Cryo-electron microscopy reveals structures of a muscle-type nicotinic acetylcholine receptor

New research co-led by a University of Ottawa Faculty of Medicine professor is shedding light on some of the mysterious dynamics that define the interplay between nerves and muscle. The findings could lead to a better understanding of a range of neurological disorders and help pave the way for the design of drugs to target them.

With a team of international collaborators, uOttawa's Dr. John Baenziger employed a technique called cryo-electron microscopy, a groundbreaking technology in structural biology that provides scientists with unprecedented views of the inner workings of the molecules in cells. This work was done while he was on sabbatical in France, benefiting from powerful microscopes at L'Institut de Biologie Structurale in Grenoble.

The state-of-the-art technology helped the research team solve atomic resolution structures of the muscle-type nicotinic acetylcholine receptor, or nAChR. That's an important family of proteins that has been studied widely in large part because understanding its function can help unlock treatment paths for neurological and neurodegenerative disorders. But over decades, progress has been limited by the absence of high-resolution images of structures that allow scientists to better understand their atomic details.

Now, in a study just published online in Neuron, an influential peer-reviewed journal in the field of neuroscience, Dr. Baenziger and his colleagues solved for the first time three structures of the nAChR found in electric rays. In a quirk of science, these ocean bottom-dwellers of the Torpedo genus happen to have nAChR in abundance.

One of the structures was solved in the absence of any bound neurotransmitter, one in the presence of a bound neurotransmitter, and a third in the presence of bound nicotine.

These newly revealed structures provide the first atomic-level insight into the mechanisms by which neurotransmitter binding leads to muscle nAChR activation, according to Dr. Baenziger, one of the two senior authors and the lead contact for the study.

"To better understand how these proteins work and to better understand how to target them with pharmaceuticals we need to solve their structures and then understand how neurotransmitter binding changes their structures leading to their activation" he says.

One of the paper's reviewers said the new research made "several unique and important contributions" and there was enough material to generate "dozens of further studies correlating structure with function."

Nerves communicate with other nerves and with muscle by releasing chemical neurotransmitters that bind to receptors to generate a response. This receptor-mediated response is critical to proper function. But genetic mutations ultimately alter this response leading to disease.

Dr. Baenziger suggests that the team's new insights will be of deep interest to scientists studying diseases such as congenital myasthenic syndrome and myasthenia gravis, both muscle-weakening disorders caused by a breakdown in the communication between nerves and muscles. He says the research might eventually lead to the development of new treatments for both, as well as other neurological ailments.

These structures will help us understand the molecular processes that underlie both diseases and may eventually help us design therapeutics."

Dr. John Baenziger, Professor, Department of Biochemistry, Microbiology and Immunology, University of Ottawa

The research detailed in Neuron also expands knowledge into how specific receptors bind nicotine-;the highly addictive compound found in tobacco. Nicotine binding to nAChRs ultimately leads to the qualities that hook smokers and make that drug such a preventable cause of disease and death.

Dr. Baenziger says he hopes to return to France later this year to conduct more innovative research with his collaborators, including the study's co-lead author Dr. Hugues Nury of L'Institut de Biologie Structurale and the Université Grenoble Alpes. Dr. Baenziger's sabbatical stay between 2019 and 2020 was partly funded by the Université Grenoble Alpes.

"I hope that many more exciting things will come out of this collaboration," he says.

Source:
Journal reference:

Zarkadas, E., et al. (2022) Conformational transitions and ligand-binding to a muscle-type nicotinic acetylcholine receptor. Neuron. doi.org/10.1016/j.neuron.2022.01.013.

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