Project Summary

Abraham Kovoor, Ph.D. (Young Investigator 2004) of Langley Porter Psychiatric Institute/University of California, San Francisco, plans on studying what role a protein called dishevelled might play in how antipsychotic drugs work in the dopamine pathway. Antipsychotics block signaling by the neurotransmitter dopamine by binding to cell surface proteins called D2-dopamine receptors (D2-DR). D2-DRs transmit the dopamine signal into the neuron to modulate its electrical activity. Although the receptors are targets for antipsychotics, how the drugs produce their therapeutic effect is unknown. The drug can block the effect of dopamine on the electrical activity of a neuron in seconds but it takes weeks to produce their therapeutic effect. Dr. Kovoor hypothesizes that the antipsychotics work on the dopamine pathway to somehow override abnormal circuitry in the brain created during development. In preliminary experiments, Dr. Kovoor found that D2-DRs interact with a section of a protein called disheveled, an important relay molecule in Wnt signaling pathways that play a critical role in the development of multicellular organisms from Hydra to humans and in brain development. D2-DRs can inhibit Wnt signals in test-tube experiments. In the proposed project, Dr. Kovoor plans to determine if D2-DRs can interact with the complete dishevelled molecule, and to determine if D2-DRs can also inhibit Wnt signals in the brain and thus suggest a mechanism of action for antipsychotic drugs.

Program Area: SCHIZOPHRENIA/PSYCHOTIC DISORDERS\Schizophrenia

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