Molecular Neurobiology Group, Max-Delbrück-Centrum, Berlin, Germany.
Neuron. 2011 May 12;70(3):522-35. doi: 10.1016/j.neuron.2011.04.013.
Nicotine dependence is linked to single nucleotide polymorphisms in the CHRNB4-CHRNA3-CHRNA5 gene cluster encoding the α3β4α5 nicotinic acetylcholine receptor (nAChR). Here we show that the β4 subunit is rate limiting for receptor activity, and that current increase by β4 is maximally competed by one of the most frequent variants associated with tobacco usage (D398N in α5). We identify a β4-specific residue (S435), mapping to the intracellular vestibule of the α3β4α5 receptor in close proximity to α5 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 α5 D398N variant in the medial habenula (MHb). Thus, this study both provides insights into α3β4α5 receptor-mediated mechanisms contributing to nicotine consumption, and identifies the MHb as a critical element in the circuitry controlling nicotine-dependent phenotypes.
尼古丁依赖与编码α3β4α5 烟碱型乙酰胆碱受体 (nAChR) 的 CHRNB4-CHRNA3-CHRNA5 基因簇中的单核苷酸多态性有关。在这里，我们表明β4 亚基是受体活性的限速因子，而与烟草使用相关的最常见变体之一（α5 中的 D398N）最大程度地竞争β4 的电流增加。我们确定了一个β4 特异性残基（S435），该残基映射到α3β4α5 受体的细胞内前庭，与 α5 D398N 非常接近，这对于其增加电流的能力至关重要。在中枢内有核中靶向过表达 Chrnb4 的转基因小鼠对尼古丁表现出强烈的厌恶，这种厌恶可以通过病毒介导的 MHb 中 α5 D398N 变体的表达来逆转。因此，这项研究不仅深入了解了导致尼古丁消费的α3β4α5 受体介导机制，还确定了 MHb 作为控制尼古丁依赖表型的电路的关键元件。
