This proposal for a Mentored Clinical Scientist Development Award focuses on elucidating the role membrane trafficking mechanisms play in the regulation of D1 and D2 dopamine receptor cell-surface number and how antipsychotics influence this process. These studies are of critical clinical significance since dopamine receptor number is dysregulated in various neuropsychiatric disorders including schizophrenia and secondary to treatment with antipsychotics. Membrane trafficking is fundamental for achieving the ordered placement of receptors and for the processes of up- and down-regulation of the number of receptors present in specific membrane domains. Disturbances in membrane trafficking processes have been implicated in the pathophysiology of several different disorders such as retinitis pigrnentosa, diabetes insipidus, and schizophrenia. The proposed studies examine the hypothesis that regulated membrane trafficking mechanisms, in particular post-endocytic mechanisms which target receptors to either recycling or degradation, play an important role in 1) regulating the cell surface receptor number of D1 receptors and 2) in mediating antipsychotic-induced upregulation of specific D2-like dopamine receptor subtypes. The proposal will examine the subtype-specific endocytic trafficking of dopamine receptors, examine how antipsychotics affect the endocytic trafficking of D2- like receptors and determine the mechanisms of D 1 receptor membrane insertion. Studies will utilize the well-established HEK-293 cell heterologous model system which is amenable to biochemical studies, and cultured striatal neurons which are more physiologically relevant. These studies are expected to provide insight into the dysregnlation of dopamine receptors observed in a variety of psychiatric disorders. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08MH068691-04
Application #
7091389
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Desmond, Nancy L
Project Start
2003-07-01
Project End
2008-06-30
Budget Start
2006-07-01
Budget End
2008-06-30
Support Year
4
Fiscal Year
2006
Total Cost
$172,584
Indirect Cost
Name
University of California San Francisco
Department
Psychiatry
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143