Unexpectedly complex interactions between neurotransmitter receptors and other key proteins help explain how the brain processes information so quickly, according to a new study, published in the journal Neuron.
Understanding how the brain transmits information is a major focus of neuroscientists, since problems in this area are thought to underlie many brain disorders, from autism to Alzheimer’s disease. A major unknown, however, has been how receptors responsible for rapid signalling between neurones are able to respond so quickly.
University of Liverpool researchers from the Institute of Translational Medicine, in collaboration with groups at McGill University in Canada and the University of Oxford, have addressed this question by combining a number of experimental techniques to examine these fast-acting proteins. Known as AMPA receptors, they play a major role in brain signalling, but their full function cannot be understood by studying them in isolation.
Dr Tim Green, a Senior Lecturer who headed the team working at the University of Liverpool and member of the Liverpool Neuroscience Group, said: “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.
“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.”
Derek Bowie, lead researcher and Professor of Pharmacology at McGill and Director of GÉPROM, a Quebec interuniversity research group that studies the function and role of membrane proteins in health and disease, said: “The findings reveal that the interplay between AMPA receptors and their protein partners that modulate them is much more complex than previously thought. A computational method called molecular dynamics has been key to understanding what controls these interactions.”
Philip Biggin, an Associate Professor at the University of Oxford and another of the senior authors, said: “A computational method called molecular dynamics has been key to understanding what controls these interactions. These simulations are effectively a computational microscope that allow us to examine the motions of these proteins in very high detail.”
Professor Bowie, adds: “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. 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 Canadian Institutes of Health Research, the Leverhulme Trust, the Medical Research Council, 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).
The study, entitled “Distinct Structural Pathways Coordinate the Activation of AMPA Receptor-Auxiliary Subunit Complexes”, can be found here.