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-ð interaction, in which a positively charged ion and an electron-rich ð system come together.
Back in the late 1990s, Dougherty and colleagues had shown that the cation-ð 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-ð 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."