The study, published in the Oct. 18 issue of the journal Cell, examined the interaction between two proteins known as dopamine D1 and NMDA receptors. The research group, led by Fang Liu, an assistant professor in U of T's Department of Psychiatry and CAMH's Section of Molecular Neurobiology, Neuroscience Research Department, found that two parts of the D1 receptor interact directly with two subunits of the NMDA receptor. These interactions modulate two separate NMDA functions in the brain - cell death and normal cell-to-cell communication. This study is the first to show that the interaction between D1 and the NMDA receptor also regulates - and, in fact, prevents - cell death.
"It may be possible to design a medication that specifically enhances this interaction leading to reduced cell death in the brain," says Liu. "This prevention of NMDA-mediated cell death could have important implications in terms of preventing brain damage in severe epilepsy, traumatic brain injury, neurodegenerative disorders and stroke."
Because cell death and cell-to-cell communication are regulated separately by the different D1 interactions, researchers may be able to manipulate one function without impacting the other, adds Liu. For example, it may be possible to design medication to enhance the interaction that regulates cell death, thereby preventing brain cells from dying, without inhibiting the other interaction regulating cell-to-cell communication. Cell death mediated by the NMDA receptor plays a critical role in the consequences and severity of stroke.
The discovery could also have significant impact on research into schizophrenia and other psychiatric disorders, creating the possibility that new antipsychotic medication could be designed to modify the interaction related to cell-to-cell communication to prevent abnormal NMDA receptor activity. Malfunction of the NMDA receptor's cell-to-cell communication function can induce symptoms that resemble schizophrenia.
The study also found that the dopamine D1 and NMDA receptors communicate directly with each other and not only through secondary messengers as previously thought. This finding will provide the opportunity for researchers to take a new approach in designing medications by targeting the receptor interactions directly, says Liu. The next step will be to study the D1 and NMDA interactions in an animal model, she adds.
Other researchers participating in the study included Xian-Min Yu, an assistant professor in U of T's Faculty of Dentistry and CAMH, and Professor Yu-Tian Wang of the University of British Columbia, as well as CAMH-based U of T graduate student Frank Lee and post-doctoral fellows Sheng-Xue, Lin Pei, Nadege Chery and Yushan Wang, research co-ordinator Brian Vukusic and the late Professor Hyman Niznik.
The study was supported by the Canadian Institutes of Health Research, Ontario Mental Health Foundation, Canadian Psychiatric Research Foundation and National Alliance for Research on Schizophrenia and Depression (USA).
The University of Toronto, Canada's leading research university with 60,000 students, is celebrating its 175th anniversary in 2002. On March 15, 1827, King's College - precursor to the University of Toronto - was granted its royal charter by King George IV. The university now comprises 31 divisions, colleges and faculties on three campuses, including 14 professional faculties, numerous research centres and Canada's largest university library system - the fifth largest research library in North America.
The Centre for Addiction and Mental Health is the largest mental health and addiction facility in Canada. CAMH is fully affiliated with the University of Toronto and the World Health Organization.
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