A Signal Peptide Missense Mutation Associated With Nicotine Dependence Alters Î±2*-Nicotinic Acetylcholine Receptor Function
A cytosine to thymidine (C â†’ T) missense mutation in the signal peptide (SP) sequence (rs2472553) of the nicotinic acetylcholine receptor (nAChR) Î±2 subunit produces a threonine-to-isoleucine substitution (T22I) often associated with nicotine dependence (ND). We assessed effects on function of Î±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 ratio of Î±:Î² subunit cRNAs injected) Î±2Î²2- or Î±2Î²4-nAChR and increased for putative high sensitivity (HS; 1:10 Î±:Î² subunit ratio) Î±2Î²2- (5.7-15-fold) or Î±2Î²4- (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 Î±2(T22I)Î²2-nAChR or for either Î±2*-nAChR subtype formed in the presence of equal amounts of subunit cRNA, slightly decreased for LS Î±2(T22I)Î²4-nAChR, but increased 1.4-2.4-fold for HS Î±2(T22I)Î²4-nAChR relative to receptors containing wild-type Î±2 subunits. These effects suggest that the Î±2 subunit SP mutation generally favors formation of LS receptor isoforms. We hypothesize that lower sensitivity of human Î±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. Â© 2014 Elsevier Ltd. All rights reserved.
Digital Object Identifier (DOI)
Dash, Bhagirathi; Lukas, Ronald J.; and Li, Ming D., "A Signal Peptide Missense Mutation Associated With Nicotine Dependence Alters Î±2*-Nicotinic Acetylcholine Receptor Function" (2014). Translational Neuroscience. 182.