Gene ORPHA119414 (Hs)
PharmGKB Gene PA26490 (Hs)
PhosphoSitePlus P43681 (Hs), O70174 (Mm), P09483 (Rn)
Protein Ontology (PRO) PRO:000005457 (Hs)
RefSeq Nucleotide NM_000744 (Hs), NM_015730 (Mm), NM_024354 (Rn)
RefSeq Protein NP_000735 (Hs), NP_056545 (Mm), NP_077330 (Rn)
TreeFam ENSG00000101204 (Hs), ENSMUSG00000027577 (Mm), ENSRNOG00000011202 (Rn)
UniGene Hs. 10734 (Hs)
UniProt P43681 (Hs), O70174 (Mm), P09483 (Rn)
Wikipedia α4
Nicotinic acetylcholine receptors
Search for 3D structures on the PDB
Search by keyword: Nicotinic acetylcholine receptors α4 Search by accession number: P43681, P09483, O70174
Natural/Endogenous Ligand(s)
acetylcholine
Commonly used antagonists (Human)
α4β2: DHβE (KB = 0.1 μM; IC50 = 0.08 - 0.9 μM), (+)-tubocurarine (KB = 3.2 μM, IC50 = 34 μM); α4β4: DHβE (KB = 0.01 μM, IC50 = 0.19 – 1.2 μM), (+)-tubocurarine (KB = 0.2 μM, IC50 = 50 μM)
Tissue Distribution
Brain:-
High levels of expression in most thalamic nuclei, although deeper layers of cortex (IV-VI) express much more α4 mRNA that the more superficial layers. Expression is very dense in the substantia nigra pars compacta and ventral tegmental area. In contrast to rat, significant expression is observed in locus coeruleus of the mouse. α4 mRNA is also prominent in the hindbrain, with particularly strong signal in the dorsal tegmental nucleus. α4 mRNA expression is quite low in the caudate putamen, hippocampus (except for subiculum), and cerebellum.
Expression level:  High
Species:  Mouse
Technique:  in situ hybridisation
References:  16
Brain:-
Binding studies in wild-type mice (e.g. with [3H]-cytisine, [3H]- or [125I]-epibatidine or [3H]-nicotine) detect high levels of binding sites in thalamic nuclei, medial habenula, interpeduncular nucleus, superior colliculus and presubiculum. Moderate levels are detected in the cortex, caudate-putamen and fasciculus retroflexus. Most of these binding sites are lost in α4 knockout mice but [3H]-nicotine and [3H]-epibatidine binding is still detected at high levels in the medial habenula and interpeduncular nucleus. Also, low levels of binding are detected in the substantia nigra, superior colliculus and fasciculus retroflexus. Knockout mice show decreased binding of [125I]α−conotoxin MII in the mesolimbic (ventral tegmental area, nucleus accumbens , lateral habenula) and visual pathways (olivary pretectal nucleus, dorsal and ventral lateral geniculate nuclei and superior colliculus).
Species:  Mouse
Technique:  Radioligand binding
References:  17-18,22
Brain:-
Immunoprecipitation studies from wild-type and α4 knockout mice have confirmed the presence of α4-containing receptors in the cortex, thalamus, hippocampus, retina, superior colliculus, nucleus geniculate lateralis, habenula, nucleus interpeduncularis, mesencephalon and striatum. α4–containing receptors are also expressed at early developmental stages in superior cervical ganglia.
Species:  Mouse
Technique:  immunoprecipitation, radioligand binding
References:  2,8-10,24
Brain:-
Immunolocalisation studies of wild-type and α4 knockout mice confirmed significant variations in the levels of α4 subunit in different brain regions. Comparison with β2 mAb immunostaining in wild-type and knockout mice demonstrated that the expression of α4 subunits is almost universally dependent on the expression of β2 subunits.
Expression level:  High
Species:  Mouse
Technique:  immunohistochemistry (immunolocalisation)
References:  32
Brain:-
Widely expressed with intense expression in thalamus and cerebral cortex.
Expression level:  High
Species:  Rat
Technique:  in situ hybridisation
References:  7
Tissue Distribution Comments
Using in situ hybridisation research reveals that in rhesus monkey α4 mRNA distribution in brain is similar to redents:- high expression in thalamic nuclei, substantia nigra pars compacta and ventral tegmental area, lesser expression in cortex (layer VI showing the most intense labeling) and little labeling in hippocampus and caudate [11].
