NIH Funds Popescu Study of NMDA Receptor Filter Modulation

The research is a continuation of her decade-long study of NMDA receptors and focuses on a new mechanism that allows a cell to control how much calcium passes through the receptor’s pore.

The grant is being administered by the NIH’s National Institute of Neurological Disorders and Stroke.

Popescu says her lab focuses on NMDA receptors for two reasons: They are implicated in almost every fundamental brain function, playing critical roles in learning and memory, and they contribute to a number of pernicious disorders — such as addiction and chronic pain, schizophrenia and neuropathologies such as stroke and Alzheimer’s disease.

The basic function of NMDA receptors is to sense glutamate, the main excitatory neurotransmitter in the brain.

“Any time glutamate is released from a presynaptic site in response to whatever — pain, excitement, emotion — these receptors sense it, engulf the glutamate and then change conformation,” Popescu says.

When this occurs, a narrow pore opens across the membrane, and according to its filtration properties, it allows only certain ions such as sodium and calcium to pass through.

“Sodium and calcium do important, but different, things,” Popescu says. “Sodium, because it is positively charged, is going to change the membrane potential and excite the cell.”

“This is important for a number of things — this is how sensation happens, how thinking happens, how pain happens,” Popescu says. “Neuron-to-neuron information gets transmitted such that we can perceive what is in the environment and have a meaningful response.”

Popescu says that while studying how intracellular signals can influence how the receptor senses or responds to glutamate, her research team “found something amazing.”

“Depending on the structure of the intracellular tails of these receptors, not only does the signal change, but it changes the nature of the filter.”

“It turns out if you modify these intracellular tails, you can modify the filter so that the sodium still goes through and you get the excitation, but the calcium does not go through anymore,” she says.

Calcium is enormously important because it is necessary for memory formation, but too high of a concentration activates other proteins that kill neurons.

“This is the main mechanism for how we lose neurons after a stroke,” Popescu says.

If blood is not flowing to where it is needed, neurons are deprived of sugar and oxygen and become weak. When they are depleted of energy, glutamate leaks out because they can no longer hold it in.

The leaked glutamate binds to receptors that open in an uncontrolled manner and allow too much calcium to go in, which kills neurons in a penumbra from the site of where the stroke happened.

“Imagine now if we understand how to control the filter,” Popescu says. “We know the very short tail of the receptor is the one that regulates the filter, so we want to understand what we can do to the tail to make the filter permeable or impermeable to calcium.”

Popescu says the fact that modulating the filter can be accomplished in real time can be extremely beneficial.

“This is great because you do not have to wait for a new molecule to be created, you just change it as you go,” she says. “If you need it now, you allow calcium to go through; if you don’t, you turn the spigot and close it up.”

The potential public health outcomes are enormous, but not immediate, Popescu emphasizes.

“We know that this happens, but we want to understand why it happens, how it happens, when it happens and find out if we can change it at will,” she says. “And if you can change it at will, then you have a new tool.”

These investigations are important because they will allow scientists to focus on receptors that are present in specific brain areas and to target therapies without causing adverse side effects — for instance, treating a stroke in the cerebellum without influencing the cortex.  

“Some drugs are already used in this way, but they are unsophisticated,” Popescu says. “They inhibit all of the receptors. They block anything, anywhere.”

“Hopefully, our research is going to open news ways of thinking, knowing that you can change the filter rather than just blocking everything.”

Several of Popescu’s prior trainees have received NIH research funding, and she focuses on providing opportunities for graduate, post-doctorate and undergraduate trainees in her lab.

Popescu says she likes having people with different levels of expertise working together in her lab, noting she currently works with longtime lab manager and senior technician Eileen Kasperek, post-doctorate fellows Bruce Maki and Sophie Belin, doctoral student Gary Iacobucci and several undergraduate students.

In fact, she says Maki is actually the one who published the initial research on the intracellular tail that was published in the Journal of Biological Chemistry.

“We are now writing up the preliminary data for this grant with him as a first author to show how this filter works,” Popescu says. “It was his data that convinced the reviewers who said ‘this is something we need to understand more because it looks like it can be important.’”