If nicotine liked muscle receptors as much as it likes brain receptors, a single cigarette would kill. Scientists have finally figured out why the molecule is so picky--a finding that may shed light on the addictiveness of smoking.
For nicotine--or any molecule--to interact with its receptor, the two must bind. Having opposite charges on the molecule and the receptor's binding site, referred to as the "box," helps. But the nicotine receptors in the brain and muscles are nearly identical--nicotine has a positive charge, and both receptors' boxes have a negative charge. So something else must explain why the brain loves nicotine whereas muscles shun it.
After more than a decade of work, Dennis Dougherty, a chemist at the California Institute of Technology in Pasadena, and his colleagues finally have the answer. It turns out that a single amino acid makes all the difference. Near the box region, the brain receptor has a lysine molecule, whereas the muscle receptor has a glycine molecule. What the lysine does, Dougherty and colleagues report online this week in Nature, is change the shape of the brain receptor's box, effectively making its negative charge more accessible to nicotine--a situation known as a cation-pi interaction. "The box reshapes so nicotine can cozy up," Dougherty says.
For its part, the box in the muscle receptor is ideally configured for a molecule known as acetylcholine, which helps muscles contract. When Dougherty's team switched out the muscle receptor's glycine for a lysine, the muscle embraced nicotine as if it were acetylcholine. It's a good thing that doesn't happen in the body, says Mark Levandoski, a chemist at Grinnell College in Iowa, who was not part of the study. Smoking would immediately trigger abnormal contractions that would paralyze muscles, like those involved in breathing. "If nicotine were lighting up our muscles the way acetylcholine does, we'd be in big trouble," Levandoski says.
Scientists can only speculate about why the brain and muscle receptors differ so much. For now, Dougherty and his lab want to determine whether the binding between other nicotine-family receptors and pharmaceutical drugs also involves cation-pi interactions. Studying the binding interactions within the nicotine receptor family might lead not only to new ways of helping people stop smoking, he says, but also to new treatments for illnesses such as Alzheimer's disease, autism, Parkinson's disease, and schizophrenia.