The long-term goal of our research program is to elucidate the structure-function basis of angiotensin II type 1 receptor (AT1R). Angiotensin II (AngII) is the classical mediator of the effects of renin-angiotensin system on cardiovascular, renal and nervous systems. AngII induced sub-cellular events include rapid second messenger response followed by activation of various signal transduction cascades and transcription of genes including genes for early growth response, growth factors, cytokines and oxidative stress. These effects are elicited by the binding of AngII to the AT1R, a seven transmembrane G protein-coupled receptor. If the AT1R activity is not regulated properly, AngII stimulus becomes chronic and can damage the cells and tissue, as well as contribute to chronic disorders of myocardium (heart failure), blood vessels (atherosclerosis) or kidney (renal failure) for example. Drugs that inhibit the production of AngII or the AT1R blockers (ARB) are prescribed to effectively alleviate hypertension, many cardiovascular complications and to prevent end-organ damage in humans. However, the AT1R-targeted therapeutic potential is not fully harnessed. We have shown G protein- independent signaling from AT1R. The novel AT1R responses to Ang II includes receptor conformation driven assembly of cytoplasmic scaffolds that enable AT1R crosstalk with other GPCRs, growth factor receptors or adhesion receptors and a capacity to form receptor dimer/oligomer complexes with altered pharmacology. Remarkably, the novel AT1R scaffolding complexes consist of "typical signaling" proteins specifically co-opted for G protein independent function. Focus of our research has been the molecular basis of AT1R pharmacology, activation and signaling. We propose that specific conformational changes are induced by agonist and inverse-agonist binding which facilitate AT1R to selectively engage/exclude signal transduction proteins;different motifs exposed during the dynamic conformational changes enable the AT1R to recognize the cytoplasmic or plasma membrane proteins and thereby increase the variety of signals that are generated. We will test the hypothesis under three Specific Aims:
Specific Aim 1 will determine the conformational and structural basis of AT1R inhibition caused by ARBs.
Specific Aim 2 will determine the AT1R interactions with the adhesion receptor required for mechanical stretch-induced ERK1/2 activation.
Specific Aim 3 will determine the mechanism by which AT1R dimer/oligomer complexes are formed. These proposed studies will advance our knowledge of AT1R biology.

Public Health Relevance

Our studies will elucidate the molecular basis for the multiple signaling response to the vasoactive hormone AngII and the efficacy of ARBs. The receptor which mediates the response to AngII is AT1R. The non- canonical pathways activated by AT1R may contribute to the progression of cardiovascular pathophysiology. A deeper understanding of these aspects of AT1R biology may offer unique opportunities to develop new therapeutics to modulate responses selectively to therapeutic advantage.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL057470-16
Application #
8484417
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Reid, Diane M
Project Start
1997-08-20
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
16
Fiscal Year
2013
Total Cost
$353,206
Indirect Cost
$128,234
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
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Kemp, Jacqueline R; Unal, Hamiyet; Desnoyer, Russell et al. (2014) Angiotensin II-regulated microRNA 483-3p directly targets multiple components of the renin-angiotensin system. J Mol Cell Cardiol 75:25-39
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Unal, Hamiyet; Karnik, Sadashiva S (2012) Domain coupling in GPCRs: the engine for induced conformational changes. Trends Pharmacol Sci 33:79-88
Jagannathan, Rajaganapathi; Kaveti, Suma; Desnoyer, Russell W et al. (2010) AT1 receptor induced alterations in histone H2A reveal novel insights into GPCR control of chromatin remodeling. PLoS One 5:e12552
Yue, Hong; Li, Wei; Desnoyer, Russell et al. (2010) Role of nuclear unphosphorylated STAT3 in angiotensin II type 1 receptor-induced cardiac hypertrophy. Cardiovasc Res 85:90-9
Unal, Hamiyet; Jagannathan, Rajaganapathi; Bhat, Manjunatha B et al. (2010) Ligand-specific conformation of extracellular loop-2 in the angiotensin II type 1 receptor. J Biol Chem 285:16341-50
Jang, Sei-Heon; Hwang, Si Ae; Kim, Mijin et al. (2009) A protein tyrosine phosphatase inhibitor, pervanadate, inhibits angiotensin II-Induced beta-arrestin cleavage. Mol Cells 28:25-30

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