The organic anion transporter (OAT) family mediates the absorption, distribution, and excretion of a diverse array of environmental toxins, and clinically important drugs, including anti-HIV therapeutics, anti-tumor drugs, antibiotics, anti-hypertensives, and anti-inflammatories, and therefore is critical for the survival of mammalian species. 5 OATs have been identified (OAT1, OAT2, OAT3, OAT4, and OAT5) and their expression detected in kidney, liver, brain and placenta. OAT dysfunction in these organs significantly contributes to the renal, hepatic, neurological and fetal toxicity and disease. Our long-term goal is to define the molecular mechanisms underlying drug/toxin disposition through the OAT pathway. During the previous grant period, significant progress and productivity have been achieved. We have mapped the membrane topology of OAT 1. We have identified the amino acid residues critical for OAT function. We have showed that OAT1 form homo-oligomer in kidney LLC-PK1 cells. The new findings from the previous grant period led to the establishment of a fine-tuned research plan and strategy in this competing renewal. We propose to test the central hypothesis that OATs form not only homo- but also hetero-oligomeric complexes in vivo and that transport activities of OATs are conferred by their oligomerization states.
4 Specific Aims (SAs) are outlined. In SA-1, we will determine the nature of OAT oligomerization (homo-versus hetero-oligomers). In SA-2, we will assess the importance of OAT oligomerization in maintenance of its function. In SA-3, we will dissect the molecular determinants of OAT oligomerization. In SA-4, we will compare the pharmacological and regulatory properties of OAT homo-and hetero-oligomers. Combined approaches of biochemistry, molecular biology, and biophysics will be employed for the proposed studies in tissue slices, and cultured cells. The knowledge gained from these studies will be invaluable toward the rational design of novel drugs and inhibitors to maximize therapeutic efficacy and minimize toxicity, and will permit insight into the molecular, cellular, and clinical bases of renal, hepatic, neurological and fetal toxicity and disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK060034-10
Application #
7678394
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Ketchum, Christian J
Project Start
2001-08-01
Project End
2013-05-31
Budget Start
2009-09-01
Budget End
2013-05-31
Support Year
10
Fiscal Year
2009
Total Cost
$264,562
Indirect Cost
Name
Rutgers University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
001912864
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
Li, Shanshan; Zhang, Qiang; You, Guofeng (2013) Three ubiquitination sites of organic anion transporter-1 synergistically mediate protein kinase C-dependent endocytosis of the transporter. Mol Pharmacol 84:139-46
Zhang, Qiang; Li, Shanshan; Patterson, Cam et al. (2013) Lysine 48-linked polyubiquitination of organic anion transporter-1 is essential for its protein kinase C-regulated endocytosis. Mol Pharmacol 83:217-24
Duan, Peng; Li, Shanshan; You, Guofeng (2012) Regulation of human organic anion transporter 4 by parathyroid hormone-related protein and protein kinase A. Int J Biochem Mol Biol 3:322-7
Zhang, Qiang; Suh, Wonmo; Pan, Zui et al. (2012) Short-term and long-term effects of protein kinase C on the trafficking and stability of human organic anion transporter 3. Int J Biochem Mol Biol 3:242-9
Duan, Peng; Li, Shanshan; Ai, Ni et al. (2012) Potent inhibitors of human organic anion transporters 1 and 3 from clinical drug libraries: discovery and molecular characterization. Mol Pharm 9:3340-6
Duan, Peng; Li, Shanshan; You, Guofeng (2011) Transmembrane peptide as potent inhibitor of oligomerization and function of human organic anion transporter 1. Mol Pharmacol 79:569-74
Duan, Peng; Wu, Jinwei; You, Guofeng (2011) Mutational analysis of the role of GXXXG motif in the function of human organic anion transporter 1 (hOAT1). Int J Biochem Mol Biol 2:1-7
Zhang, Qiang; Wu, Jinwei; Pan, Zui et al. (2011) The Role of Dileucine in the Expression and Function of Human Organic Anion Transporter 1 (hOAT1). Int J Biochem Mol Biol 2:31-38
Hong, Mei; Li, Shanshan; Zhou, Fanfan et al. (2010) Putative transmembrane domain 12 of the human organic anion transporter hOAT1 determines transporter stability and maturation efficiency. J Pharmacol Exp Ther 332:650-8
Li, Shanshan; Duan, Peng; You, Guofeng (2010) Regulation of human organic anion transporter 3 by peptide hormone bradykinin. J Pharmacol Exp Ther 333:970-5

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