Key brain cell linker region a potential target for neuromodulatory drugs

In the brain, a flood of tens of millions of neurotransmitters is handed off from one neuron to another in just a fraction of a second. Memories, dreams, and learning share a common thread in the exchange of electrical and chemical signals by nearly 100 billion neurons — each cell networked to tens of thousands of others. A protective ion channel encloses the neurons and acts as gatekeeper, keeping out the signal flow of brain activity. However, a chemical neurotransmitter, can ‘unlock’ the channel.

Neuroscientists at Stony Brook University in New York, US, teamed up with computational biophysicists at Florida State University (FSU), US, and found that the key brain cell receptor NMDA (N-methyl-D-aspartate) depends on a short polypeptide segment (linker) to function. Parkinson's disease, Alzheimer's disease, schizophrenia, and a number of other mental disorders are associated with malfunctions of NMDA. The results are published in the journal Nature Neuroscience. The National Institutes of Health (NIH) funded the research.

The team ran modeling and molecular dynamics simulations of the full NMDA receptor molecule using computational resources provided by XSEDE (Extreme Science and Engineering Discovery Environment). NAMD and MODELLER ran on the Stampede supercomputer at the Texas Advanced Computing Center (TACC) at The University of Texas at Austin, US.

The NMDA receptor sits on the membrane of a neuron, or nerve cell, and acts like a gate. The terminal end of the neuron releases the neurotransmitter glutamate, and unlocks the gate of another neuron, opening a channel that allows calcium ions into the cell.

"This can have a variety of downstream effects, including how we learn and how we can remember events in our lives," says study lead Lonnie Wollmuth, a professor of neurobiology and behavior at the Center for Nervous System Disorders at Stony Brook.

Previous studies, says Wollmuth, show that the clamshell-shaped part of the NMDA receptor — the part that accepts the neurotransmitter key — is mechanically coupled by a linker region to another part that forms the ion channel embedded in the cell. The linker region is made of a string of amino acids that act like a rope to pull on the gate of the ion channel and open it.

"If the process is impeded even slightly, you completely lose the efficiency of the signaling process. The idea is that there's this mechanical coupling. Without it, the ability of the NMDA receptor to convert transient glutamate into a robust and efficient signal is lost," explains Wollmuth.

"What we found, and this was really the most fascinating part, is that the ability of the transient glutamate to cause the ion channel to open was largely lost," says Wollmuth. "That suggested that it was critical to how the NMDA receptor functions at a synapse, how it's able to convert that transient glutamate into a signal."

"These experiments demonstrate the critical role that the linker region plays in the functioning of NMDARs and suggests that this pivotal junction may be an important target to explore for the development of neuromodulatory drugs," says Chiiko Asanuma, program chief of the Signal Transduction Program at the NIH.

"One of the things that we constantly ask ourselves is, how can our predictions be tested by functional studies," says study co-designer and author Huan-Xiang Zhou, a computational biophysicist at FSU. "The resources that are present at TACC and at XSEDE facilities go far beyond what can be obtained in a single lab, or even an institution. Having this national infrastructure is really critical for us to move science forward."

"The approach used in this study further demonstrates the power that multi-disciplinary strategies involving computational analysis and dynamic simulations can bring to solving a challenging neuroscience puzzle," adds Asanuma. "We anticipate an increase in collaborations in the future involving experimental neuroscientists with experts from statistics, physics, mathematics, engineering and computer science."

To read the original, extended version of Jorge Salazar’s article, visit the Texas Advanced Computing Center’s website.