However in squirrel monkey (Saimiri sciureus), the expression pattern differs markedly from that of either rodents or macaques. Expression in the thalamus is quite low relative to cortex, as is labeling in the substantia nigra pars compacta and the medial habenula.Expression in caudate, putamen, and hippocampus is relatively high [21].
Physiological Consequences of Altering Gene Expression
Knock-in mice containing an S248 mutation associated with autosomal dominant fromtal lobe epilepsy display responses to nicotine resembling a dystonal arousal complex.
Species:  Mouse
Tissue:  in vivo
Technique:  Knock-in
References:  30
Knock-in mice containing an L9’A mutation in the second transmembrane domain are hypersensitive to activation by nicotine (in contrast to L9'S mice, homozygous L9'A mice are viable and fertile). Mutant mice are nearly 100 times more sensitive to nicotine-induced hypothermia than wild-type mice. They are more sensitive to nicotine-induced seizures and sleep disruptions. nAChRs in the preBötzinger complex are hypersensitive to nicotine and have altered nicotinic modulation of respiratory rhythm.
Species:  Mouse
Tissue:  in vivo
Technique:  Knock-in
References:  5,25,28-29
Transgenic rats containing an S284L mutation associated with nocturnal frontal lobe epilepsy show attenuation of synaptic and extrasynaptic GABAergic transmission and exhibit the nocturnal frontal lobe epilepsy phenotype.
Species:  Rat
Tissue: 
Technique:  Transgenesis
References:  34
Knockout mice lack high-affinity nicotine binding in the brain; absence of nicotine-induced release of dopamine; reduced antinociceptive effect of nicotine; enhanced exploratory behavior and evidence of enhanced anxiety; enhanced sensitivity to seizures induced by GABA receptor blockers.
Species:  Mouse
Tissue:  in vivo
Technique:  Knockout (homologous recombination)
References:  17-18,22,33
Homozygous knock-in mice containing an L9’S mutation in the second transmembrane domain are not viable. Mice expressing a single α4 L9’S subunit are approximately 8-fold more sensitive more sensitive to nicotine-induced seizures than their wild-type littermates. The L9'S mice also show increased EEG and theta rhythm activity following nicotine injection.
Species:  Mouse
Tissue:  in vivo
Technique:  Knock-in
References:  6,14
Knock-in mice with either of two mutations (S252F or +L264) associated with autosomal dominant frontal lobe epilepsy exhibit frequent spontaneous seizures and increased sensitivity to the proconvulsant action of nicotine.
Species:  Mouse
Tissue:  in vivo
Technique:  Knock-in
References:  13
Clinically-Relevant Mutations and Pathophysiology
Disease:  Sporadic nocturnal frontal lobe epilepsy
References:  3
Click column headers to sort
Type Species Molecular location Description Reference
Missense Human S256L (S252L, C755T) 12,20
Disease:  Sporadic amyotrophic lateral sclerosis
References:  23
Click column headers to sort
Type Species Molecular location Description Reference
Missense Human M3-M4 intracellular loop 23
Disease:  Autosomal dominant nocturnal frontal lobe epilepsy
OMIM:  600513, 603204
Orphanet:  98784
References:  12,15,20,26-27,31
Click column headers to sort
Type Species Molecular location Description Reference
Insertion Human 263insL (788insGCT, 776ins3) 26
Missense Human S252F (S248F) 27,31
Missense Human S256L (S252L, C755T) 12,20
Missense Human T265I 15
Missense Human R308H 3
Clinically-Relevant Mutations and Pathophysiology Comments
The nomenclature of α4 subunit mutations associated with nocturnal frontal lobe epilepsy has been inconsistent (for further details see Duga et al. 2002 [4] ). Alternative nomenclature is given in parenthesis.

