G protein-coupled receptors (GPCRs) play critical roles in physiology, pathophysiology, and organismal development and they are the target of a large fraction of clinically used drugs. Understanding factors that modulate signaling through GPCRs is critical to the full knowledge of signal transduction mechanisms and how they can go wrong in disease. Furthermore, such modulatory mechanisms represent interesting potential drug targets. In the present proposal, we continue to explore the role of Regulators of G protein Signaling (RGS proteins) in physiology, development, and pathophysiology to understand basic signaling mechanisms and to assess the potential of RGS-targeted drugs in the treatment of important medical conditions. This work focuses on two novel mouse models in which RGS-mediated control of the Gi/o signaling pathways is lost. These RGS- insensitive (GaG184S) knock-in models result in enhanced Gai2 and Gao signaling and the mice exhibit an array of interesting phenotypes.
Aims 1 & 2 assess the role of RGS proteins and Gai2 signaling in the heart. The RGSi Gai2 mice show protection against ischemia-reperfusion injury but also show worsened heart failure in catecholamine-induced and genetic heart failure models.
The aims examine the differential contribution of Gai2 signaling in myocytes and fibroblasts in these two processes and address the mechanisms and specific RGS proteins involved.
Aim 3 studies the relative contributions of Gao and Gai2 in GABA function and seizure susceptibility.
Aim 4 examines functions of the enigmatic Gao protein. The GaoG184S mice in which Gao signaling is enhanced, show neonatal lethality in homozygotes - virtually none survive past 24 hours - and heterozygotes show a strain-dependent adult lethality at about 15-25 weeks of age.
This aim will use genetic methods to understand the unexpected adult lethality. This should provide novel insights into sudden death syndromes as well as uncovering novel potential Gao effector signaling mechanisms.

Public Health Relevance

A key goal in pharmacology is to create medicines that produce desirable therapeutic effects while minimizingside effects. In this project; we explore signaling pathways inside heart cells that can protect against injury fromheart attacks and inside brain cells that can suppress seizures. By improving those therapeutically usefulsignals at the expense of signals leading to side effects; we can produce better medicines or can make existingmedicines better tolerated.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
7R01GM039561-26
Application #
8827511
Study Section
Special Emphasis Panel (ZRG1-CB-J (03))
Program Officer
Dunsmore, Sarah
Project Start
1988-12-01
Project End
2014-07-31
Budget Start
2013-12-01
Budget End
2014-07-31
Support Year
26
Fiscal Year
2013
Total Cost
$438,510
Indirect Cost
$141,787
Name
Michigan State University
Department
Pharmacology
Type
Schools of Osteopathic Medicine
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
Parra, Sergio; Huang, Xinyan; Charbeneau, Raelene A et al. (2014) Conditional disruption of interactions between G?i2 and regulator of G protein signaling (RGS) proteins protects the heart from ischemic injury. BMC Pharmacol Toxicol 15:29
Kaur, Kuljeet; Parra, Sergio; Chen, Rong et al. (2012) G*i2 signaling: friend or foe in cardiac injury and heart failure? Naunyn Schmiedebergs Arch Pharmacol 385:443-53
Waterson, Rachael E; Thompson, Corbin G; Mabe, Nathaniel W et al. (2011) G?(i2)-mediated protection from ischaemic injury is modulated by endogenous RGS proteins in the mouse heart. Cardiovasc Res 91:45-52
Sjogren, Benita; Neubig, Richard R (2010) Thinking outside of the "RGS box": new approaches to therapeutic targeting of regulators of G protein signaling. Mol Pharmacol 78:550-7
Blazer, Levi L; Roman, David L; Muxlow, Molly R et al. (2010) Use of flow cytometric methods to quantify protein-protein interactions. Curr Protoc Cytom Chapter 13:Unit 13.11.1-15
Evelyn, Chris R; Bell, Jessica L; Ryu, Jenny G et al. (2010) Design, synthesis and prostate cancer cell-based studies of analogs of the Rho/MKL1 transcriptional pathway inhibitor, CCG-1423. Bioorg Med Chem Lett 20:665-72
Goldenstein, Brianna L; Nelson, Brian W; Xu, Ke et al. (2009) Regulator of G protein signaling protein suppression of Galphao protein-mediated alpha2A adrenergic receptor inhibition of mouse hippocampal CA3 epileptiform activity. Mol Pharmacol 75:1222-30
Evelyn, Chris R; Ferng, Timothy; Rojas, Rafael J et al. (2009) High-throughput screening for small-molecule inhibitors of LARG-stimulated RhoA nucleotide binding via a novel fluorescence polarization assay. J Biomol Screen 14:161-72
Blazer, Levi L; Neubig, Richard R (2009) Small molecule protein-protein interaction inhibitors as CNS therapeutic agents: current progress and future hurdles. Neuropsychopharmacology 34:126-41
Huang, Xinyan; Fu, Ying; Charbeneau, Raelene A et al. (2009) GNAI2 and regulators of G protein signaling as a potential Noonan syndrome mechanism. Med Hypotheses 73:56-9

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