Gabriela K. Popescu, PhD.

Gabriela Popescu, PhD, and her team have found N3A receptors reactivate in acidic conditions, causing neurons to be more glutamate-sensitive, which can kill them.

Finding Provides Insight Into Cause of Neuron Death After Stroke

Published May 31, 2016

Gabriela K. Popescu, PhD — with first author Kirstie A. Cummings, a candidate in the biochemistry doctoral program — has published a paper in Scientific Reports showing that an elusive brain receptor may play an important role in the death of neurons from neurological diseases.

“Finding ways to prevent acidification or the reactivation of N3A receptors may present brain damage from strokes or seizures, for example. ”
Professor of biochemistry

Popescu and her team study a family of brain receptors that are critical to learning and memory, called NMDA (N-methyl-D-aspartate) receptors.

They found that one of these receptors, called N3A, functions through a different mechanism than all other NMDA receptors.

Acidity Can Reactivate Dormant N3A Receptors

“We found that in contrast to all other NMDA receptors, acidity can reactivate dormant N3A receptors,” says Popescu, senior author and professor in the Department of Biochemistry.

“This insight led us to hypothesize that N3A receptors are silent in normal conditions, which may explain why other researchers have failed to observe them previously.”

Popescu and her team found that when the N3A receptors were exposed to acidic conditions — as occurs in brain disorders such as stroke or epilepsy — they reactivate, causing neurons to become more sensitive to the neurotransmitter glutamate, which can kill them under certain circumstances.

Their research was done in cell culture with recombinant receptors.

Preventing Reactivation May Prevent Brain Damage

“Given that acidity increases after a stroke or an epileptic seizure, reactivation of N3A receptors may be one reason why neurons die after these neurologic events,” says Popescu. 

“Finding ways to prevent acidification or the reactivation of N3A receptors may prevent brain damage from strokes or seizures, for example.”

She adds that N3A proteins appear to be more abundant in brains of people with schizophrenia. “This is in line with our findings, since schizophrenia, a disease associated with high acidity in the brain, causes brains to shrink,” she says.

Identifying Site Where Acidity Reactivates Receptors

The paper, published in March 2016, reveals that electrical currents passed by N3A receptors can excite cells in response to acidity.

The researchers have identified the site on the receptor where acidity acts to reactivate these receptors, a different location from the site where acidity acts to inhibit all other NMDA receptors.

“This site is new and unique and thus can be used to make drugs that are very specific to the N3A receptor,” says Popescu.

Past Attempts to Understand N3A Were Unsuccessful

Popescu notes that the finding also sheds much-needed light on the N3A receptors. 

“Since their discovery more than 20 years ago, attempts to understand the roles of N3A receptors in the brain have been unsuccessful,” she says. 

“Because many labs have failed to record N3A activity from neurons, some researchers even began to doubt their relevance to brain activity.”

Doctoral Candidate ‘Brought Project to Fruition’

Popescu has worked closely with first author Cummings, her trainee, since 2012. She says Cummings’ role in the research was indispensable. “It was all her hard work that brought this project to fruition,” Popescu emphasizes.

One year after joining Popescu’s lab, Cummings was awarded a competitive fellowship from the National Institute of Neurological Disorders and Stroke, and she said Popescu’s support and guidance helped contribute to her success.