REFERENCES

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1. 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]

2. Champtiaux, N; Gotti, C; Cordero-Erausquin, M; David, DJ; Przybylski, C; Léna, C; Clementi, F; Moretti, M; Rossi, FM; Le Novère, N; et al.. (2003) Subunit composition of functional nicotinic receptors in dopaminergic neurons investigated with knock-out mice. J. Neurosci., 23 (21): 7820-9. [PMID:12944511]

3. Chen, Y; Wu, L; Fang, Y; He, Z; Peng, B; Shen, Y; Xu, Q. (2009) A novel mutation of the nicotinic acetylcholine receptor gene CHRNA4 in sporadic nocturnal frontal lobe epilepsy. Epilepsy Res., 83 (2-3): 152-6. [PMID:19058950]

4. Duga, S; Asselta, R; Bonati, MT; Malcovati, M; Dalprà, L; Oldani, A; Zucconi, M; Ferini-Strambi, L; Tenchini, ML. (2002) Mutational analysis of nicotinic acetylcholine receptor beta2 subunit gene (CHRNB2) in a representative cohort of Italian probands affected by autosomal dominant nocturnal frontal lobe epilepsy. Epilepsia, 43 (4): 362-4. [PMID:11952766]

5. Fonck, C; Cohen, BN; Nashmi, R; Whiteaker, P; Wagenaar, DA; Rodrigues-Pinguet, N; Deshpande, P; McKinney, S; Kwoh, S; Munoz, J; et al.. (2005) Novel seizure phenotype and sleep disruptions in knock-in mice with hypersensitive alpha 4* nicotinic receptors. J. Neurosci., 25 (49): 11396-411. [PMID:16339034]

6. Fonck, C; Nashmi, R; Deshpande, P; Damaj, MI; Marks, MJ; Riedel, A; Schwarz, J; Collins, AC; Labarca, C; Lester, HA. (2003) Increased sensitivity to agonist-induced seizures, straub tail, and hippocampal theta rhythm in knock-in mice carrying hypersensitive alpha 4 nicotinic receptors. J. Neurosci., 23 (7): 2582-90. [PMID:12684443]

7. Goldman, D; Deneris, E; Luyten, W; Kochhar, A; Patrick, J; Heinemann, S. (1987) Members of a nicotinic acetylcholine receptor gene family are expressed in different regions of the mammalian central nervous system. Cell, 48 (6): 965-73. [PMID:3829125]

8. Gotti, C; Moretti, M; Clementi, F; Riganti, L; McIntosh, JM; Collins, AC; Marks, MJ; Whiteaker, P. (2005) Expression of nigrostriatal alpha 6-containing nicotinic acetylcholine receptors is selectively reduced, but not eliminated, by beta 3 subunit gene deletion. Mol. Pharmacol., 67 (6): 2007-15. [PMID:15749993]

9. Gotti, C; Moretti, M; Zanardi, A; Gaimarri, A; Champtiaux, N; Changeux, JP; Whiteaker, P; Marks, MJ; Clementi, F; Zoli, M. (2005) Heterogeneity and selective targeting of neuronal nicotinic acetylcholine receptor (nAChR) subtypes expressed on retinal afferents of the superior colliculus and lateral geniculate nucleus: identification of a new native nAChR subtype alpha3beta2(alpha5 or beta3) enriched in retinocollicular afferents. Mol. Pharmacol., 68 (4): 1162-71. [PMID:16049166]

10. Grady, SR; Moretti, M; Zoli, M; Marks, MJ; Zanardi, A; Pucci, L; Clementi, F; Gotti, C. (2009) Rodent habenulo-interpeduncular pathway expresses a large variety of uncommon nAChR subtypes, but only the alpha3beta4* and alpha3beta3beta4* subtypes mediate acetylcholine release. J. Neurosci., 29 (7): 2272-82. [PMID:19228980]

11. 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]

