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

NEUROPHARMACOLOGY

卷:79

Article

Dash, Bhagirathi¹  Lukas, Ronald J.²  Li, Ming D.¹ 

[1] Univ Virginia, Sch Med, Dept Psychiat & Neurobehav Sci, Charlottesville, VA 22911 USA

[2] Barrow Neurol Inst, Div Neurobiol, Phoenix, AZ 85013 USA

关键词: Nicotinic acetylcholine receptor;    Signal peptide;    Single nucleotide polymorphism;    Missense mutation;    Receptor structure-function;    Electrophysiology;   

DOI  :  10.1016/j.neuropharm.2014.01.021

来源: Elsevier

【 摘 要 】

A cytosine to thymidine (C -> T) missense mutation in the signal peptide (SP) sequence (rs2472553) of the nicotinic acetylcholine receptor (nAChR) alpha 2 subunit produces a threonine-to-isoleucine substitution (T22I) often associated with nicotine dependence (ND). We assessed effects on function of alpha 2*-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 ratib of alpha:beta subunit cRNAs injected) alpha 2 beta 2- or alpha 2 beta 4-nAChR and increased for putative high sensitivity (HS; 1:10 alpha:beta subunit ratio) alpha 2 beta 2- (5.7-15-fold) or alpha 2 beta 4- (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 alpha 2(T22I)beta 2-nAChR or for either alpha 2*-nAChR subtype formed in the presence of equal amounts of subunit cRNA, slightly decreased for LS alpha 2(T22I)beta 4-nAChR, but increased 1.4-2.4-fold for HS alpha 2(T22I)beta 4-nAChR relative to receptors containing wild-type alpha 2 subunits. These effects suggest that the alpha 2 subunit SP mutation generally favors formation of LS receptor isoforms. We hypothesize that lower sensitivity of human alpha 2*-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. (C) 2014 Elsevier Ltd. All rights reserved.

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