From The Quarterly, Winter 2011
NARSAD Scientific Council member Jonathan Javitch, M.D., Ph.D., of Columbia University, is part of a team that recently determined the structure of one of the five dopamine receptors in the human brain — the culmination of three years of study and experimentation.
Expressed widely throughout the brain, dopamine is a message-carrying molecule called a neurotransmitter, which is involved in a number of regulatory processes related to movement and aspects of cognition such as attention, memory and learning. Dopamine depletion is characteristic of Parkinson’s disease, while increased dopamine levels in the brain are thought by many to play a role in psychotic symptoms such as delusions and hallucinations in schizophrenia. Significant increases in dopamine levels are also thought to play a central role in drug abuse and addiction.
Dr. Javitch is seeking to obtain a finely detailed understanding of the different types of dopamine receptors and their specific impacts in disease, including their properties as pharmacological targets. Using a technique called x-ray crystallography, a method used widely in molecular biology in which an x-ray beam is fired at a crystallized form of a given molecule, Dr. Javitch and colleagues at Weill Cornell Medical College, the National Institute of Drug Abuse and the Scripps Research Institute recently were able to capture a detailed three-dimensional atomic structure of the dopamine-3 receptor (D3R).
D3R is implicated in schizophrenia, Parkinson’s disease, depression and drug addiction. Antipsychotic drugs used to treat schizophrenia activate receptors on nerve cells in the brain that inhibit dopamine. This lowers dopamine levels and can thereby reduce symptoms. However, anti-psychotic drugs that target D3R are known for side effects, such as reduced motivation and pleasure, fatigue, weight gain, and diabetes. Patients taking these drugs over a long period of time sometimes also develop even more severe side effects such as the movement disorder tardive dyskinesia.
The new data on D3R, published in the journal Science this past November, is important in part because each of the five dopamine receptors is unique in structure, and likely also in function. Knowledge of their differences as well as similarities at the level of atoms and molecules is vital if scientists are to better understand how dopamine is regulated. The work also directly informs efforts to develop more effective drugs that interact with the dopamine receptors to produce therapeutic effects in illnesses in which dopamine regulation plays an important role.
The hope is that this new, detailed view of the receptor will provide the basis for the design of new drugs that will target the receptor more accurately. New drugs could possibly provide a therapeutic advantage over existing drugs that block the receptor and perhaps also cause fewer side effects.
Members of the team now intend to use this same method to determine the structure of another dopamine receptor, D2R, which is similar although, importantly, not structurally identical to D3R. As with the work just completed, subtle differences between the two receptors will inform efforts to build more accurate models of the human dopamine system and predict the therapeutic potential of novel drug treatments, not only for schizophrenia and Parkinson’s, but also for addiction.
Dr. Javitch received NARSAD Young Investigator grants in 1990 and 1992, an Independent Investigator grant in 2003 and a Distinguished Investigator grant in 2010.