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. ? ?
| Rochdi, Moulay D; Vargas, Gabriel A; Carpentier, Eric et al. (2010) Functional characterization of vasopressin type 2 receptor substitutions (R137H/C/L) leading to nephrogenic diabetes insipidus and nephrogenic syndrome of inappropriate antidiuresis: implications for treatments. Mol Pharmacol 77:836-45 |
| Urban, Jonathan D; Vargas, Gabriel A; von Zastrow, Mark et al. (2007) Aripiprazole has functionally selective actions at dopamine D2 receptor-mediated signaling pathways. Neuropsychopharmacology 32:67-77 |
