Abstract

Signal transduction via guanine nucleotide binding proteins (G proteins) is crucial in regulation of cardiovascular, neural, endocrine, and immune cell function as well as in cell growth and differentiation. It has been increasingly recognized that turning off cellular signals is as important as turning them on. This is evident in the function of the novel protein family, regulators of G protein signaling (RGS proteins). They are responsible for the subsecond turn-off of G protein regulated potassium channels in heart and strongly inhibit Gi and Gq signal transduction pathways. While much is known about the biochemistry of RGS proteins, little is known about their in vivo functions or their potential as targets of drug design. We have developed two mouse models in which Gi family G proteins are mutated to prevent RGS action (Gai2 and Goto G184S). The Gaj2G184S/G184S mouse shows dramatic alterations in cardiovascular, central nervous system, hematologic, and metabolic processes. In this proposal will ask """"""""What are the roles of Ga subunits and RGS proteins in cardiovascular and metabolic function?"""""""" by use of these RGS insensitive G

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM039561-21
Application #
7579129
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Dunsmore, Sarah
Project Start
1988-12-01
Project End
2010-02-28
Budget Start
2009-03-01
Budget End
2010-02-28
Support Year
21
Fiscal Year
2009
Total Cost
$575,099
Indirect Cost

  Institution

Name
University of Michigan Ann Arbor
Department
Pharmacology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109

  Publications

Rorabaugh, Boyd R; Chakravarti, Bandana; Mabe, Nathaniel W et al. (2017) Regulator of G Protein Signaling 6 Protects the Heart from Ischemic Injury. J Pharmacol Exp Ther 360:409-416
Feng, Huijie; Sjögren, Benita; Karaj, Behirda et al. (2017) Movement disorder in GNAO1 encephalopathy associated with gain-of-function mutations. Neurology 89:762-770
Sjögren, Benita; Parra, Sergio; Atkins, Kevin B et al. (2016) Digoxin-Mediated Upregulation of RGS2 Protein Protects against Cardiac Injury. J Pharmacol Exp Ther 357:311-9
Evelyn, Chris R; Lisabeth, Erika M; Wade, Susan M et al. (2016) Small-Molecule Inhibition of Rho/MKL/SRF Transcription in Prostate Cancer Cells: Modulation of Cell Cycle, ER Stress, and Metastasis Gene Networks. Microarrays (Basel) 5:
Blazer, Levi L; Storaska, Andrew J; Jutkiewicz, Emily M et al. (2015) Selectivity and anti-Parkinson's potential of thiadiazolidinone RGS4 inhibitors. ACS Chem Neurosci 6:911-9
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
Lamberts, Jennifer T; Smith, Chelsea E; Li, Ming-Hua et al. (2013) Differential control of opioid antinociception to thermal stimuli in a knock-in mouse expressing regulator of G-protein signaling-insensitive G?o protein. J Neurosci 33:4369-77
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

Showing the most recent 10 out of 29 publications