Scientists expect the findings – published in Nature – to eventually lead to new treatments.
In the United States, 1 in 5 deaths are attributed to smoking, and tobacco use is responsible for nearly 6 million deaths globally every year.
Smoking is the number one cause of preventable death in the U.S., according to the Centers for Disease Control and Prevention (CDC).
Existing drugs, nicotine patches, and chewing gum have had mixed success in helping people to quit using nicotine products.
For decades, scientists have been trying to identify the 3-D structure of a protein known as the alpha-4-beta-2 (α4β2) nicotinic receptor.
Until now, there has been no way to study nicotine’s effects on the brain, and how it becomes addictive, at the atomic level.
The current breakthrough should lead to a new understanding of the molecular effects of nicotine.
The α4β2 nicotinic receptor is located on nerve cells in the brain. When a person smokes a cigarette or chews tobacco, the nicotine binds to this receptor. This opens a pathway for ions to enter the cell.
There are cognitive benefits, including an enhancement of memory and focus, but it is also very addictive.
Searching for clues in the torpedo ray
For years, teams from around the world have been expecting the torpedo ray to provide the clues they needed to understand how this protein works.
The ray’s electric organ is known to be a rich source of nicotinic receptors, and it provided a wealth of key information. However, the close-up view the scientists craved remained elusive.
The protein from the ray was too unstable. It could not be genetically modified, and it would not crystallize.
The present team tried a new strategy; they found a way to produce large numbers of nicotinic receptors by infecting a human cell line with a virus.
They inserted genes into the virus, and these genes encoded the required proteins. The cells that were infected with the virus began to produce large amounts of the receptor.
Using detergent and other methods of purification, the researchers separated the receptor from the cell membrane, and they eliminated all the other proteins. They were left with milligrams of the pure receptor.
Next, they mixed the receptor with chemicals that normally promote crystallization. They looked at thousands of chemical combinations, and they finally succeeded in growing crystals of the receptor.
The crystals were bound by nicotine, and they measured around 0.2 millimeters in length.
To obtain a high-resolution structure of the receptor, the researchers used X-ray diffraction measurements.
The next step will be to look at the structures when there is no nicotine, and when molecules with different functional effects are applied.
Comparing the structures in this way is expected to shed light on how nicotine acts and what it does differently from other chemicals.
Possible future applications
Study co-author Dr. Ryan Hibbs, assistant professor of neuroscience and biophysics with the O’Donnell Brain Institute at the University of Texas Southwestern Medical Center in Dallas, notes that it could take years to develop and test any treatment.
“It’s going to require a huge team of people and a pharmaceutical company to study the protein and develop the drugs, but I think this is the first major stepping stone to making that happen.”
Dr. Ryan Hibbs
Other conditions linked to the nicotinic receptor include some types of epilepsy, mental illness, and dementia – for example, Alzheimer’s disease. These, too, could benefit from the discovery.
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