Keywords:
signal transduction through dopamine receptors, regulation of G protein-coupled receptor signal strength, dopamine receptor-mediated behaviors

Research Interests and Goals

The focus of my laboratory is on the regulation of intracellular signaling by G protein-coupled receptors, or 7 transmembrane receptors (GPCR/7TMR).  In particular, we are interested in the signaling mediated by dopamine receptors, as these receptors are implicated in several human neurological and psychiatric disorders, such as schizophrenia, Parkinson’s Disease, drug addiction, and ADHD.  It is now appreciated that GPCR/7TMRs signal through multiple intracellular pathways, both G protein-dependent and G protein-independent.  Several critical questions thus arise:  How is such signaling regulated?  Are particular signaling pathways associated with particular behaviors, both physiological and pathological?  Can drugs be designed that target a particular pathway but spare other pathways?  To what extent does the disruption of signaling through these multiple pathways contribute to disorders such as schizophrenia—is one pathway differentially affected?  That is, can drugs cause “cellular side effects” by affecting multiple intracellular signaling pathways when only one of these pathways may be the source of the pathology?  Our goal is to use molecular and behavioral approaches to answer these questions.      

Current Research

We are currently investigating the regulation of dopamine receptor signaling by the protein Rhes, Ras Homolog Enriched in Striatum.  We have shown, through behavioral studies in mice, that Rhes differentially affects dopamine-mediated behavior, depending on the signaling pathway involved.  Thus, Rhes inhibits Gi- and Gs/olf-mediated behaviors, but promotes Gq-mediated behaviors.  We are currently testing the role of Rhes in regulating signaling through G protein-dependent versus G protein-independent pathways.  To this end, we have shown that Rhes binds to beta-arrestins and is necessary for the D2 receptor-mediated dephosphorylation of Akt.  As Akt aberrations have been strongly associated with schizophrenia, we will continue to investigate the mechanism for this effect with goal of providing information for the design of more efficient drugs to treat this disorder.