Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Neuropharmacology
2014 Oct 01;85:471-81. doi: 10.1016/j.neuropharm.2014.05.014.
Show Gene links
Show Anatomy links
Two rare variations, D478N and D478E, that occur at the same amino acid residue in nicotinic acetylcholine receptor (nAChR) α2 subunit influence nAChR function.
Dash B
,
Li MD
.
???displayArticle.abstract???
There occur two rare variations, Asp(D)478Asn(N) and Asp(D)478Glu(E), in the putative cytoplasmic amphipathic α-helices of human nicotinic acetylcholine receptor (nAChR) α2 subunit as a result of mutation in the 1st (G → A: rs141072985) and 3rd (C → A: rs56344740) nucleotide of its 478th triplet codon (GAC). We assessed the effects of these two variations on the function of α2β2- and α2β4-nAChRs as they could alter the electronegativity and/or the structure of the cytoplasmic 'portals' (framed by subunit amphipathic α-helices) necessary for obligate ion permeation from extracellular space to cytoplasm. We injected decreasing ratio of subunit cRNAs (α:β; 10:1, 1:1 and 1:10) into Xenopus oocytes to express putative low-sensitivity (LS; 10:1), intermediate-sensitivity (IS; 1:1) and high sensitivity (HS; 1:10) isoforms of wild type and variant α2β2- and α2β4-nAChRs. Two-electrode voltage clamp analyses indicate that the agonist (ACh or nicotine) induced peak current responses (Imax) of α2β2-nAChR isoforms and those of α2β4-nAChR isoforms are increased (1.3-4.7-fold) as a result of D478E variation. The α2 subunit D478N variation only increases the Imax of IS (∼2-fold) or HS (1.4-2.1-fold) α2β2-nAChRs. Concentration-response curves constructed indicate no effect on agonist sensitivities of LS and HS isoforms of α2β2- or α2β4-nAChRs as a result of either variation in α2 subunit. Between the two variant nAChRs, α2(D478E)*-nAChR isoforms generally yield higher Imax than those of respective α2(D478N)*-nAChR isoforms. These effects could be attributed to alteration in cytoplasmic 'portals' and/or ion permeation through it owing to change in amino acid electronegativity (D → N) and side chain length (D → E) in nAChR α2 subunit.
Bierut,
Variants in nicotinic receptors and risk for nicotine dependence.
2008, Pubmed
Bierut,
Variants in nicotinic receptors and risk for nicotine dependence.
2008,
Pubmed
Carland,
Mutagenic analysis of the intracellular portals of the human 5-HT3A receptor.
2013,
Pubmed
Dash,
Identification of N-terminal extracellular domain determinants in nicotinic acetylcholine receptor (nAChR) α6 subunits that influence effects of wild-type or mutant β3 subunits on function of α6β2*- or α6β4*-nAChR.
2011,
Pubmed
,
Xenbase
Dash,
Reporter mutation studies show that nicotinic acetylcholine receptor (nAChR) α5 Subunits and/or variants modulate function of α6*-nAChR.
2011,
Pubmed
,
Xenbase
Dash,
Modulation of recombinant, α2*, α3* or α4*-nicotinic acetylcholine receptor (nAChR) function by nAChR β3 subunits.
2012,
Pubmed
,
Xenbase
Dash,
Modulation of gain-of-function α6*-nicotinic acetylcholine receptor by β3 subunits.
2012,
Pubmed
,
Xenbase
Dash,
A signal peptide missense mutation associated with nicotine dependence alters α2*-nicotinic acetylcholine receptor function.
2014,
Pubmed
,
Xenbase
Finer-Moore,
Amphipathic analysis and possible formation of the ion channel in an acetylcholine receptor.
1984,
Pubmed
Frahm,
Aversion to nicotine is regulated by the balanced activity of β4 and α5 nicotinic receptor subunits in the medial habenula.
2011,
Pubmed
,
Xenbase
George,
Function of human α3β4α5 nicotinic acetylcholine receptors is reduced by the α5(D398N) variant.
2012,
Pubmed
,
Xenbase
Groot-Kormelink,
Formation of functional alpha3beta4alpha5 human neuronal nicotinic receptors in Xenopus oocytes: a reporter mutation approach.
2001,
Pubmed
,
Xenbase
Hales,
Common determinants of single channel conductance within the large cytoplasmic loop of 5-hydroxytryptamine type 3 and alpha4beta2 nicotinic acetylcholine receptors.
2006,
Pubmed
Hong,
A genetically modulated, intrinsic cingulate circuit supports human nicotine addiction.
2010,
Pubmed
Kelley,
A cytoplasmic region determines single-channel conductance in 5-HT3 receptors.
2003,
Pubmed
Kukhtina,
Intracellular domain of nicotinic acetylcholine receptor: the importance of being unfolded.
2006,
Pubmed
Kuryatov,
Acetylcholine receptor (AChR) α5 subunit variant associated with risk for nicotine dependence and lung cancer reduces (α4β2)₂α5 AChR function.
2011,
Pubmed
,
Xenbase
Li,
Functional characterization of the α5(Asn398) variant associated with risk for nicotine dependence in the α3β4α5 nicotinic receptor.
2011,
Pubmed
Lukas,
International Union of Pharmacology. XX. Current status of the nomenclature for nicotinic acetylcholine receptors and their subunits.
1999,
Pubmed
Miyazawa,
Structure and gating mechanism of the acetylcholine receptor pore.
2003,
Pubmed
Nelson,
Alternate stoichiometries of alpha4beta2 nicotinic acetylcholine receptors.
2003,
Pubmed
,
Xenbase
Slimko,
Codon optimization of Caenorhabditis elegans GluCl ion channel genes for mammalian cells dramatically improves expression levels.
2003,
Pubmed
,
Xenbase
Tammimäki,
Impact of human D398N single nucleotide polymorphism on intracellular calcium response mediated by α3β4α5 nicotinic acetylcholine receptors.
2012,
Pubmed
Thompson,
A single ring of charged amino acids at one end of the pore can control ion selectivity in the 5-HT3 receptor.
2003,
Pubmed
Thorgeirsson,
A variant associated with nicotine dependence, lung cancer and peripheral arterial disease.
2008,
Pubmed
Unwin,
Refined structure of the nicotinic acetylcholine receptor at 4A resolution.
2005,
Pubmed
Zwart,
Four pharmacologically distinct subtypes of alpha4beta2 nicotinic acetylcholine receptor expressed in Xenopus laevis oocytes.
1998,
Pubmed
,
Xenbase
