A research team from McGill and Vanderbilt Universities describes for the first time the mechanism of calcium transmission by ionotropic glutamate receptors, a mechanism that contributes to the cellular processes underlying learning and memory.
In a new study , a research team from McGill and Vanderbilt Universities sheds light on the molecular origins of certain forms of autism and intellectual disability.
For the first time, a research team has successfully produced atomic resolution images of the rapid transmission of calcium influx by the ionotropic glutamate receptor (iGluR). Because of their ability to transport calcium, iGluRs are of vital importance for many brain functions, including vision and the transmission of information from sensory organs. Calcium also induces changes in iGluR signaling and nerve connections, which are key cellular factors in the acquisition of knowledge and the storage of memories.
iGluRs also play a major role in brain development. We already knew that malfunctioning of these receptors, caused by genetic mutations, gave rise to certain forms of autism and intellectual disability. However, fundamental questions remained unanswered about the biochemical changes that iGluRs trigger in the brain by transporting calcium.
In the course of the study, the research team took millions of snapshots of an iGluR in action and discovered, against all odds, the existence of a pocket that temporarily traps calcium outside the receptor. Armed with this discovery, the team used high-resolution electrophysiological recordings to track the transmission of calcium to the nerve cell.
"The importance of these results lies in the fact that, for the first time, it has been possible to describe the calcium transport mechanism that governs the cellular processes underlying learning and memory," says Derek Bowie, lead author from McGill University for the study published in Nature Structural and Molecular Biology, and co-director of the School of Biomedical Sciences’ Cellular Information Systems Group.McGill University for the study published in Nature Structural and Molecular Biology, and co-director of the Cellular Information Systems Group in the School of Biomedical Sciences.
The biological mechanism uncovered has been preserved over time not only in all mammalian species, but also in organisms that took a different evolutionary path from humans over 500 million years ago.
"This protein was so well designed from the outset that it doesn’t seem to have needed to evolve," concludes Derek Bowie.
"Thanks to cryo-electron microscopy, we were able to visualize the tiny ions and water molecules in the canal pore, a quite incredible experience. This revealed an ancestral calcium-binding pocket, the function of which we were able to better understand with the help of Derek Bowie’s laboratory. Our discovery is fundamental from the point of view of calcium signaling in neurons, and raises interesting hypotheses about synaptic function that could be tested in future experiments," notes Teru Nakagawa, lead author from Vanderbilt University and Professor in the Department of Molecular Physiology and Biophysics at the Vanderbilt School of Medicine.
The study
The article "The open gate of the AMPA receptor forms a Ca2+ binding site critical in regulating ion transport", by Teru Nakagawa, Derek Bowie et al, was published in Nature Structural & Molecular Biology.
