The secrets of fast neurotransmission in the brain

New study reveals what controls the speed of neurotransmission

AMPA Receptor and auxiliary protein

AMPA Receptor and auxiliary protein (Click to enlarge)

Recent work from departmental researchers in collaboration with groups at McGill University in Canada and the University of Liverpool has provided new insights into a crucial aspect of neuronal receptor behaviour. The work, published in Neuron (1) reveals that surprisingly complex interactions between neurotransmitter receptors and other key proteins help explain the brain's ability to process information with phenomenal speed.

A major goal of neuroscientists is to understand how the brain signals information, since this is the basis for memory and learning. Moreover, problems in signalling are though to contribute to many brain disorders from Alzheimer's disease to autism. At the heart of this signalling are fast-acting protein molecules called AMPA receptors, but exactly why these receptors are able to respond so quickly has been difficult to answer.

To tackle this problem, the teams from Oxford, McGill and Liverpool combined multiple techniques to examine the atomic structure of the AMPA receptor and how it interacts with its partner or auxiliary proteins.

"A computational method called molecular dynamics has been key to understanding what controls these interactions" says Philip Biggin, an Associate Professor at the University of Oxford and one of the senior authors. "These simulations are effectively a computational microscope that allow us to examine the motions of these proteins in very high detail," he says.

"The findings reveal that the interplay between AMPA receptors and their protein partners that modulate them is much more complex than previously thought," says Derek Bowie, Professor of Pharmacology at McGill and another of the senior authors.

"A key aspect of this work has been the way that the three groups have used a mix of experimental and theoretical approaches to answer these questions" says Tim Green, a Senior Lecturer who headed the team working at the University of Liverpool. "Our work, using X-ray crystallography, allowed us to confirm many of the study's findings by looking at the atomic structure of AMPA receptors."

"By combining the efforts of three labs with expertise in different experimental techniques, we've been able to achieve an important breakthrough in understanding how the brain transmits information so rapidly," Bowie says. "Our next steps will be to understand if these rapid interactions can be targeted for the development of novel therapeutic compounds."

This research was supported by the Leverhulme Trust, the Medical Research Council, the Canadian Institutes of Health Research, the Natural Sciences and Engineering Research Council of Canada, the Alfred Benzon Foundation, and the Canada Research Chairs program. Funding for GÉPROM is provided by the Fonds de recherche du Québec - Santé (FRQS). Beam-time at the Diamond synchrotron was provided through the Biotechnology and Biological Sciences Research Council (BBSRC). ARCHER supercomputer time was made available via the HecBioSim consortium.

Reference

  1. “Distinct Structural Pathways Coordinate the Activation of AMPA Receptor-Auxiliary Subunit Complexes,” G. Brent Dawe et al, Neuron, published online February 25, 2016. http://www.cell.com/neuron/fulltext/S0896-6273(16)00063-5

 

 

 

 





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