Washington D.C. [USA], Oct. 5 : A recent research could pave the way to end tobacco cravings after researchers crystallized a protein that holds answers to how nicotine addiction occurs in the brain.
The breakthrough at the Peter O'Donnell comes after decades of failed attempts to crystallize and determine the 3D structure of a protein that will help scientists to develop new treatments by understanding nicotine's molecular effects.
Co-author Ryan Hibbs said, "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." The protein, called the a4a2 (alpha-4-beta-2) nicotinic receptor, sits on nerve cells in the brain.
Nicotine binds to the receptor when someone smokes a cigarette or chews tobacco, causing the protein to open a path for ions to enter the cell.
The process produces cognitive benefits such as increased memory and focus but is also highly addictive.
Until the new findings were generated, scientists didn't have a way to examine at atomic resolution how nicotine achieves these cognitive and addictive effects.
The 3D structures will help researchers understand how nicotine influences the activity of the receptor and lead to a medication that mimics its actions in the brain.
The finding may also have benefits in creating medications for certain types of epilepsy, mental illness, and dementia such as Alzheimer's, which are also associated with the nicotinic receptor.
However, Hibbs cautioned that testing of any ensuing treatment would likely take many years. Studies have shown that smoking cessation drugs have mixed results in treating nicotine addiction, as have other methods such as nicotine patches and chewing gum.
The receptor is "a critically important therapeutic target" for addiction and various mental and neurological disorders, said expert Joseph Takahashi.
For years scientists around the globe had concentrated efforts on the receptor found in the electric organ of a torpedo ray, a rich source of nicotinic receptors that yielded a wealth of biochemical information and held promise for obtaining a high-resolution atomic map of the protein.
"But they were never able to get the torpedo protein to crystallize. The protein from the ray proved too unstable and couldn't be genetically modified. Many very good research groups had tried to do this and failed. We took a different approach," Hibbs said. Instead, UT Southwestern researchers developed a method for mass producing nicotinic receptors by viral infection of a human cell line.
The team inserted genes encoding the proteins that make the receptor into the virus, and the infected human cells started producing large amounts of the receptor.
They then used detergent and other purification steps to separate the receptor from the cell membrane and wash away all other proteins.
Researchers were left with milligrams of the pure receptor that they mixed with chemicals known to promote crystallization.
The team looked at thousands of chemical combinations before eventually being able to grow crystals of the receptor, bound by nicotine and about 0.2 mm long.
Lastly, they used X-ray diffraction measurements to obtain a high-resolution structure of the receptor.
The findings were published in Nature..