Workings of Key Protein That Affects Neuron Signaling in Brain Seen in Study

Researchers are one step closer to fully understanding how a group of proteins, called the AMPA receptors, work — potentially gaining an insight into how neurological diseases like Parkinson’s develop in the brain, a new study reports.

These findings may also help in the design of new treatment approaches.

The study, titled “Channel opening and gating mechanism in AMPA-subtype glutamate receptors,” was published in the journal Nature.

Several proteins contribute to the propagation of electrical signals in the brain, which are the basis of communication among neurons. AMPA receptors are a group of proteins that play a crucial role in neuronal signaling and, thus, in processes such as learning and memory. These proteins, which work as channels that let ion currents pass in order for neurons to communicate with other neurons, are activated by glutamate, the most important excitatory (or signal-sending) neurotransmitter in the brain.

AMPA receptors exist everywhere in the brain and have a crucial role in neuronal communication. Their malfunction has been implicated in the development of severe neurological diseases, including Parkinson’s, Alzheimer’s, anxiety, depression, and schizophrenia.

“With our new findings, we can now, for the first time, visualize how the neurotransmitter glutamate opens glutamate receptor ion channels,” Alexander Sobolevsky, a professor of biochemistry and molecular biophysics at Columbia University  and study’s senior author, said in a news release. “This is the fundamental process that directly affects learning and memory, and finding its structural determinants has been the primary goal of molecular neuroscience since the ’90s.”

Using cryo-electron microscopy, a technique that captures an array of two-dimensional images of a molecule and combines them into a three-dimensional structural image, researchers studied the activation mechanism of the AMPA receptors alone and when bound to auxiliary proteins that regulate their activity.

They were able to observe the behavior of these proteins from the moment that glutamate binds to them, triggering the opening of the channel and the start of neuronal signaling. It was the first time that AMPA receptors essentially were caught in action.

“These new fundamental discoveries have implications for our understanding of neurotransmission by glutamate, our brain’s major neurotransmitter” said Edward Twomey, the study’s first author and a PhD candidate at Columbia. “Understanding these processes will impact future studies on glutamate receptor signaling in neurodegenerative diseases as well as drug design.”