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nicotinic acetylcholine receptor α4 subunit

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Target id: 465

Nomenclature: nicotinic acetylcholine receptor α4 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 4 627 20q13.33 CHRNA4 cholinergic receptor nicotinic alpha 4 subunit 29
Mouse 4 629 2 103.54 cM Chrna4 cholinergic receptor, nicotinic, alpha polypeptide 4 2
Rat 4 630 3q43 Chrna4 cholinergic receptor nicotinic alpha 4 subunit 14
Previous and Unofficial Names Click here for help
EBN | EBN1 | NARAC | neuronal acetylcholine receptor subunit alpha-4 | Acra4 | BFNC | Neuronal, α-bungarotoxin-insensitive | cholinergic receptor, nicotinic, alpha 4 (neuronal) | cholinergic receptor, nicotinic alpha 4 | cholinergic receptor
Database Links Click here for help
Alphafold P43681 (Hs), O70174 (Mm), P09483 (Rn)
CATH/Gene3D 2.70.170.10
ChEMBL Target CHEMBL1882 (Hs), CHEMBL4457 (Mm), CHEMBL307 (Rn)
DrugBank Target P43681 (Hs)
Ensembl Gene ENSG00000101204 (Hs), ENSMUSG00000027577 (Mm), ENSRNOG00000011202 (Rn)
Entrez Gene 1137 (Hs), 11438 (Mm), 25590 (Rn)
Human Protein Atlas ENSG00000101204 (Hs)
KEGG Gene hsa:1137 (Hs), mmu:11438 (Mm), rno:25590 (Rn)
OMIM 118504 (Hs)
Orphanet ORPHA119414 (Hs)
Pharos P43681 (Hs)
RefSeq Nucleotide NM_000744 (Hs), NM_015730 (Mm), NM_024354 (Rn)
RefSeq Protein NP_000735 (Hs), NP_056545 (Mm), NP_077330 (Rn)
UniProtKB P43681 (Hs), O70174 (Mm), P09483 (Rn)
Wikipedia CHRNA4 (Hs)
Functional Characteristics Click here for help
α4β2: PCa/PNa = 1.65, Pf = 2.6 – 2.9%; α4β4: Pf = 1.5 – 3.0 %
Natural/Endogenous Ligands Click here for help
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)

