A signal peptide missense mutation associated with nicotine dependence alters α2-nicotinic acetylcholine receptor function

A cytosine to thymidine (C → T) missense mutation in the signal peptide (SP) sequence (rs2472553) of the nicotinic acetylcholine receptor (nAChR) α2 subunit produces a threonine-to-isoleucine substitution (T22I) often associated with nicotine dependence (ND). We assessed effects on function of α2*-n...

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Veröffentlicht in:Neuropharmacology 2014-04, Vol.79, p.715-725
Hauptverfasser: Dash, Bhagirathi, Lukas, Ronald J., Li, Ming D.
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Sprache:eng
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Zusammenfassung:A cytosine to thymidine (C → T) missense mutation in the signal peptide (SP) sequence (rs2472553) of the nicotinic acetylcholine receptor (nAChR) α2 subunit produces a threonine-to-isoleucine substitution (T22I) often associated with nicotine dependence (ND). We assessed effects on function of α2*-nAChR (‘*’indicates presence of additional subunits) of this mutation, which could alter SP cleavage, RNA/protein secondary structure, and/or efficiency of transcription, translation, subunit assembly, receptor trafficking or cell surface expression. Two-electrode voltage clamp analyses indicate peak current responses to ACh or nicotine are decreased 2.8–5.8-fold for putative low sensitivity (LS; 10:1 ratio of α:β subunit cRNAs injected) α2β2- or α2β4-nAChR and increased for putative high sensitivity (HS; 1:10 α:β subunit ratio) α2β2- (5.7–15-fold) or α2β4- (1.9–2.2-fold) nAChR as a result of the mutation. Agonist potencies are decreased 1.6–4-fold for putative LS or HS α2(T22I)β2-nAChR or for either α2*-nAChR subtype formed in the presence of equal amounts of subunit cRNA, slightly decreased for LS α2(T22I)β4-nAChR, but increased 1.4–2.4-fold for HS α2(T22I)β4-nAChR relative to receptors containing wild-type α2 subunits. These effects suggest that the α2 subunit SP mutation generally favors formation of LS receptor isoforms. We hypothesize that lower sensitivity of human α2*-nAChR to nicotine could contribute to increased susceptibility to ND. To our knowledge this is the first report of a SP mutation having a functional effect in a member of cys-loop family of ligand-gated ion channels. •nAChR α2 signal peptide mutation (T22I) is often associated with nicotine dependence.•Effects of this mutation on α2β2- and α2β4-nAChR function were studied.•Risk allele, isoleucine, reduces the Imax of low sensitivity α2(β2 or β4)-nAChR.•Risk variant increases Imax of high-sensitivity α2(β2 or β4)-nAChR.•Risk variant generally favors formation of low-sensitivity receptor isoforms.
ISSN:0028-3908
1873-7064
DOI:10.1016/j.neuropharm.2014.01.021