This renewal application seeks to continue studies that use Madin Darby Canine Kidney (MDCK) cells and knockout mice to assess molecular and functional aspects of adrenergic and P2Y (nucleotide, purinergic) receptors. The proposed studies will test hypotheses related to findings that we have obtained in MDCK cells and more recently in mouse primary kidney collecting duct (mpkCCD) cells as well as in P2Y2 knockout mice, which we have recently shown have salt-resistant hypertension and multiple abnormalities in renal function.
The Specific Aims i nvolve studies of: 1) Expression and compartmentation in raft/caveolar microdomains of G protein-coupled receptor/G-proteins/effectors of adrenergic and P2Y receptors in MDCK and mpkCCD cells and assessment of sumoylation (a novel modification that we have recently identified) of caveolins;2) Functional roles of renal P2Y and adrenergic receptors using receptor-knockout mice. The combined use of cultured renal epithelial cells and knockout mice provides a complementary strategy that is designed to reveal new insights regarding the regulation of epithelial cells and renal function by adrenergic and P2Y receptors. The findings may have implications for cardiovascular, renal and other disorders that involve the sympathetic nervous system or in which cell injury leads to release of nucleotides.

Public Health Relevance

This project will assess 2 important classes of proteins, receptors for adrenaline (and adrenaline-like drugs) and for a major cell constituent, ATP. The receptors, which are located on the surface of cells, recognize those molecules in the extracellular environment but then alter intracellular function. Experiments are proposed in: 1) tissue culture cells to assess the organization of the components involved in information transfer across the cell surface and 2) mice engineered to have loss in receptors for ATP or adrenaline with the goal of understanding how the receptors regulate fluid and salt handling, in particular by the kidney.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Molecular and Integrative Signal Transduction Study Section (MIST)
Program Officer
Dunsmore, Sarah
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University of California San Diego
Schools of Medicine
La Jolla
United States
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Wilderman, Andrea; Guo, Yurong; Divakaruni, Ajit S et al. (2015) Proteomic and Metabolic Analyses of S49 Lymphoma Cells Reveal Novel Regulation of Mitochondria by cAMP and Protein Kinase A. J Biol Chem 290:22274-86
Lu, David; Insel, Paul A (2013) Hydrolysis of extracellular ATP by ectonucleoside triphosphate diphosphohydrolase (ENTPD) establishes the set point for fibrotic activity of cardiac fibroblasts. J Biol Chem 288:19040-9
Vallon, Volker; Stockand, James; Rieg, Timo (2012) P2Y receptors and kidney function. Wiley Interdiscip Rev Membr Transp Signal 1:731-742
Toney, Glenn M; Vallon, Volker; Stockand, James D (2012) Intrinsic control of sodium excretion in the distal nephron by inhibitory purinergic regulation of the epithelial Na(+) channel. Curr Opin Nephrol Hypertens 21:52-60
Fridolfsson, Heidi N; Kawaraguchi, Yoshitaka; Ali, Sameh S et al. (2012) Mitochondria-localized caveolin in adaptation to cellular stress and injury. FASEB J 26:4637-49
Guo, Yurong; Wilderman, Andrea; Zhang, Lingzhi et al. (2012) Quantitative proteomics analysis of the cAMP/protein kinase A signaling pathway. Biochemistry 51:9323-32
Vallon, Volker; Thomson, Scott C (2012) Renal function in diabetic disease models: the tubular system in the pathophysiology of the diabetic kidney. Annu Rev Physiol 74:351-75
Insel, P A; Zhang, L; Murray, F et al. (2012) Cyclic AMP is both a pro-apoptotic and anti-apoptotic second messenger. Acta Physiol (Oxf) 204:277-87
Horikawa, Yousuke T; Panneerselvam, Mathivadhani; Kawaraguchi, Yoshitaka et al. (2011) Cardiac-specific overexpression of caveolin-3 attenuates cardiac hypertrophy and increases natriuretic peptide expression and signaling. J Am Coll Cardiol 57:2273-83
Vallon, Volker; Rieg, Timo (2011) Regulation of renal NaCl and water transport by the ATP/UTP/P2Y2 receptor system. Am J Physiol Renal Physiol 301:F463-75

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