期刊
NEURON
卷 70, 期 3, 页码 522-535出版社
CELL PRESS
DOI: 10.1016/j.neuron.2011.04.013
关键词
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资金
- Helmholtz Association [31-002]
- Sonderforschungsbereich [SFB 665]
- Deutsche Forschungsgemeinschaft DFG [RA 424/5-1]
- MCB RAS
- RFBR
Nicotine dependence is linked to single nucleotide polymorphisms in the CHRNB4-CHRNA3-CHRNA5 gene cluster encoding the alpha 3 beta 4 alpha 5 nicotinic acetylcholine receptor (nAChR). Here we show that the beta 4 subunit is rate limiting for receptor activity, and that current increase by beta 4 is maximally competed by one of the most frequent variants associated with tobacco usage (D398N in alpha 5). We identify a beta 4-specific residue (S435), mapping to the intracellular vestibule of the alpha 3 beta 4 alpha 5 receptor in close proximity to alpha 5 D398N, that is essential for its ability to increase currents. Transgenic mice with targeted overexpression of Chrnb4 to endogenous sites display a strong aversion to nicotine that can be reversed by viral-mediated expression of the alpha 5 D398N variant in the medial habenula (MHb). Thus, this study both provides insights into alpha 3 beta 4 alpha 5 receptor-mediated mechanisms contributing to nicotine consumption, and identifies the MHb as a critical element in the circuitry controlling nicotine-dependent phenotypes.
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