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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 9.7 – 11.0 pKd
⤷ pKd 10.5 – 11.0 (Kd 3.3x10-11 – 1x10-11 M) α4β2
pKd 9.7 (Kd 1.87x10-10 M) α4β4
[3H]epibatidine Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Full agonist 9.7 – 11.0 pKd
⤷ pKd 10.5 – 11.0 (Kd 3.3x10-11 – 1x10-11 M) α4β2
pKd 9.7 (Kd 1.87x10-10 M) α4β4
[3H]cytisine Small molecule or natural product Ligand is labelled Ligand is radioactive Rn Full agonist 10.0 pKd
⤷ pKd 10.0 (Kd 1x10-10 M) α4β2
[3H]cytisine Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Full agonist 9.2 – 10.0 pKd
⤷ pKd 10.0 (Kd 1x10-10 M) α4β4
pKd 9.2 – 9.4 (Kd 6.3x10-10 – 4.3x10-10 M) α4β2
[3H]nicotine Small molecule or natural product Ligand is labelled Ligand is radioactive Rn Full agonist 9.4 pKd
⤷ pKd 9.4 (Kd 4x10-10 M) α4β2
[125I]epibatidine Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Rn Full agonist 9.0 – 9.5 pKd
⤷ pKd 9.3 – 9.5 (Kd 4.6x10-10 – 3x10-10 M) α4β2
pKd 9.0 – 9.1 (Kd 9.4x10-10 – 8.5x10-10 M) α4β4
[3H]epibatidine Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Rn Full agonist 9.0 – 9.5 pKd
⤷ pKd 9.3 – 9.5 (Kd 4.6x10-10 – 3x10-10 M) α4β2
pKd 9.0 – 9.1 (Kd 9.4x10-10 – 8.5x10-10 M) α4β4
tebanicline Small molecule or natural product Rn Partial agonist 10.4 pKi 9
⤷ pKi 10.4 (Ki 3.7x10-11 M) [9]
varenicline Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Agonist 10.0 – 10.4 pKi 7,30
⤷ pKi 10.4 (Ki 4x10-11 M) α4β2 [30]
Description: In vitro affinity for recombinant human α4β2 receptors in membranes from transfected CHO-K1 cells, determined by displacement of [3H]-(−)-cytisine.
pKi 10.0 (Ki 1.1x10-10 M) [7]
Description: Binding affinity to human nicotinic acetylcholine receptor α4β2 expressed in IMR32 cells using [3H]epibatidine radioligand.
nicotine Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Agonist 8.7 pKi 30
⤷ pKi 8.7 (Ki 2.2x10-9 M) α4β2 [30]
Description: In vitro affinity for recombinant human α4β2 receptors in membranes from transfected CHO-K1 cells, determined by displacement of [3H]-(−)-cytisine.
lobeline Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Agonist 8.3 pKi 11
⤷ pKi 8.3 (Ki 5x10-9 M) [11]
Description: Binding affinity for α4β2 nAChR, mesuring [3H]epibatidine displacement
rivanicline Small molecule or natural product Hs Agonist ~7.6 pKi 8
⤷ pKi ~7.6 (Ki ~2.5x10-8 M) [8]
Description: Binding affinity for the α4β2 nicotinic acetylcholine receptor.
rivanicline Small molecule or natural product Rn Agonist 7.6 pKi 1
⤷ pKi 7.6 (Ki 2.6x10-8 M) [1]
TC-2559 Small molecule or natural product Hs Full agonist - - 5
⤷ α4β2 [5]
View species-specific agonist tables
Agonist Comments
We have tagged the nicotinic acetylcholine receptor α4 subunit as the primary drug target for varenicline, but note that the interaction is with the α4β2 heteromer, and binding site is not identified.
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
SUVN-911 Small molecule or natural product Hs Antagonist 8.8 pKi 30
⤷ pKi 8.8 (Ki 1.5x10-9 M) α4β2 [30]
Description: In vitro affinity for recombinant human α4β2 receptors in membranes from transfected CHO-K1 cells, determined by displacement of [3H]-(−)-cytisine.
atracurium Small molecule or natural product Approved drug Click here for species-specific activity table Immunopharmacology Ligand Hs Antagonist 7.7 – 8.1 pIC50 20
⤷ pIC50 7.7 – 8.1 (IC50 2.11x10-8 – 7.9x10-9 M) [20]
Description: Antagonism of ACh activation of human α4β2 nACh receptors expressed in Xenopus oocytes, at different ACh concentrations.
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 Click here for species-specific activity table Hs - no 5.3 – 6.5 pIC50 - no
⤷ pIC50 5.3 – 6.5 (IC50 4.9x10-6 – 3.3x10-7 M) α4β4
Not voltage dependent
pIC50 5.4 – 5.4 (IC50 4.1x10-6 – 3.6x10-6 M) α4β2
Not voltage dependent
hexamethonium Small molecule or natural product Click here for species-specific activity table Hs - no 4.0 – 5.2 pIC50 - no
⤷ pIC50 4.5 – 5.2 (IC50 2.9x10-5 – 6.8x10-6 M) α4β2
Not voltage dependent
pIC50 4.0 (IC50 9.1x10-5 M) α4β4
Not voltage dependent
A-867744 Small molecule or natural product Click here for species-specific activity table Hs - no - - - no 25
⤷ α4β2 [25]
Not voltage dependent
NS1738 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs - no - - - no 42
⤷ α4β2 [42]
Not voltage dependent
Allosteric Modulators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Concentration range (M) Voltage-dependent (mV) Reference
LY2087101 Small molecule or natural product Click here for species-specific activity table Hs Positive - - - no 3
⤷ potentiates α4β2 and α4β4 [3]
Not voltage dependent
NS9283 Small molecule or natural product Ligand has a PDB structure Hs Positive - - - no 23
⤷ α4β2 and α4β4 [23]
Not voltage dependent
Immuno Process Associations
Immuno Process:  B cell (activation)
Immuno Process:  Cellular signalling
Tissue Distribution Click here for help
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:  26
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:  27-28,33
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:  44
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:  4,15-17,35
Brain:-
Widely expressed with intense expression in thalamus and cerebral cortex.
Expression level:  High
Species:  Rat
Technique:  in situ hybridisation
References:  14
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 [18]. 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 [32].
Physiological Consequences of Altering Gene Expression Click here for help
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:  12,36,39-40
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:  27-28,33,45
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:  13,22
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:  21
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:  41
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:  46
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Epilepsy, nocturnal frontal lobe, 1; ENFL1
Synonyms: Autosomal dominant nocturnal frontal lobe epilepsy [Orphanet: ORPHA98784]
OMIM: 600513
Orphanet: ORPHA98784
References:  19,24,31,37-38,43
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
In-frame insertion Human 263insL 788insGCT The insertion does not alter the reading frame and results in the insertion of a leucine residue. This affects the M2 region of the protein and results in reduced permeability to calcium. 37
Missense Human S248F 38,43
Missense Human S252L 755C>T The amino acid substitution is in the Torpedo α subunit of the receptor 19,31
Missense Human T265I C>T Mutation results in increased acetylcholine sensitivity 24
Disease:  Sporadic amyotrophic lateral sclerosis
Synonyms: SALS
Disease Ontology: DOID:332
OMIM: 105400
References:  34
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Missense Human T32N c.95C>A Exon 2. Extracellular loop. 34
Missense Human R336C c.1006 C>T Exon 5. Intracellular loop. 34
Missense Human R345C c.1033C>T Exon 5. Intracellular loop. 34
Missense Human P446L c.1337C>T Exon 5. Intracellular loop. 34
Missense Human P451L c.1352C>T Exon 5. Intracellular loop. 34
Missense Human G454S c.1360G>A Exon 5. Intracellular loop. 34
Missense Human R487Q c.1460G>A Exon 5. Intracellular loop. 34
Missense Human R495Q c.1484G>A Exon 5. Intracellular loop. 34
Missense Human Q572R c.1715 >G Exon 5. Intracellular loop. 34
Disease:  Sporadic nocturnal frontal lobe epilepsy
OMIM: 600513
References:  6
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Missense Human S252L 755C>T The amino acid substitution is in the Torpedo α subunit of the receptor 19,31
Missense Human R308H 923G>A Exon 5 6
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 [10]). Alternative nomenclature is given in parenthesis.

