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Celver J.,University of Rhode Island | Celver J.,Kovogen LLC | Sharma M.,University of Rhode Island | Kovoor A.,University of Rhode Island | Kovoor A.,Kovogen LLC
Journal of Neurochemistry | Year: 2010

Regulator of G protein signaling 9-2 (RGS9-2), a member of the RGS family of GTPase accelerating proteins, is expressed specifically in the striatum, a brain region involved in controlling movement, motivation, mood and addiction. RGS9-2 can be found co-localized with D2-class dopamine receptors in medium spiny striatal neurons and altered functioning of both RGS9-2 and D 2-like dopamine receptors have been implicated in schizophrenia, movement disorders and reward responses. Previously we showed that RGS9-2 can specifically co-localize with D2-dopamine receptors (D2R). Here we provide further evidence of the specificity of RGS9-2 for regulating D2R cellular functions: the expression of RGS9-2 inhibits dopamine-mediated cellular internalization of D2R, while the expression of another RGS protein, RGS4, had no effect. In addition, the agonist-mediated internalization of the G protein coupled delta opioid receptor was unaffected by RGS9-2 expression. We utilized mutant constructs of RGS9-2 to show that the RGS9-2 DEP (for Disheveled, EGL-10, Pleckstrin homology) domain and the GTPase accelerating activity of RGS9-2 were necessary for mediating specific inhibition of D2R internalization. © 2010 International Society for Neurochemistry. Source


Naumiec G.R.,University of Rhode Island | Lincourt G.,University of Rhode Island | Clever J.P.,Kovogen LLC | McGregor M.A.,University of Rhode Island | And 3 more authors.
Organic and Biomolecular Chemistry | Year: 2015

The development of a β-CCT-lanthanide conjugate that binds the dopamine transporter (DAT) with high affinity (Kd = 303 nM) is described. Contrast agents such as the one described herein could be used as molecular probes to directly study the binding of small molecules to receptors such as DAT via MRI, PET or SPECT. This journal is © The Royal Society of Chemistry 2015. Source


Waugh J.L.,University of Texas Southwestern Medical Center | Celver J.,University of Rhode Island | Celver J.,Kovogen LLC | Sharma M.,University of Rhode Island | And 15 more authors.
PLoS ONE | Year: 2011

Regulator of G protein signaling 9-2 (RGS9-2) is a protein that is highly enriched in the striatum, a brain region that mediates motivation, movement and reward responses. We identified a naturally occurring 5 nucleotide deletion polymorphism in the human RGS9 gene and found that the mean body mass index (BMI) of individuals with the deletion was significantly higher than those without. A splicing reporter minigene assay demonstrated that the deletion had the potential to significantly decrease the levels of correctly spliced RGS9 gene product. We measured the weights of rats after virally transduced overexpression of RGS9-2 or the structurally related RGS proteins, RGS7, or RGS11, in the nucleus accumbens (NAc) and observed a reduction in body weight after overexpression of RGS9-2 but not RGS7 or 11. Conversely, we found that the RGS9 knockout mice were heavier than their wild-type littermates and had significantly higher percentages of abdominal fat. The constituent adipocytes were found to have a mean cross-sectional area that was more than double that of corresponding cells from wild-type mice. However, food intake and locomotion were not significantly different between the two strains. These studies with humans, rats and mice implicate RGS9-2 as a factor in regulating body weight. © 2011 Waugh et al. Source


Celver J.,University of Rhode Island | Celver J.,Kovogen LLC | Sharma M.,University of Rhode Island | Kovoor A.,University of Rhode Island | Kovoor A.,Kovogen LLC
Journal of Neurochemistry | Year: 2012

Detergent-resistant membranes (DRM) are thought to contain structures such as lipid rafts that are involved in compartmentalizing cell membranes. We report that the majority of D 2-dopamine receptors (D 2R) expressed endogenously in mouse striatum or expressed in immortalized cell-lines is found in DRM. In addition, exogenous co-expression of D 2R in a cell line shifted the expression of regulator of G protein signaling 9-2 (RGS9-2) into DRM. RGS9-2 is a protein that is highly enriched in the striatum and specifically regulates striatal D 2R. In the striatum, RGS9-2 is mostly associated with DRMs but when expressed in cell lines, RGS9-2 is present in the soluble cytoplasmic fraction. In contrast, the majority of mu opioid receptors and delta opioid receptors are found in detergent-soluble membrane and there was no shift of RGS9-2 into DRM after co-expression of mu opioid receptor. These data suggest that the targeting of RGS9-2 to DRM in the striatum is mediated by D 2R and that DRM is involved in the formation of a D 2R signaling complex. D 2R-mediated targeting of RGS9-2 to DRM was blocked by the deletion of the RGS9-2 DEP domain or by a point mutation that abolishes the GTPase accelerating protein function of RGS9-2. © 2011 International Society for Neurochemistry. Source

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