尼古丁安逸地“躺”在大腦受體“骨架”中,。（圖片提供:Dennis Dougherty）
如果尼古丁像喜歡大腦受體那樣愛(ài)上肌肉受體，那么只需一根煙就可以讓你斃命,。如今,，科學(xué)家終于搞清了這種分子為何如此挑剔——這一發(fā)現(xiàn)為解決吸煙成癮的問(wèn)題帶來(lái)了曙光。
尼古?。ɑ蚴侨魏我环N分子）如果想要與它的受體相互結(jié)合,，這兩種物質(zhì)之間必須要形成化學(xué)鍵，即分子要攜帶相反的電荷,，同時(shí)還要具有受體的結(jié)合位點(diǎn),，從而最終形成了一副“骨架”。盡管尼古丁在大腦以及肌肉中的受體幾乎是一樣的——尼古丁攜帶一個(gè)正電荷，而這兩種受體則都攜帶一個(gè)負(fù)電荷,，但為什么只有大腦受體喜歡尼古丁,，而肌肉受體卻唯恐避之不及呢？這里面一定有其他的解釋,。
經(jīng)過(guò)十多年的研究工作,，美國(guó)帕薩迪納市加利福尼亞理工學(xué)院的化學(xué)家Dennis Dougherty和他的同事終于找到了問(wèn)題的答案——所有的差別都是由一個(gè)簡(jiǎn)單的氨基酸造成的。在“骨架”的附近,，大腦受體具有一個(gè)賴氨酸分子,，而肌肉受體則具有一個(gè)甘氨酸分子。那么賴氨酸分子到底產(chǎn)生了什么樣的作用呢,？研究人員發(fā)現(xiàn),，它改變了大腦受體“骨架”的形狀，使它的負(fù)電荷能夠更加有效地接近尼古丁分子,，這一過(guò)程即人們所說(shuō)的陽(yáng)離子—派交互作用,。Dougherty表示：“經(jīng)過(guò)改造的‘骨架’使尼古丁感到很舒服。”Dougherty和同事在本周的英國(guó)《自然》雜志網(wǎng)絡(luò)版上報(bào)告了這一研究成果,。
而對(duì)于肌肉受體的“骨架”而言,，它能夠完美地轉(zhuǎn)化為已知的乙酰膽堿分子。當(dāng)Dougherty的研究小組將肌肉受體的甘氨酸替換為賴氨酸后,，肌肉受體便能夠像乙酰膽堿那樣“擁抱”尼古丁了,。幸虧這一切沒(méi)有真的發(fā)生在人體中，并未參與此項(xiàng)研究的美國(guó)愛(ài)荷華州Grinnell學(xué)院的化學(xué)家Mark Levandoski這樣說(shuō)道,。吸煙能夠迅速引發(fā)反常的收縮從而麻痹肌肉,，這會(huì)使一些人感到呼吸急促。Levandoski表示：“如果尼古丁能夠像點(diǎn)燃乙酰膽堿那樣喚醒我們的肌肉,，那可真是一個(gè)大麻煩,。”
科學(xué)家暫時(shí)只能推測(cè)大腦受體和肌肉受體為什么具有如此大的差別。目前,，Dougherty和他的實(shí)驗(yàn)室打算確定其他尼古丁類受體和藥物的結(jié)合是否也存在陽(yáng)離子—派交互作用,。Dougherty指出，搞清尼古丁受體家族中的結(jié)合交互作用不但能夠幫助人們戒煙,，同時(shí)還可以為早老性癡呆癥,、孤獨(dú)癥、帕金森氏癥以及精神分裂癥的治療提供新的方法,。（生物谷Bioon.com）
生物谷推薦原始出處：
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.