12. Hirose, S; Iwata, H; Akiyoshi, H; Kobayashi, K; Ito, M; Wada, K; Kaneko, S; Mitsudome, A. (1999) A novel mutation of CHRNA4 responsible for autosomal dominant nocturnal frontal lobe epilepsy. Neurology, 53 (8): 1749-53. [PMID:10563623]

13. Klaassen, A; Glykys, J; Maguire, J; Labarca, C; Mody, I; Boulter, J. (2006) Seizures and enhanced cortical GABAergic inhibition in two mouse models of human autosomal dominant nocturnal frontal lobe epilepsy. Proc. Natl. Acad. Sci. U.S.A., 103 (50): 19152-7. [PMID:17146052]

14. Labarca, C; Schwarz, J; Deshpande, P; Schwarz, S; Nowak, MW; Fonck, C; Nashmi, R; Kofuji, P; Dang, H; Shi, W; et al.. (2001) Point mutant mice with hypersensitive alpha 4 nicotinic receptors show dopaminergic deficits and increased anxiety. Proc. Natl. Acad. Sci. U.S.A., 98 (5): 2786-91. [PMID:11226318]

15. Leniger, T; Kananura, C; Hufnagel, A; Bertrand, S; Bertrand, D; Steinlein, OK. (2003) A new Chrna4 mutation with low penetrance in nocturnal frontal lobe epilepsy. Epilepsia, 44 (7): 981-5. [PMID:12823585]

16. 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]

17. Marubio, LM; del Mar Arroyo-Jimenez, M; Cordero-Erausquin, M; Léna, C; Le Novère, N; de Kerchove d'Exaerde, A; Huchet, M; Damaj, MI; Changeux, JP. (1999) Reduced antinociception in mice lacking neuronal nicotinic receptor subunits. Nature, 398 (6730): 805-10. [PMID:10235262]

18. Marubio, LM; Gardier, AM; Durier, S; David, D; Klink, R; Arroyo-Jimenez, MM; McIntosh, JM; Rossi, F; Champtiaux, N; Zoli, M; et al.. (2003) Effects of nicotine in the dopaminergic system of mice lacking the alpha4 subunit of neuronal nicotinic acetylcholine receptors. Eur. J. Neurosci., 17 (7): 1329-37. [PMID:12713636]

19. Monteggia, LM; Gopalakrishnan, M; Touma, E; Idler, KB; Nash, N; Arneric, SP; Sullivan, JP; Giordano, T. (1995) Cloning and transient expression of genes encoding the human alpha 4 and beta 2 neuronal nicotinic acetylcholine receptor (nAChR) subunits. Gene, 155 (2): 189-93. [PMID:7721089]

20. Phillips, HA; Marini, C; Scheffer, IE; Sutherland, GR; Mulley, JC; Berkovic, SF. (2000) A de novo mutation in sporadic nocturnal frontal lobe epilepsy. Ann. Neurol., 48 (2): 264-7. [PMID:10939581]

21. Quik, M; Polonskaya, Y; Gillespie, A; Jakowec, M; Lloyd, GK; Langston, JW. (2000) Localization of nicotinic receptor subunit mRNAs in monkey brain by in situ hybridization. J. Comp. Neurol., 425 (1): 58-69. [PMID:10940942]

22. Ross, SA; Wong, JY; Clifford, JJ; Kinsella, A; Massalas, JS; Horne, MK; Scheffer, IE; Kola, I; Waddington, JL; Berkovic, SF; et al.. (2000) Phenotypic characterization of an alpha 4 neuronal nicotinic acetylcholine receptor subunit knock-out mouse. J. Neurosci., 20 (17): 6431-41. [PMID:10964949]

23. 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]

24. Scholze, P; Ciuraszkiewicz, A; Groessl, F; Orr-Urtreger, A; McIntosh, JM; Huck, S. (2011) α4β2 nicotinic acetylcholine receptors in the early postnatal mouse superior cervical ganglion. Dev Neurobiol,  [Epub ahead of print]. [PMID:21207369]