References

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1. Bencherif M, Lovette ME, Fowler KW, Arrington S, Reeves L, Caldwell WS, Lippiello PM. (1996) RJR-2403: a nicotinic agonist with CNS selectivity I. In vitro characterization. J Pharmacol Exp Ther, 279 (3): 1413-21. [PMID:8968366]

2. 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]

3. Broad LM, Zwart R, Pearson KH, Lee M, Wallace L, McPhie GI, Emkey R, Hollinshead SP, Dell CP, Baker SR et al.. (2006) Identification and pharmacological profile of a new class of selective nicotinic acetylcholine receptor potentiators. J Pharmacol Exp Ther, 318 (3): 1108-17. [PMID:16738207]

4. 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]

5. Chen Y, Sharples TJ, Phillips KG, Benedetti G, Broad LM, Zwart R, Sher E. (2003) The nicotinic alpha 4 beta 2 receptor selective agonist, TC-2559, increases dopamine neuronal activity in the ventral tegmental area of rat midbrain slices. Neuropharmacology, 45 (3): 334-44. [PMID:12871651]

6. 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]

7. Coe JW, Brooks PR, Wirtz MC, Bashore CG, Bianco KE, Vetelino MG, Arnold EP, Lebel LA, Fox CB, Tingley 3rd FD et al.. (2005) 3,5-Bicyclic aryl piperidines: a novel class of alpha4beta2 neuronal nicotinic receptor partial agonists for smoking cessation. Bioorg Med Chem Lett, 15 (22): 4889-97. [PMID:16171993]

8. Dogruer D, Lee M, Dukat M, Damaj MI, Martin BR, Glennon RA. (2004) 3-(4-Aminobutyn-1-yl)pyridines: binding at alpha 4 beta 2 nicotinic cholinergic receptors. Bioorg Med Chem Lett, 14 (2): 523-6. [PMID:14698195]

9. Donnelly-Roberts DL, Puttfarcken PS, Kuntzweiler TA, Briggs CA, Anderson DJ, Campbell JE, Piattoni-Kaplan M, McKenna DG, Wasicak JT, Holladay MW et al.. (1998) ABT-594 [(R)-5-(2-azetidinylmethoxy)-2-chloropyridine]: a novel, orally effective analgesic acting via neuronal nicotinic acetylcholine receptors: I. In vitro characterization. J Pharmacol Exp Ther, 285 (2): 777-86. [PMID:9580626]

10. 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]

11. Edink E, Akdemir A, Jansen C, van Elk R, Zuiderveld O, de Kanter FJ, van Muijlwijk-Koezen JE, Smit AB, Leurs R, de Esch IJ. (2012) Structure-based design, synthesis and structure-activity relationships of dibenzosuberyl- and benzoate-substituted tropines as ligands for acetylcholine-binding protein. Bioorg Med Chem Lett, 22 (3): 1448-54. [PMID:22243960]

12. 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]

13. 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]

14. 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]

15. 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]

16. 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]

17. 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]

18. 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]

19. 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]

20. 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]

21. 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 USA, 103 (50): 19152-7. [PMID:17146052]

22. 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 USA, 98 (5): 2786-91. [PMID:11226318]

23. Lee CH, Zhu C, Malysz J, Campbell T, Shaughnessy T, Honore P, Polakowski J, Gopalakrishnan M. (2011) α4β2 neuronal nicotinic receptor positive allosteric modulation: an approach for improving the therapeutic index of α4β2 nAChR agonists in pain. Biochem Pharmacol, 82 (8): 959-66. [PMID:21763685]

24. 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]

25. 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]

26. 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]

27. 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]

28. 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]

29. 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]

30. 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]

31. 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]

32. 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]

33. 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]

34. 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]

35. 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, 71 (5): 390-9. [PMID:21485013]

36. 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]

37. 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]

38. 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]

39. 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]

40. 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]

41. 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]

42. 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]

43. 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]

44. 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]

45. 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]

46. 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]

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