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Mar 24, 2009

Mutation Discovered that Allows Nicotine to Bind to Brain Receptors but Not Muscle Cells

  • A tiny genetic mutation is the key to understanding why nicotine, which binds to brain receptors with such addictive potency, is rendered powerless in muscle cells that contain the same type of receptor, according to research at the California Institute of Technology.

    Unlike acetylcholine’s ability to bind to the acetylcholine receptors in both the brain and muscles, nicotine is only able to make the same kind of strong cation-pi interaction in the brain.

    “In addition, we found that nicotine makes a strong hydrogen bond in the brain's acetylcholine receptors,” notes Dennis Dougherty, Ph.D., the George Grant Hoag professor of chemistry at Caltech. “This same hydrogen bond, in the receptors in muscle cells, is weak.”

    This difference in binding potency is caused by a single point mutation that occurs in the receptor near the key tryptophan amino acid that makes the cation-pi 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,” Dr. Dougherty explains. “And that is what allows the nicotine to make the strong cation-p interaction.”

    Back in the late 1990s, Dr. Dougherty and colleagues had shown that the cation-pi interaction is a key part of acetylcholine’s ability to bind to the acetylcholine receptors in muscles. Though they assumed that nicotine’s charge would cause it to have a similar reaction to acetylcholine, they found that wasn’t the case. It then took them another 10 years to see what happens in brain cell acetylcholine receptors when presented with nicotine.

    The current study appears in the March 26 issue of Nature in a paper titled “Nicotine binding to brain receptors requires a strong cation-p interaction”.



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