"New Therapies for Addiction"

UT Southwestern researchers today published in Nature atomic-scale blueprints of the most abundant class of brain nicotinic acetylcholine receptors. A structural understanding of the protein, found in neurons, could lead to new ways to treat nicotine addiction from smoking and vaping.

Three-dimensional structures of nicotinic acetylcholine receptor determined by cryo-EM, courtesy of Hibbs Lab. "When this receptor binds to either the neurotransmitter acetylcholine or to nicotine, it leads to activation of the neuron, which then sends signals to other neurons," said Dr. Ryan Hibbs, corresponding author of the study and Assistant Professor of Neuroscience and Biophysics with the Peter O'Donnell Jr. Brain Institute at UT Southwestern. "This process of 'chemical neurotransmission' underlies all fast communication between neurons. This specific receptor is tightly linked to nicotine addiction."

Researchers obtained the high-resolution structures using the University's $22.5 million cryo-electron microscopy (cryo-EM) facility, where samples are rapidly frozen to prevent the formation of damaging ice crystals and then viewed at minus 321 degrees Fahrenheit (cryogenic temperatures). UT Southwestern's facility -- which runs round-the-clock -- is one of the world's top facilities for cryo-EM structural biology.

Two novel aspects of the study make it stand out in the fields of structural biology and neuroscience. First, the researchers uncovered new biology about how the receptor binds nicotine in the brain, Dr. Hibbs said. Second are the findings related to technical aspects of how the protein assembles.

"The discovery we made about different ways in which nicotine interacts with this receptor may help in designing drugs to treat nicotine addiction and neurodegeneration," he added. "With respect to assembly of the receptor, classical structure determination techniques generally require a homogeneous sample. However, for this protein, the receptor assembles in multiple ways that have important biological consequences. For example, a misbalance in the ratio of the two subunit arrangements is tied to both nicotine addiction and to congenital epilepsy."

The protein they studied is made up of five sub-units, of two types -- α and β. These α and β sub-units assemble in two different ratios into two distinct five-sub-unit complexes, a 3α:2β form and a 2α:3β form. Complexes of both ratios are found in the brain.

Source: Science Daily