A hidden prepared passage is found in the nerve-muscle communication

Summary: An international research team has mapped the millisecond-by-millisecond process by which nerve signals activate muscles, discovering an intermediate “priming” step never before seen. This advance reveals that neuromuscular receptors move asynchronously (not in perfect unison as scientists long believed), redefining how communication between nerves and muscles is understood.

Using single-molecule imaging, the researchers captured atomic-level structures of the nicotinic acetylcholine receptor as it transitions from the resting state to the active state. The discovery could pave the way for the development of precision drugs to treat muscle-wasting diseases such as congenital myasthenic syndrome.

Key facts:

New ‘ready’ state identified: Researchers discovered that an intermediate step was missing in how neurotransmitter receptors activate muscle fibers. Rewriting a 50-year-old model: The team discovered that receiver components move asynchronously, overturning decades of scientific assumptions. Therapeutic promise: Insights can guide the design of new medications targeting neuromuscular and neurodegenerative disorders.

Source: University of Ottawa

An international research team led by a uOttawa Faculty of Medicine researcher has revealed highly detailed complexities in how nerve signals are activated at the neuromuscular junction, a specialized synapse that connects motor neurons to skeletal muscle fibers.

The team’s discovery offers a groundbreaking look at how neuromuscular signals are communicated on a millisecond time scale, findings that could have wide-ranging implications for our understanding of the interaction between nerves and muscles throughout the body.

This new knowledge could also help scientists design drugs for a group of conditions that weaken muscles as a result of disease-causing mutations.

Published in the high-impact journal Science, the collaborative team led by Dr. John Baenziger, professor at uOttawa School of Medicine, used cutting-edge “single molecule” techniques to capture several atomic resolution structures of a neurotransmitter receptor along its activation pathway.

In the end, the collaborators ended up capturing a missing link: an intermediate “ready” state that helps define communication between nerves and muscles.

“This new intermediate structure, called the primed state, is extremely important because it plays a critical role in shaping neuromuscular communication,” says Dr. Baenziger, lead author of the recently published paper.

“Our study provides the first look at this key intermediate along the activation pathway, in particular the step called priming.”

Dr. Baenziger says that since similar protein receptors are found in the brain, this “new knowledge has a broad impact on our understanding of communication at neuronal synapses.”

According to Dr. Baenziger, the groundbreaking new study and its insights at the atomic level dispel a scientific myth that has been assumed for decades.

He explains that for more than 50 years it has been assumed that these protein receptors are activated by a phenomenon called “concerted conformational transition.”

In this protein switching event, all parts of the protein were understood to move together synchronously, leading to a final activated state. The concerted conformational transition framework has ultimately been used to try to understand how disease-causing mutations or different drugs modulate function.

But in this major research publication, the team reveals that this “is absolutely false,” says Dr. Baenziger.

Their hard-won research reveals that, in fact, the individual components of the protein receptor move asynchronously, meaning that some parts move first while others move later.

“This information will be critical to understanding how disease-causing mutations and different drugs modulate neuromuscular communication, information that should ultimately lead to better drugs to treat congenital myasthenic syndrome and other diseases resulting from impaired synaptic communication.”

Dr. Baenziger’s dynamic laboratory at uOttawa Faculty of Medicine focuses on understanding how a protein neurotransmitter receptor, the “nicotinic acetylcholine receptor” (nAChR), shapes communication at the neuromuscular junction.

This receptor is an important member of a family of proteins that has been studied extensively, largely because understanding its function can help unlock treatment pathways for neurological and neurodegenerative disorders.

Now, armed with the findings of this new study, he and the collaborative team hope to fully understand how nAChR function is influenced in the context of this activation model. The research team will seek to resolve the structures of this receptor that harbor disease-causing mutations and evaluate how they react in the presence of different drugs.

“We want to use these new structures as templates to design better therapies,” says Dr. Baenziger, senior lecturer in the Faculty’s Department of Biochemistry, Microbiology and Immunology.

The new structures were solved by first author Dr. Mackenzie Thompson, who until recently was a doctoral student in Dr. Baenziger’s lab and is now a postdoctoral researcher at the University of California, Berkeley.

The team also included close coordination with Drs. Hugues Nury and Elefterios Zarkadas, both at the Institute of Structural Biology, a research institution in Grenoble, France, where Dr. Baenziger has cultivated fruitful collaborations. Dr. Corrie daCosta from uOttawa’s Faculty of Science also played an important role, bringing sophisticated single-molecule functional experiments to the study.

About this neuroscience research news

Author: Pablo Logotetis
Source: University of Ottawa
Contact: Paul Logothetis – University of Ottawa
Image: Image is credited to Neuroscience News.

Original Research: Closed access.
“Asynchronous subunit transitions stimulate acetylcholine receptor activation” by John Baenziger et al. Science

Abstract

Asynchronous subunit transitions stimulate acetylcholine receptor activation

Communication at synapses is facilitated by postsynaptic receptors, which convert a chemical signal into an electrical response.

For ligand-gated ion channels, agonist binding triggers rapid transitions through intermediate states leading to a transient open-pore conformation, and these transitions shape the postsynaptic response.

Here, we determined the structures of the muscle-type nicotinic acetylcholine receptor in unliganded, monoliganded, and diliganded states.

Agonist binding to a single site stabilizes a closed structure where an entire agonist-binding major subunit transitions into an active-like conformation, while the other unoccupied major subunit remains inactive, although primed for activation.

Binding this intermediate structure to single-channel recordings reports a sequential gating mechanism where asynchronous subunit transitions prime the receptor for gating, a finding with implications for an entire superfamily of pentameric ligand-gated ion channels.