Project Summary

Dawn Thompson, Ph.D. (Young Investigator 2006) of the Ernest Gallo Clinic & Research Center at the University of California, San Francisco, will study the role of a protein called GASP in relation to the activity of the D2 dopamine receptor, which is the target of many antipsychotic drugs used in schizophrenia. Sorting of G protein-coupled receptors (GPCRs) is a fundamental mechanism that controls the regulation of receptors. Dr. Thompson’s laboratory has shown that the cellular fate of some GPCR receptors is controlled by specific protein interaction with GASP (GPCR-associated sorting protein). Specifically, GPCRs that interact with GASP are targeted to the degradative pathway, and those receptors that do not, recycle. GASP binds to D2 receptors but not Dl receptors, and the D2 receptor is targeted for degradation, unlike the recycling Dl receptor. D2 receptor antagonists are one of the primary treatments for schizophrenia, implicating aberrant dopamine signaling in this disease. Indeed, schizophrenia symptoms may be due, in part, to downregulation of D2R signaling. D2R antagonists, the primary anti-psychotic therapeutic, would be predicted to prevent downregulation of D2-type receptors by blocking their endocytosis in response to dopamine. Dr. Thompson proposes that, while these antagonist drugs could prevent the downregulation of D2Rs, their anti-psychotic effectiveness would still be limited because D2Rs would not signal efficiently in the presence of the antagonist. Preventing downregulation of D2Rs without blocking their function, perhaps by inhibiting their interaction with GASP, might provide an improved therapeutic strategy. This proposal will identify whether D2 receptors are downregulated by GASP and whether disruption of GASP function can alter dopamine receptor responses.

Program Area: SCHIZOPHRENIA/PSYCHOTIC DISORDERS\Schizophrenia

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