Neurotransmitter signaling often involves activation of G protein-coupled receptors (GPCRs). Modulation of neurotransmitter receptor signaling is a key therapeutic tool in ameliorating the cognitive pathologies of diseases such as schizophrenia and depression. """"""""Regulator of G-protein signaling"""""""" (RGS) proteins are key components of GPCR signaling that act as GTPase-accelerating proteins or """"""""GAPs"""""""" for Ga subunits, dramatically increasing their intrinsic GTP hydrolysis activity. In order to advance the utility of RGS proteins as drug discovery targets for cognitive pathologies, the specific aims of this research proposal are to delineate the structural determinants of allosteric modulation of RGS-box GAP activity and to identify small molecule inhibitors and activators of RGS-box GAP activity by computational approaches. Statistical coupling analyses of RGS-box sequences and site identification algorithms applied to known RGS-box structures will guide in silico docking of compounds from commercial and public compound libraries. The activity of compound """"""""hits"""""""" identified in these screens will be evaluated using fluorescence- and surface plasmon resonance-based in vitro assays of RGS-box Ga-binding and Ga-GAP activities. Verified modulators of RGS-box GAP activity will then be evaluated in cellular assays of receptor/G-protein/effector function, including receptor-dependent activation of heterotrimer steady-state GTPase activity and of phospholipase C activity. These pursuits should identify proof-of-principle small molecule modulators of RGS protein action that will establish RGS proteins as valid targets for therapeutic intervention in future pharmacotherapy of CNS disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30MH074266-05
Application #
8032540
Study Section
Special Emphasis Panel (ZRG1-F03B-G (20))
Program Officer
Vogel, Michael W
Project Start
2007-03-31
Project End
2012-03-30
Budget Start
2011-03-31
Budget End
2012-03-30
Support Year
5
Fiscal Year
2011
Total Cost
$32,894
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Pharmacology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Kimple, Adam J; Garland, Alaina L; Cohen, Staci P et al. (2014) RGS21, a regulator of taste and mucociliary clearance? Laryngoscope 124:E56-63
Kimple, Adam J; Austin, Grace K; Shah, Rupali N et al. (2014) Polymorphous low-grade adenocarcinoma: a case series and determination of recurrence. Laryngoscope 124:2714-9
Bosch, Dustin E; Kimple, Adam J; Manning, Alyssa J et al. (2013) Structural determinants of RGS-RhoGEF signaling critical to Entamoeba histolytica pathogenesis. Structure 21:65-75
Kimple, Adam J; Leight, W Derek; Wheless, Stephen A et al. (2012) Reducing nasal morbidity after skull base reconstruction with the nasoseptal flap: free middle turbinate mucosal grafts. Laryngoscope 122:1920-4
Kimple, Adam J; Eliades, Steven J; Richmon, Jeremy D (2012) Transoral robotic resection of a lingual thyroglossal duct cyst. J Robot Surg 6:367-9
Bosch, Dustin E; Kimple, Adam J; Muller, Robin E et al. (2012) Heterotrimeric G-protein signaling is critical to pathogenic processes in Entamoeba histolytica. PLoS Pathog 8:e1003040
Kimple, Adam J; Bosch, Dustin E; Giguere, Patrick M et al. (2011) Regulators of G-protein signaling and their Gýý substrates: promises and challenges in their use as drug discovery targets. Pharmacol Rev 63:728-49
Bosch, Dustin E; Kimple, Adam J; Sammond, Deanne W et al. (2011) Structural determinants of affinity enhancement between GoLoco motifs and G-protein alpha subunit mutants. J Biol Chem 286:3351-8
Nakamura, Kazuhiro; Kimple, Adam J; Siderovski, David P et al. (2010) PB1 domain interaction of p62/sequestosome 1 and MEKK3 regulates NF-kappaB activation. J Biol Chem 285:2077-89
Muller, Robin E; Klein, Klara R; Hutsell, Stephanie Q et al. (2010) A homogeneous method to measure nucleotide exchange by ýý-subunits of heterotrimeric G-proteins using fluorescence polarization. Assay Drug Dev Technol 8:621-4

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