At the University at Buffalo, a research team led by Gabriela K. Popescu has shown that the proportion of calcium ions flowing through NMDA receptors is not fixed, contrary to long-held assumptions. Their study, demonstrates that the calcium-to-sodium ratio in NMDA receptor currents can vary in real time depending on environmental and molecular factors.
Weaver, M. G., & Popescu, G. K. (2025). Dynamic control of NMDA receptor Ca 2+ permeability by endogenous and synthetic modulators. Proceedings of the National Academy of Sciences, 122(42). https://doi.org/10.1073/pnas.2511783122
NMDA receptors are essential for synaptic transmission, learning, memory, and moment-by-moment cognition. Traditional understanding holds that when these receptors are activated, the fraction of calcium in the current remains constant. Popescu’s team discovered that small changes in the receptor’s environment, including pH shifts or molecules that interact with the receptor’s N-terminal domain, can alter how much calcium is carried by the current independently of overall receptor activity.
The researchers developed methods to measure calcium and sodium flows through individual NMDA receptor channels. They found that the receptor’s N-terminal domain acts as a lever controlling calcium permeability. For example, mild acidosis reduces calcium flow without significantly affecting sodium transmission. Other modulators that influence the N-terminal domain were also found to adjust calcium content, revealing a previously unrecognized mechanism of receptor regulation.
Gabriela K. Popescu from the University at Buffalo stated,
“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”.
This finding has important implications for neuroscience and therapeutics. Modulating calcium influx through NMDA receptors could influence synaptic plasticity, learning, memory formation, and excitotoxicity. Excessive calcium influx is associated with neurodegeneration following prolonged seizures, stroke, brain injury, and conditions such as Alzheimer’s disease. Drugs that specifically reduce calcium currents while preserving sodium-mediated transmission may offer new therapeutic strategies.
From an engineering perspective, the discovery provides guidance for designing neural interfaces, pharmacological interventions, and experimental systems. Drug development could focus on tuning receptor calcium permeability, and computational models of neural circuits may need to account for variable calcium flux rather than fixed ratios. Experimental assays that mimic physiological fluctuations in pH and ligand environments could provide more predictive insights into receptor behavior.
Although the results are promising, further research is needed to understand how these modulatory effects operate in vivo within the complex brain environment, the magnitude of calcium modulation under physiological conditions, and the potential for safe and selective therapeutic modulators.
By demonstrating that calcium influx through NMDA receptors is tunable rather than fixed, Gabriela K. Popescu’s team has challenged a foundational assumption in synaptic physiology. This work opens new avenues for drug development, neural engineering, and the study of neurodegenerative processes, providing a new framework for understanding and controlling NMDA receptor function.
Adrian graduated with a Masters Degree (1st Class Honours) in Chemical Engineering from Chester University along with Harris. His master’s research aimed to develop a standardadised clean water oxygenation transfer procedure to test bubble diffusers that are currently used in the wastewater industry commercial market. He has also undergone placments in both US and China primarely focused within the R&D department and is an associate member of the Institute of Chemical Engineers (IChemE).
