吸烟不会引起肌肉收缩之谜已解开
2009-05-26 20:37:38   来源：   作者：  评论：0 点击：

尼古丁有使人上瘾的显著倾向，这种倾向是从其以高亲合力与大脑乙酰胆碱（ACh）受体相结合的能力开始的。如果它以相似的效率激发肌肉中的Ach受体（与 脑中的几乎完全相同）的话，那么吸烟将会引起严重肌肉收缩。

但这种现象不会发生，这是药理学上一个长期未解之谜，现在这个谜底在关于尼古丁与两种受体类型 相互作用之化学机制的一项深度研究中已被解开。与作为尼古丁上瘾分子基础的α4 和 β2受体亚单元的结合，既涉及氢键的形成，又涉及尼古丁的正电荷与一种特定的、保守的色氨酸残迹之间的阳离子-π强相互作用。

肌肉型受体也含有这种色氨 酸，但阳离子-π强相互作用不存在，氢键也较弱。这似乎是由于“结合袋”的总体形状的差别，而这种差别与关键色氨酸残迹附近一个单点突变相关。这些结果在 解决了一个分子谜题的同时，也可指导有可能用于神经疾病及戒烟治疗的新型类尼古丁药物的开发。

Nature458, 534-537 (26 March 2009) | doi :10.1038/nature07768 ; Received 26 November 2008; Accepted 9 January 2009; Published online 1 March 2009

Nicotine binding to brain receptors requires a strong cation–π interaction

Xinan Xiu 1 , 3 , Nyssa L. Puskar 1 , 3 , Jai A. P. Shanata 1 , Henry A. Lester 2 & Dennis A. Dougherty 1

Nicotine addiction begins with high-affinity binding of nicotine to acetylcholine (ACh) receptors in the brain. The end result is over 4,000,000 smoking-related deaths annually worldwide and the largest source of preventable mortality in developed countries. Stress reduction, pleasure, improved cognition and other central nervous system effects are strongly associated with smoking. However, if nicotine activated ACh receptors found in muscle as potently as it does brain ACh receptors, smoking would cause intolerable and perhaps fatal muscle contractions. Despite extensive pharmacological, functional and structural studies of ACh receptors, the basis for the differential action of nicotine on brain compared with muscle ACh receptors has not been determined. Here we show that at the α4 β2 brain receptors thought to underlie nicotine addiction, the high affinity for nicotine is the result of a strong cation–π interaction to a specific aromatic amino acid of the receptor, TrpB. In contrast, the low affinity for nicotine at the muscle-type ACh receptor is largely due to the fact that this key interaction is absent, even though the immediate binding site residues, including the key amino acid TrpB, are identical in the brain and muscle receptors. At the same time a hydrogen bond from nicotine to the backbone carbonyl of TrpB is enhanced in the neuronal receptor relative to the muscle type. A point mutation near TrpB that differentiates α4 β2 and muscle-type receptors seems to influence the shape of the binding site, allowing nicotine to interact more strongly with TrpB in the neuronal receptor. ACh receptors are established therapeutic targets for Alzheimer's disease, schizophrenia, Parkinson's disease, smoking cessation, pain, attention-deficit hyperactivity disorder, epilepsy, autism and depression . Along with solving a chemical mystery in nicotine addiction, our results provide guidance for efforts to develop drugs that target specific types of nicotinic receptors.