Abstract

EXCEED THE SPACE PROVIDED. A long term objective of our research effort is to define factors that influence the specificity and efficiency of signal propagation by receptors (R) coupled to heterotrimeric G-proteins (G). OVERALL HYPOTHESIS: Signalling efficiency/specificity is determined in part by accessory proteins found in the receptor's microenvironment which segregate a signaling complex to microdomains of the cell, regulate the efficiency and/or specificity of signal transfer, regulate the basal activity of the system and/or provide alternative modes of signal input to G-protein signaling systems that operate independent of a typical GPCR coupling mechanism. Our goals are to define such accessory proteins, their mechanism of regulation and their dysfunction in various diseases. We identified a group of proteins, Activators of G-protein signaling (AGS) 1-3, that directly regulate the activation state of G-proteins by novel mechanisms. This proposal focuses on AGS3 as a template for understanding the role of such proteins in signal processing. In addition, this proposal will also move toward the identification of novel regulators of Go and Gs.
SPECIFIC AIM #1 Define the functional role of the TPR domain of AGS3.
SPECIFIC AIM #2 Define the regulation of AGS3 by extracellular stimuli and phosphorylation.
SPECIFIC AIM #3 Define the role of AGS3 in G-protein signaling.
SPECIFIC AIM #4 Identify and characterize receptor-independent regulators of Go and Gs. AGS3 and related accessory proteins provide unexpected mechanisms for regulation of the G-protein activation cycle and have opened up a new area of research related to the cellular role of G-proteins as signal transducers. As such, these proteins and the concepts advanced with their discovery provide unexpected avenues for therapeutics and understanding disease mechanisms. PERFORMANCE SITE ========================================Section End===========================================

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS024821-16
Application #
6823303
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Stewart, Randall R
Project Start
1987-07-01
Project End
2007-11-30
Budget Start
2004-12-01
Budget End
2005-11-30
Support Year
16
Fiscal Year
2005
Total Cost
$337,250
Indirect Cost

  Institution

Name
Louisiana State University Hsc New Orleans
Department
Pharmacology
Type
Schools of Medicine
DUNS #
782627814
City
New Orleans
State
LA
Country
United States
Zip Code
70112

  Publications

Vural, Ali; Fadillioglu, Ersin; Kelesoglu, Fatih et al. (2018) Role of G-proteins and phosphorylation in the distribution of AGS3 to cell puncta. J Cell Sci 131:
Robichaux 3rd, William G; Branham-O'Connor, Melissa; Hwang, Il-Young et al. (2017) Regulation of Chemokine Signal Integration by Activator of G-Protein Signaling 4 (AGS4). J Pharmacol Exp Ther 360:424-433
Robichaux 3rd, William G; Oner, Sukru S; Lanier, Stephen M et al. (2015) Direct Coupling of a Seven-Transmembrane-Span Receptor to a G?i G-Protein Regulatory Motif Complex. Mol Pharmacol 88:231-7
Appleton, Kathryn M; Bigham, Kevin J; Lindsey, Christopher C et al. (2014) Development of inhibitors of heterotrimeric G?i subunits. Bioorg Med Chem 22:3423-34
Blumer, Joe B; Lanier, Stephen M (2014) Activators of G protein signaling exhibit broad functionality and define a distinct core signaling triad. Mol Pharmacol 85:388-96
Oner, Sukru Sadik; Blumer, Joe B; Lanier, Stephen M (2013) Group II activators of G-protein signaling: monitoring the interaction of Gýý with the G-protein regulatory motif in the intact cell. Methods Enzymol 522:153-67
Kwon, Michelle; Pavlov, Tengis S; Nozu, Kandai et al. (2012) G-protein signaling modulator 1 deficiency accelerates cystic disease in an orthologous mouse model of autosomal dominant polycystic kidney disease. Proc Natl Acad Sci U S A 109:21462-7
Blumer, J B; Oner, S S; Lanier, S M (2012) Group II activators of G-protein signalling and proteins containing a G-protein regulatory motif. Acta Physiol (Oxf) 204:202-18
Simon, Violaine; Oner, Sukru S; Cohen-Tannoudji, Joelle et al. (2012) Influence of the accessory protein SET on M3 muscarinic receptor phosphorylation and G protein coupling. Mol Pharmacol 82:17-26
Chan, PuiYee; Gabay, Meital; Wright, Forrest A et al. (2011) Purification of heterotrimeric G protein alpha subunits by GST-Ric-8 association: primary characterization of purified G alpha(olf). J Biol Chem 286:2625-35

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