New research is changing what we thought we knew about a common brain receptor in the brain. Glutamate receptors modulate most of the excitatory neural activity in the central nervous system. The glutamate receptor itself has several layers. When glutamate is bound, ion channels on the structure open, conducting ions and electrical charge through the channel; neural signals are propagated using those electrical charges. Disruption in glutamate receptors has been implicated in many disorders.
New research reported in Nature has revealed novel details about how glutamate binds to its receptor, changing what we thought we knew. Glutamate's association with disease has made it a target of therapeutic drugs, so this study could have implications on the development and application of current and new medications.
Previous work has suggested that up to four molecules of glutamate can bind to the receptor in a simple progressive fashion, and neural conductivity was thought to increase as the number of glutamate molecules bound to the receptor increased.
But in this study, the researchers used cryo-electron microscopy and computational tools to show that glutamate molecules bind the receptor in selective patterns, and the subunits of the receptor don't bind to glutamate molecules independently.
“We actually carried out experiments in the conditions where we see all these intermediates, one glutamate and then two glutamates, three glutamates, and then it binds all four,” said senior study author Alexander Sobolevsky, Ph.D., an associate professor of biochemistry and molecular biophysics at Columbia University.
The research showed that a molecule of glutamate must bind to one of two subunits on the receptor before other subunits are able to bind to additional glutamate molecules. Conductivity was also not directly correlated to the number of glutamate molecules that were attached; conduction did not necessarily increase incrementally. Glutamate seems to have a more complex influence on neural signaling than we understood.
Now, the researchers want to learn more about how other molecules may be influencing the binding between glutamate and the receptor subunits.
Glutamate is thought to play a role in a variety of disorders, so this study may help scientists create better therapeutics for disorders including depression, epilepsy, Parkinson's disease, stroke, or dementia.