Popescu Studying NMDA Receptor Gating Mechanisms

The research is a continuation of her 15 years of study of NMDA receptors and focuses on investigating how subtle changes in the receptor structure causes them to produce altered electrical signals.

The five-year, $1.75 million study is funded through the NIH’s National Institute of Neurological Disorders and Stroke (NINDS).

NMDA receptors are a unique type of neurotransmitter receptors that can initiate biochemical and structural changes in the brain that lead to the formation of new memories — the basis of learning.

Through her research, Popescu has contributed leading edge knowledge to how these receptors become active to generate electrical signals and has developed a unique method to measure how drugs or mutations change the shape of the signal produced by stimulated receptors.

“This project also builds on two seminal advances in receptor biology that have revolutionized the field,” says Popescu, principal investigator on the NINDS study.

The first is the development of atomic resolution models for the three dimensional structure of NMDA receptors (through cryogenic electron microscopy technology) and the other is the discovery through hundreds of patient-derived point mutations (through whole-genome sequencing), which cause or aggravate neuropsychiatric diseases.

NMDA receptors play critical roles during the normal development and function of central synapses, but also in psychiatric conditions such as epilepsy, schizophrenia, addiction and chronic pain, and in neurodegenerative pathologies such as stroke, Alzheimer’s, Parkinson’s and Huntington’s diseases, Popescu says.

“Mutant receptors were recently identified in patients with neurologic and psychiatric conditions and were found to be causal to the diagnosed dysfunctions,” she notes.

“The long-term objective of this project is to assign structural conformations for the main functional states of the NMDA receptor — and to delineate the mechanism by which these states interconvert during normal and disease states — and thus generate basic knowledge necessary for rational therapies.”

Specific aims of the study are:

• to identify the structural and functional changes that accompany NMDA receptor gating
• to identify structural and functional changes produced by disease-associated mutations

“The two aims will integrate molecular dynamics simulations and electrophysiological measurements to delineate plausible conformations for the adult NMDA receptor isoform in closed and open conformations and for a series of rationally-targeted and naturally occurring, pathologic NMDA receptor mutants,” Popescu says.

“Results will elucidate the NMDA receptor gating reaction and the mechanism by which single-residue substitutions change structure and cause dysfunction.”

In preparation for the project, Popescu used a sabbatical leave in 2014 to gain new expertise in structural biology by working with leading researchers Alexander Sobolevsky, PhD, at Columbia University and Rachelle Gaudet, PhD, at Harvard University.

Key collaborators are Wenjun Zheng, PhD, professor of physics in the College of Arts and Sciences, and Han Wen, a doctoral candidate in his lab, who have developed new algorithms to manipulate in silico receptor structures and to simulate the movements that may happen during activation.

“I am confident that our methodological innovations will enable us to uncover unprecedented molecular details of NMDA receptor gating mechanism, along with new predictions to guide experimental studies by Dr. Popescu,” says Zheng, a co-investigator on the study.

Gary J. Iacobucci, PhD, a postdoctorate fellow in the Popescu laboratory, is the lead author on a paper that constituted the impetus for the successful NIH application.

Other study participants from the Department of Biochemistry are:

• Jamie A. Abbott, PhD, a postdoctoral fellow
• Beiying Liu, PhD, a research scientist