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Posted on May 10, 2018, 3 a.m.
Atomic scale blueprints have been published of the most abundant class of brain nicotinic acetylcholine receptors of which structural understandings found may lead to new therapies for vaping and smoking nicotine addictions, as published in Nature.
High resolution cryo-Em microscopy determined 3D structures of brain nicotinic acetylcholine receptors courtesy of Hibbs Lab, were used to show that when the receptor binds to either the nicotine or neurotransmitter acetylcholine it will lead to activation of the neuron sending signals to other neurons, the process of chemical neurotransmission underlies all fast communications between neurons, the specific receptor is strongly linked to nicotine addiction. The samples were rapidly frozen to prevent formation of damaging ice crystals then viewed at cryogenic temperatures. This study stands out in structural biology and neurosciences fields due to 2 novel aspects: new biology was uncovered about how receptors bind nicotine in the brain, and findings related to technical aspects of how the protein assembles.
The protein is made up of 5 subunits of two types - α and β. These α and β subunits assemble into 2 different ratios into 2 distinctive 5 subunit complexes, 3α:2β and 2α:3β complexes of both ratios can be found within the brain. Using antibody which only binds to β subunits researchers were able to tease out the structures from one sample; one receptor has 2 bound antibodies, the other has 3.
Previously the lab was able to obtain structure if one of the complexes using V-ray crystallography which was a first at the time due to crystallizing membrane protein difficulty. Obtaining crystals which refract high resolution is challenging, making cryo-Em powerful as it provides both arrangements from a single sample at higher resolutions.
Materials provided by UT Southwestern Medical Center.
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