尼古丁安逸地“躺”在大脑受体“骨架”中。（图片提供:Dennis Dougherty）
如果尼古丁像喜欢大脑受体那样爱上肌肉受体，那么只需一根烟就可以让你毙命。如今，科学家终于搞清了这种分子为何如此挑剔——这一发现为解决吸烟成瘾的问题带来了曙光。
尼古丁（或是任何一种分子）如果想要与它的受体相互结合，这两种物质之间必须要形成化学键，即分子要携带相反的电荷，同时还要具有受体的结合位点，从而最终形成了一副“骨架”。尽管尼古丁在大脑以及肌肉中的受体几乎是一样的——尼古丁携带一个正电荷，而这两种受体则都携带一个负电荷，但为什么只有大脑受体喜欢尼古丁，而肌肉受体却唯恐避之不及呢？这里面一定有其他的解释。
经过十多年的研究工作，美国帕萨迪纳市加利福尼亚理工学院的化学家Dennis Dougherty和他的同事终于找到了问题的答案——所有的差别都是由一个简单的氨基酸造成的。在“骨架”的附近，大脑受体具有一个赖氨酸分子，而肌肉受体则具有一个甘氨酸分子。那么赖氨酸分子到底产生了什么样的作用呢？研究人员发现，它改变了大脑受体“骨架”的形状，使它的负电荷能够更加有效地接近尼古丁分子，这一过程即人们所说的阳离子—派交互作用。Dougherty表示：“经过改造的‘骨架’使尼古丁感到很舒服。”Dougherty和同事在本周的英国《自然》杂志网络版上报告了这一研究成果。
而对于肌肉受体的“骨架”而言，它能够完美地转化为已知的乙酰胆碱分子。当Dougherty的研究小组将肌肉受体的甘氨酸替换为赖氨酸后，肌肉受体便能够像乙酰胆碱那样“拥抱”尼古丁了。幸亏这一切没有真的发生在人体中，并未参与此项研究的美国爱荷华州Grinnell学院的化学家Mark Levandoski这样说道。吸烟能够迅速引发反常的收缩从而麻痹肌肉，这会使一些人感到呼吸急促。Levandoski表示：“如果尼古丁能够像点燃乙酰胆碱那样唤醒我们的肌肉，那可真是一个大麻烦。”
科学家暂时只能推测大脑受体和肌肉受体为什么具有如此大的差别。目前，Dougherty和他的实验室打算确定其他尼古丁类受体和药物的结合是否也存在阳离子—派交互作用。Dougherty指出，搞清尼古丁受体家族中的结合交互作用不但能够帮助人们戒烟，同时还可以为早老性痴呆症、孤独症、帕金森氏症以及精神分裂症的治疗提供新的方法。（生物谷Bioon.com）
生物谷推荐原始出处：
Nature advance online publication 1 March 2009 | doi:10.1038/nature07768
Nicotine binding to brain receptors requires a strong cation–π interaction
Xinan Xiu1,3, Nyssa L. Puskar1,3, Jai A. P. Shanata1, Henry A. Lester2 & Dennis A. Dougherty1
1 Divisions of Chemistry and Chemical Engineering and,
2 Biology, California Institute of Technology, 1200 East California Boulevard, Pasadena, California 91125, USA
3 These authors contributed equally to this work.
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 42 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 42 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 depression1. 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.
