Study: UB research overturns prevailing assumptions about NMDA receptor calcium signals

BUFFALO, N.Y. – Drugs that act on NMDA (N-methyl-D-aspartate) receptors, which are essential for learning, memory and moment-by-moment consciousness, are key for treating neuropsychiatric disorders. These drugs were developed based on the assumption that the proportion of calcium in the current produced by these receptors remains constant. That assumption turns out to be false, according to University at Buffalo research published last month in the Proceedings of the National Academy of Sciences.

“Our research reveals that small variations in the brain environment in which NMDA receptors operate can increase or decrease the amount of calcium in the currents fluxed by these receptors,” explains Gabriela K. Popescu, PhD, corresponding author and professor of biochemistry in the Jacobs School of Medicine and Biomedical Sciences at UB. “This, in turn, could mean the difference between normal and impaired learning, memory and cognition, symptoms that accompany many neuropsychiatric conditions.”

Disentangling sodium and calcium

NMDA receptor currents have two basic functions, Popescu says: transmission of information, which depends on the amount of sodium that flows through receptors, and the neuroplasticity related to learning or neurodegeneration, which depends on the amount of calcium that flows through the receptor.

“The textbooks tell us that the ratio of sodium to calcium in the currents generated by NMDA receptors is constant and therefore, if we measure how active the receptors are, we can infer how much calcium enters the cell,” she says.

“Our new results show that we’ve been wrong in this assumption, and that the flow of sodium and calcium through NMDA receptors can vary independently of one another.”

Popescu and study first author Mae Weaver, PhD, now a postdoctoral trainee at Johns Hopkins Medicine who undertook this research for her doctoral thesis in Popescu’s lab, became intrigued by a few reports in the literature suggesting that the proportion of calcium in the NMDA receptor signals can change.

Specifically, a study from a lab in Italy showed that mild acidosis, which may occur in the brain as complications of diabetes, apnea or severe epileptic seizures, decreased the amount of calcium in the current passed by the NMDA receptor.  

“This observation piqued our attention” says Popescu. “We wondered if this effect was specific to acidosis or whether it might be a more general mechanism for controlling the calcium signals produced by the NMDA receptor.”

Weaver established in Popescu’s lab the methodology necessary to measure the amount of calcium in the current produced by NMDA receptors and was able to reproduce the reducing effects of acidosis. “Once she did that, and we were certain that the effect was real, we had a smoking gun,” explains Popescu. “We then leveraged our expertise to find out the mechanism.”

Calcium content influencer

They knew that the acidity of the external milieu can change the shape of the outer part of the receptor, a mechanism that controls how active the receptors are.

“We found that the same mechanism is at work when acidosis reduces the amount of calcium in the current,” says Popescu.

They found that the receptor’s outer portion, called the N-terminal domain or NTD, which is responsible for sensitivity to acidosis, also controls the ionic composition of the current.

“With this new insight we reasoned that, if acidosis controls calcium content through the NTD, other molecules that affect the NTD will also influence the calcium content,” says Popescu. “And that turned out to be true, which means that the NTD is a lever that tunes the calcium content of the current.”

In the brain, she adds, the environment around the NMDA receptors is constantly changing, reflecting the continuous flux of information. Factors that affect the receptor’s NTD and change the fraction of calcium in the current will therefore have a pronounced effect on learning and memory, and on neurodegeneration.

“Excessive calcium currents through NMDA receptors cause neurodegeneration during intense or prolonged seizures, after a stroke or brain injury, and in several dementias, including Alzheimer’s disease,” Popescu says. “So drugs that specifically reduce the calcium current but allow sodium-based transmission may be incredibly valuable. Our discovery pioneers a new way of thinking about what can be achieved with NMDA receptor-targeted drugs.”

The work was funded by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health.