期刊
FASEB JOURNAL
卷 29, 期 8, 页码 3389-3398出版社
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.14-268102
关键词
nicotine dependence; nicotinic acetylcholine receptors; Ca2+ permeability; fractional Ca2+ current
资金
- European Research Area Net (ERA-NET) Neuron NicoGene project
- U.S. National Institutes of Health (NIH) National Cancer Institute Grant [CA089392]
- NIH National Institute on Drug Abuse Grant [DA015663]
- NATIONAL CANCER INSTITUTE [P01CA089392] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON DRUG ABUSE [P30DA015663] Funding Source: NIH RePORTER
Neuronal nicotinic acetylcholine receptors (nAChRs) containing the alpha 5 subunit modulate nicotine consumption, and the human CHRNA5 rs16969968 polymorphism, causing the replacement of the aspartic acid residue at position 398 with an asparagine (alpha 5DN), has recently been associated with increased use of tobacco and higher incidence of lung cancer. We show that in ventral midbrain neurons, the alpha 5 subunit is essential for heteromeric nAChR-induced intracellular-free Ca2+ concentration elevations and that in alpha 5(-/-) mice, a class of large-amplitude nicotine-evoked currents is lost. Furthermore, the expression of the alpha 5DN subunit is not able to restore nicotinic responses, indicating a loss of function by this subunit in native neurons. To understand how alpha 5DN impairs heteromeric nAChR functions, we coexpressed alpha 4, alpha 5, or alpha 5DN subunits with a dimeric concatemer (beta 2 alpha 4) in a heterologous system, to obtain nAChRs with fixed stoichiometry. Both alpha 5(beta 2 alpha 4)(2) and alpha 5DN(beta 2 alpha 4)(2) nAChRs yielded similar levels of functional expression and Ca2+ permeability, measured as fractional Ca2+ currents (8.2 +/- 0.7% and 8.0 +/- 1.9%, respectively), 2-fold higher than alpha 4 (beta 2 alpha 4)(2). Our results indicate that the loss of function of nicotinic responses observed in alpha 5DN-expressing ventral midbrain neurons is neither due to an intrinsic inability of this subunit to form functional nAChRs nor to an altered Ca2+ permeability but likely to intracellular modulation.
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