LA JOLLA, Calif. , January 30, 2002
Results from the Burnham Institute published today on the journal Nature’s website report the cloning of the seventh and final subunit of the N
-methyl-D-aspartate (“NMDA”) family of receptors for the brain neurotransmitter, glutamate, along with the surprising discovery that receptors containing the new, so-called NR3B subunit, are activated not by glutamate but by a different brain chemical, glycine. What makes the story so unusual is that up until now, when acting alone, glycine was thought to inhibit the nervous system rather than to excite it. The new findings are expected to provide unexpected and surprising insights into certain diseases of the brain associated with excitotoxicity or overstimulation of these receptors. This collaboration, led by Drs. Stuart Lipton and Dongxian Zhang at The Burnham Institute, cloned the gene for the NR3B subunit from rat brain, found evidence for it also in humans, and then expressed the subunit in frog eggs for functional studies. The scientists then looked at rat brain nerve cells and found evidence for the function of the new receptors there as well.
Glutamate is found in large quantities in nerve cells, and is hailed as the most important excitatory transmitter in the brain. Glutamate receptors, the NMDA family of receptors in particular, are the subject of intensive investigation by researchers, as there is a fine line between the level of stimulation required for normal nerve cell behavior and nerve cell death resulting from overstimulation of the receptors, as occurs in head and spinal cord trauma, stroke, epilepsy, Alzheimer’s disease, Lou Gehrig’s disease, Huntington’s disease, AIDS dementia, and other brain disorders.
Dr. Stuart Lipton, a corresponding author of the work, stated that “several normal brain functions previously associated with glutamate may in fact be caused by glycine. And, what may shake up all of our thinking about neurodegenerative diseases associated with excitotoxicity, is that these disorders may in fact be mediated in part by glycine rather than by glutamate.” Seeking new ways to treat neurodegenerative disorders, researchers have recently turned to drugs with known function. For example, memantine, an antagonist of the conventional, previously known NMDA family of glutamate receptors and first characterized in Dr. Lipton’s laboratory, appears to thwart progression of Alzheimer’s disease in phase III (final) clinical studies; the new information reported in this publication may help to explain related mechanisms of disease associated with glycine, and could lead to drugs to combat those components of excitotoxic damage in the brain.
Stuart A. Lipton, MD, PhD is Director of the Del E. Webb Center for Neuroscience and Aging Research at The Burnham Institute. He is also a practicing neurologist and adjunct professor at The University of California, San Diego. Dongxian Zhang, PhD is an assistant professor at The Burnham Institute and was responsible for the cloning and initial characterization of the new NR3B subunit.
The publication is the culmination of work that had been in progress for some time, starting several years ago in Lipton’s laboratory, then at Harvard, involving several collaborators, including Dr. Marc Awobuluyi, currently a medical intern at Massachusetts General Hospital in Boston; Drs. Jon (Jed) Chatterton, Hiroto Takahashi, Maria Talantova, Jiankun Cui, and Shichum Tu--all postdoctoral fellows at The Burnham Institute--Dr. Louis Premkumar, a faculty member at Southern Illinois University School of Medicine; Dr. Kevin Sevarino, formerly of Yale and now at the University of Connecticut Health Center, Farmington; Dr. Nobuki Nakanishi, an associate professor at The Burnham Institute; Yeonsook Shin, a graduate student at Kanazawa University Graduate School of Medicine in Japan, who is currently performing her thesis research in Dr. Lipton’s laboratory; and Dr. Gary Tong, a neurologist at the University of California, San Diego.
This research was funded in part by grants from the National Institutes of Health awarded to Dr. Stuart Lipton.