Caltech researchers find tiny genetic change keeps nicotine from binding to muscle cells

March 24, 2009

PASADENA, Calif.--A tiny genetic mutation is the key to understanding why nicotine--which binds to brain receptors with such addictive potency--is virtually powerless in muscle cells that are studded with the same type of receptor. That's according to California Institute of Technology (Caltech) researchers, who report their findings in the March 26 issue of the journal Nature.

By all rights, nicotine ought to paralyze or even kill us, explains Dennis Dougherty, the George Grant Hoag Professor of Chemistry at Caltech and one of the leaders of the research team. After all, the receptor it binds to in the brain's neurons--a type of acetylcholine receptor, which also binds the neurotransmitter acetylcholine--is found in large numbers in muscle cells. Were nicotine to bind with those cells, it would cause muscles to contract with such force that the response would likely prove lethal.

Obviously, considering the data on smoking, that is not what happens. The question has long been: Why not?

"It's a chemical mystery," Dougherty admits. "We knew something subtle had to be going on here, but we didn't know exactly what."

That subtlety, it turns out, lies in the slight tweaking of the structure of the acetylcholine receptor in muscle cells versus its structure in brain cells.

The shape of the acetylcholine receptor, and the way the chemicals that bind with it contort themselves to fit into that receptor, is determined by a number of different weak chemical interactions. Perhaps most important is an interaction that Dougherty calls "underappreciated"--the cation-π interaction, in which a positively charged ion and an electron-rich π system come together.

Back in the late 1990s, Dougherty and colleagues had shown that the cation-π interaction is indeed a key part of acetylcholine's ability to bind to the acetylcholine receptors in muscles. "We assumed that nicotine's charge would cause it to do the same thing, to have the same sort of strong interaction that acetylcholine has," says Dougherty. "But we found that it didn't."

This would explain why smoking doesn't paralyze us; if the nicotine can't get into the muscle's acetylcholine receptors, it can't cause the muscles to contract.

But how, then, does nicotine work its addictive magic on the brain?

It took another decade for the scientists to be able to peek at what happens in brain cells' acetylcholine receptors when nicotine arrives on the scene. Turns out that in brain cells, unlike in muscle cells, nicotine makes the exact same kind of strong cation-π interaction that acetylcholine makes in both brain and muscle cells.

"In addition," Dougherty notes, "we found that nicotine makes a strong hydrogen bond in the brain's acetylcholine receptors. This same hydrogen bond, in the receptors in muscle cells, is weak."

The cause of this difference in binding potency, says Dougherty, is a single point mutation that occurs in the receptor near the key tryptophan amino acid that makes the cation-π interaction. "This one mutation means that, in the brain, nicotine can cozy up to this one particular tryptophan much more closely than it can in muscle cells," he explains. "And that is what allows the nicotine to make the strong cation-π interaction."

Dougherty says the best way to visualize this change is to think of the receptor as a box with one open side. "In muscle cells, this box is slightly distorted, so that the nicotine can't get to the tryptophan," he says. "But in the brain, the box is subtly reshaped. That's the thing: It's the shape, not the composition, of the box that changes. This allows the nicotine to make strong interactions, to become very potent. In other words, it's what allows nicotine to be addictive in the brain."

"Several projects in our labs are converging on the molecular and cellular mechanisms of the changes that occur when the brain is repeatedly exposed to nicotine," adds study coauthor Henry Lester, the Bren Professor of Biology at Caltech. "We think that the important events begin with the rather tight and selective interaction between nicotine and certain receptors in the brain. This Nature paper teaches us how this interaction occurs, at an unprecedented level of resolution."

Dougherty notes that these findings might one day lead to better drugs to combat nicotine addiction and other neurological disorders. "The receptor we describe in this paper is an important drug target," he says. "It might help pharmaceutical companies develop a better drug than nicotine to do the good things nicotine does--enhance cognition, increase attention--without being addictive and toxic."

