Acetylcholine Receptor (AChR) alpha 5 Subunit Variant Associated with Risk for Nicotine Dependence and Lung Cancer Reduces (alpha 4 beta 2)(2)alpha 5 AChR Function

Genomic studies have identified a D398N variation in the alpha 5 subunit of nicotinic acetylcholine receptors (AChRs) that increases risk of nicotine dependence and lung cancer. (alpha 4 beta 2)(2)alpha 5 AChRs are a significant brain presynaptic subtype in brain. Their high sensitivity to activation by nicotine and high Ca2+ permeability give them substantial functional impact. alpha 3 beta 4* and alpha 3 beta 2* AChRs are predominant postsynaptic AChRs in the autonomic nervous system, but rare in brain. The amino acid 398 of alpha 5 is located in the large cytoplasmic domain near the amphipathic alpha helix preceding the M4 transmembrane domain. These helices have been shown to influence AChR conductance by forming portals to the central channel. We report that alpha 5 Asn 398 lowers Ca2+ permeability and increases short-term desensitization in (alpha 4 beta 2)(2)alpha 5 but not in (alpha 3 beta 4)(2)alpha 5 or (alpha 3 beta 2)(2)alpha 5 AChRs. This suggests that a positive allosteric modulator would augment nicotine replacement therapy for those with this risk variant. alpha 5 D398N variation does not alter sensitivity to activation. The high sensitivity to activation and desensitization of (alpha 4 beta 2)(2)alpha 5 AChRs by nicotine results in a narrow concentration range in which activation and desensitization curves overlap. This region centers on 0.2 mu M nicotine, a concentration typically sustained in smokers. This concentration would desensitize 60% of these AChRs and permit smoldering activation of the remainder. The low sensitivity to activation and desensitization of (alpha 3 beta 4)(2)alpha 5 AChRs by nicotine results in a broad region of overlap centered near 10 mu M. Thus, at the nicotine concentrations in smokers, negligible activation or desensitization of this subtype would occur.