Project Summary

Selena E. Bartlett, Ph.D. (Young Investigator 2005) of the Ernest Gallo Clinic and Research Center of the University of California at San Francisco, plans to study how the internal cellular processing of cell surface receptors—which take up drugs outside of cells—may impact antipsychotic medication action. G protein coupled receptors (GPCRs) are major therapeutic targets for many diseases, including neuropsychiatric diseases such as schizophrenia, depression and addiction. Current drug development for these disorders is focused on compounds that target the extracellular binding of these receptors. But following drug activation, most GPCRs internalize and are sorted between recycling endosomes and lysosomes. GPCRs, for example, that are recycled to the plasma membrane are able to respond to another round of drug, in contrast to receptors that degrade. Aberrant dopamine signaling has been implicated in schizophrenia and dopamine antagonism is one of the primary treatments for the disease. Recently, Dr. Bartlett’s laboratory has demonstrated that dopamine receptors are sorted inside the cell to different locations: dopamine D2 receptors (D2Rs) are degraded and can no longer return to the cell surface, unlike Dl receptors. D2Rs degrade because they bind to a sorting protein called GASP (G protein-coupled receptor Associated Sorting Protein). Dr. Bartlett’s laboratory has shown that the D2R-GASP interaction has functional consequences on D2R responses in vivo: inhibiting the degradation of D2Rs by blocking the D2 receptor-GASP interaction in the ventral tegmental area of the rat brain enables recovery of D2R signaling. Dr. Bartlett now aims to determine if the D2R-GASP interaction provides a novel therapeutic target for the treatment of schizophrenia.

Program Area: SCHIZOPHRENIA/PSYCHOTIC DISORDERS\Schizophrenia

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