Genetic Change Prevents Nicotine Binding

Smoking is the largest single preventable cause of death and disease worldwide. In Australia, in 1998, 15% of all deaths were from smoking related illnesses (1). Smoking behaviour is influenced by several factors such as nicotine dependence, genetic factors and psychosocial factors. Nicotine causes short-term increases in blood pressure, heart rate and the flow of blood from the heart. It takes approximately seven seconds for the substance to reach the brain after inhalation. Nicotine addiction begins with high-affinity binding of nicotine to acetylcholine receptors in the brain.

By all means, nicotine should paralyze us or even kill us, explains Dennis Dougherty, a Professor of Chemistry at Caltech. Nicotine binds to a receptor in the brain’s neurons, a type of acetylcholine receptor which is also found in many muscle cells. When nicotine binds to these acetylcholine receptors, it increases the levels of several neurotransmitters. If nicotine could bind with these muscle cells, it would cause the muscles to contract with such force that the response could potentially be lethal. Fortunately this is not the case, but still leaves many asking, “Why not?”

It seems to be due to a slight tweaking in the structures of the acetylcholine receptors in the muscle cells and the ones present in brain cells. The shape of the receptors and the way in which chemicals bind and contort to fit into the receptor is determined by a variety of weak chemical interactions. Possibly the most important interaction for the binding of acetylcholine to the acetylcholine receptors in muscles, is the cation-π interaction. In this interaction, a positively charged ion and an electron-rich π system come together. This interaction also happens in brain cells, however, nicotine can make the exact same kind of strong cation-π interaction that acetylcholine makes in both brain and muscle cells.

A strong hydrogen bond is made in the brain’s acetylcholine receptors unlike the receptors in muscle cells which have weak hydrogen bonding. The difference in the binding potency is caused by a single point mutation that occurs in the receptors near the key tryptophan amino acid that produces 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,” Doherty explains, “and this is what allows the nicotine to make the strong cation-π interaction.” (2)
“We expected the nicotine’s charge would cause it to do the same thing, to have the same sort of strong interaction that acetylcholine has,” Dougherty states. “But we found that it didn’t.” (3)
So this explains why smoking doesn’t paralyze us, since the nicotine can’t get into the muscle’s acetylcholine receptors, it therefore can’t cause muscle contractions.

As well as solving a chemical mystery in nicotine addictions these findings may one day lead to better drugs to combat nicotine addiction and other neurological disorders such as Alzheimer’s disease, schizophrenia, epilepsy, autism and many more. It may even aid in developing a better drug than nicotine to produce the same enhancements of cognition, increase attention and without being addictive and toxic.

(1) http://www.abs.gov.au/ausstats/abs@.nsf/mf/4831.0.55.001 (28/03/09)

(2)(3) http://www.sciencedaily.com/releases/2009/03)0903232161121.htm (27/03/09)

http://www.americanheart.org/presenter.jhtml?identifier=4753 (29/03/09)

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