California Institute of Technology

---

---

	The Nicotine Conspiracy by Arcturus Publishing In 2008 Allen Carr's Easyway to Stop Smoking celebrated its 25th anniversary in the knowledge that it has become the global leader in the field of drug-free smoking cessation. There are currently over 100 clinics in 38 countries and a publishing programme with sales of over 13 million books in 50 countries. The organisation continues to grow rapidly and the method is conservatively estimated to have cured more than 10 million smokers worldwide. Despite the phenomenal success and popularity of the method, Allen Carr's Easyway remains ignored by the Government and unavailable on the NHS which prefers to supply nicotine to addicts at taxpayers' expense via gums, patches etc and so perpetuates the addiction. In fact, the pharmaceutical industry, aided and abetted by the government...
	My Lady Nicotine A Study in Smoke by J. M. (James Matthew) Barrie (Author) This book is part of the TREDITION CLASSICS series. The creators of this series are united by passion for literature and driven by the intention of making all public domain books available in printed format again - worldwide. At tredition we believe that a great book never goes out of style. Several mostly non-profit literature projects provide content to tredition. To support their good work, tredition donates a portion of the proceeds from each sold copy. As a reader of a TREDITION CLASSICS book, you support our mission to save many of the amazing works of world literature from oblivion.
	Nicotine Safety and Toxicity by Neal L. Benowitz (Editor) Nicotine has been developed as a medication to assist smoking cessation, and is being considered as a possible drug for long-term maintenance of non-smoking. It is also undergoing evaluation as a possible treatment for several medical disorders, including ulcerative colitis, Alzheimer's disease, Parkinson's disease, Tourette's syndrome, attention deficit disorder, spasticity, and sleep apnea. Understanding its safety and toxicity is essential for drug developers, drug regulators, and clinicians making risk/benefit decisions about long-term nicotine therapy. Research on nicotine toxicity is also relevant to ongoing research on tobacco and health aimed at understanding the role of nicotine in contributing to tobacco-induced diseases. This book reviews the current scientific understanding...
	The Addicted Brain: Why We Abuse Drugs, Alcohol, and Nicotine (FT Press Science) by Michael Kuhar (Author) Addiction destroys lives. In The Addicted Brain, a leading neuroscientist explains how and why this happens–and presents advances in treatment and prevention. Using breathtaking brain imagery and other research, Michael Kuhar, Ph.D., shows the powerful, long-term brain changes that drugs can cause, revealing why it can be so difficult for addicts to escape their grip.   In plain English, Kuhar describes why some people are far more susceptible to addiction than others. He illuminates striking neural similarities between drugs and other pleasures potentially capable of causing abuse or addiction–including alcohol, gambling, sex, caffeine, and even Internet overuse. Finally, he outlines the 12 characteristics most often associated with successful treatment.   Authoritative and...
	If Only I Could Quit: Recovering From Nicotine Addiction by Karen Casey (Author) This complete resource brings together personal stories of recovery, Twelve Step guidance, and 90 daily meditations to help us become nicotine-free. If Only I Could Quit is written by one of Hazelden's most popular meditation authors and a recovering nicotine addict.
	Nicotine Dreams: A Story of Compulsive Gambling by Katie Cunningham (Author) Meet Kim, a fairly ordinary, middle-aged woman with a job, two adult children, and a difficult husband. For enjoyment, she plays the stock market, buys expensive handbags and sneaks an occasional cigarette. But when a casino opens within driving distance of her house, her life as she knows it will soon be over. This is a story of addiction. This is a story of one woman's descent into gambling hell, where the compulsion to play slots and power machines is so great, she will risk it all in order to place just one more bet.
	Quit and Stay Quit A Personal Program to Stop Smoking: Quit & Stay Quit Nicotine Cessation Program by Terry A Rustin M.D. (Author) A personal guidebook that leads smokers through the nicotine cessation program. Question and answer activities combined with information allow us to explore how smoking has subtly shaped our values, attitudes, and beliefs. By better understanding the nature and rituals surrounding smoking, we can develop a long-term program to quit and stay quit. This is part of the Quit & Stay Quit Nicotine Cessation Program. A simple, thorough, proven program to help people at any stage of nicotine use tackle the addiction--and possibly save their lives. What the Nicotine Cessation Program offers: -Imparts vital information about the nature and dangers of nicotine in clear, forthright language. -Enhances treatment outcomes with a multiformat program combining the best elements of...
	Smoking gun: cigarettes are addictive and deadly. So why are teens still smoking? (Close Up: Nicotine).: An article from: Junior Scholastic by John DiConsiglio (Author) This digital document is an article from Junior Scholastic, published by Scholastic, Inc. on October 4, 2002. The length of the article is 1268 words. The page length shown above is based on a typical 300-word page. The article is delivered in HTML format and is available in your Amazon.com Digital Locker immediately after purchase. You can view it with any web browser. Citation Details Title: Smoking gun: cigarettes are addictive and deadly. So why are teens still smoking? (Close Up: Nicotine). Author: John DiConsiglio Publication: Junior Scholastic (Magazine/Journal) Date: October 4, 2002 Publisher: Scholastic, Inc. Volume: 105 Issue: 3 Page: iv(2) Distributed by Thomson...
	New drugs emerging for nicotine dependence.(Rx): An article from: Internal Medicine News by Carl Sherman (Author) This digital document is an article from Internal Medicine News, published by Thomson Gale on February 1, 2005. The length of the article is 582 words. The page length shown above is based on a typical 300-word page. The article is delivered in HTML format and is available in your Amazon.com Digital Locker immediately after purchase. You can view it with any web browser. Citation Details Title: New drugs emerging for nicotine dependence.(Rx) Author: Carl Sherman Publication: Internal Medicine News (Magazine/Journal) Date: February 1, 2005 Publisher: Thomson Gale Volume: 38 Issue: 3 Page: 52(1) Distributed by Thomson...
	Breaking the nicotine habit (Postgraduate Medicine) by JTE Multimedia Nicotine is a powerful addictive drug. When you take a puff on a cigarette, your brain quickly gets the message that it wants more of the chemicals you're feeding it. That's why quitting smoking is just as hard, sometimes harder, than getting off drugs like cocaine or heroin. However, several new medications and devices have come along that can help you quit. Original Publication Date: December 1998