25. Shao, XM; Tan, W; Xiu, J; Puskar, N; Fonck, C; Lester, HA; Feldman, JL. (2008) Alpha4* nicotinic receptors in preBotzinger complex mediate cholinergic/nicotinic modulation of respiratory rhythm. J. Neurosci., 28 (2): 519-28. [PMID:18184794]

26. Steinlein, OK; Magnusson, A; Stoodt, J; Bertrand, S; Weiland, S; Berkovic, SF; Nakken, KO; Propping, P; Bertrand, D. (1997) An insertion mutation of the CHRNA4 gene in a family with autosomal dominant nocturnal frontal lobe epilepsy. Hum. Mol. Genet., 6 (6): 943-7. [PMID:9175743]

27. Steinlein, OK; Mulley, JC; Propping, P; Wallace, RH; Phillips, HA; Sutherland, GR; Scheffer, IE; Berkovic, SF. (1995) A missense mutation in the neuronal nicotinic acetylcholine receptor alpha 4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy. Nat. Genet., 11 (2): 201-3. [PMID:7550350]

28. Tapper, AR; McKinney, SL; Marks, MJ; Lester, HA. (2007) Nicotine responses in hypersensitive and knockout alpha 4 mice account for tolerance to both hypothermia and locomotor suppression in wild-type mice. Physiol. Genomics, 31 (3): 422-8. [PMID:17712039]

29. Tapper, AR; McKinney, SL; Nashmi, R; Schwarz, J; Deshpande, P; Labarca, C; Whiteaker, P; Marks, MJ; Collins, AC; Lester, HA. (2004) Nicotine activation of alpha4* receptors: sufficient for reward, tolerance, and sensitization. Science, 306 (5698): 1029-32. [PMID:15528443]

30. Teper, Y; Whyte, D; Cahir, E; Lester, HA; Grady, SR; Marks, MJ; Cohen, BN; Fonck, C; McClure-Begley, T; McIntosh, JM; et al.. (2007) Nicotine-induced dystonic arousal complex in a mouse line harboring a human autosomal-dominant nocturnal frontal lobe epilepsy mutation. J. Neurosci., 27 (38): 10128-42. [PMID:17881519]

31. Weiland, S; Witzemann, V; Villarroel, A; Propping, P; Steinlein, O. (1996) An amino acid exchange in the second transmembrane segment of a neuronal nicotinic receptor causes partial epilepsy by altering its desensitization kinetics. FEBS Lett., 398 (1): 91-6. [PMID:8946959]

32. Whiteaker, P; Cooper, JF; Salminen, O; Marks, MJ; McClure-Begley, TD; Brown, RW; Collins, AC; Lindstrom, JM. (2006) Immunolabeling demonstrates the interdependence of mouse brain alpha4 and beta2 nicotinic acetylcholine receptor subunit expression. J. Comp. Neurol., 499 (6): 1016-38. [PMID:17072836]

33. Wong, JY; Ross, SA; McColl, C; Massalas, JS; Powney, E; Finkelstein, DI; Clark, M; Horne, MK; Berkovic, SF; Drago, J. (2002) Proconvulsant-induced seizures in alpha(4) nicotinic acetylcholine receptor subunit knockout mice. Neuropharmacology, 43 (1): 55-64. [PMID:12213259]

34. Zhu, G; Okada, M; Yoshida, S; Ueno, S; Mori, F; Takahara, T; Saito, R; Miura, Y; Kishi, A; Tomiyama, M; et al.. (2008) Rats harboring S284L Chrna4 mutation show attenuation of synaptic and extrasynaptic GABAergic transmission and exhibit the nocturnal frontal lobe epilepsy phenotype. J. Neurosci., 28 (47): 12465-76. [PMID:19020039]

To cite this database page, please use the following:

Cecilia Gotti, Michael. J. Marks, Neil S. Millar, Susan Wonnacott.
Nicotinic acetylcholine receptors: α4. Last modified on 23/01/2012. Accessed on 23/05/2013. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=465.


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