Organic anion transporters (OATs) mediate the absorption, distribution, and excretion of clinically important drugs, including anti-HIV therapeutics, anti-tumor drugs, antibiotics, anti-hypertensives, and anti-inflammatories. OATs are mainly expressed in kidney, liver, brain and placenta. OAT dysfunction in these organs significantly contributes to the renal, hepatic, neurological and fetal toxicity and disease. We have novel preliminary data to show that the surface expression and activity of OAT3 are controlled by the ubiquitination of the transporter. The goal of this application is to determine the cellular and molecular mechanisms governing the regulation of OAT3 activity by ubiquitination, and to evaluate the physiological and pathophysiological relevance of such regulation.
Three Specific Aims (SAs) are outlined. In SA-I, we will identify the nature of OAT3 ubiquitination. In SA-II, we will assess the role of ubiquitination in OAT3-mediated drug transport. In SA-III, we will evaluate the physiological and pathophysiological relevance of ubiquitination in OAT3-mediated drug transport. Combined approaches of biochemistry and molecular biology will be employed for the proposed studies in cultured cells, in tissue slices, and in animals. Understanding the role of ubiquitination in the regulation of OATs, a novel focus in drug transport field, will have significant impact on the future design of strategies aimed at maximizing therapeutic efficacy and minimizing toxicity, and will permit insight into the molecular, cellular, and clinical bases of renal, hepatic, neurological and fetal toxicity and disease.

Public Health Relevance

The organic anion transporter (OAT) family mediates the absorption, distribution, and excretion of a diverse array of environmental toxins, and clinically important drugs. Therefore, understanding the regulation of OATs will have significant impact on the future design of therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM097000-02
Application #
8484847
Study Section
Special Emphasis Panel (ZRG1-DKUS-D (03))
Program Officer
Okita, Richard T
Project Start
2012-06-07
Project End
2016-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
2
Fiscal Year
2013
Total Cost
$277,755
Indirect Cost
$94,405
Name
Rutgers University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
001912864
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
Xu, Da; You, Guofeng (2017) Loops and layers of post-translational modifications of drug transporters. Adv Drug Deliv Rev 116:37-44
You, Guofeng (2017) Preface: Molecular Mechanisms, Novel Modes of Regulation, and Therapeutic Strategies. Adv Drug Deliv Rev 116:1-2
Xu, Da; You, Guofeng (2017) Rethinking the regulation of l-carnitine transport in skeletal muscle cells. Focus on ""Multiple AMPK activators inhibit l-carnitine uptake in C2C12 skeletal muscle myotubes"". Am J Physiol Cell Physiol 312:C687-C688
Xu, Da; Wang, Haoxun; You, Guofeng (2016) An Essential Role of Nedd4-2 in the Ubiquitination, Expression, and Function of Organic Anion Transporter-3. Mol Pharm 13:621-30
Xu, Da; Wang, Haoxun; Gardner, Carol et al. (2016) The role of Nedd4-1 WW domains in binding and regulating human organic anion transporter 1. Am J Physiol Renal Physiol 311:F320-9
Toh, May Fern; Suh, Wonmo; Wang, Haoxun et al. (2016) Inhibitory effects of chemotherapeutics on human organic anion transporter hOAT4. Int J Biochem Mol Biol 7:11-8
Wang, Haoxun; Xu, Da; Toh, May Fern et al. (2016) Serum- and glucocorticoid-inducible kinase SGK2 regulates human organic anion transporters 4 via ubiquitin ligase Nedd4-2. Biochem Pharmacol 102:120-129
Xu, Da; Wang, Haoxun; Zhang, Qiang et al. (2016) Nedd4-2 but not Nedd4-1 is critical for protein kinase C-regulated ubiquitination, expression, and transport activity of human organic anion transporter 1. Am J Physiol Renal Physiol 310:F821-31
Xu, Da; Wang, Haoxun; You, Guofeng (2016) Posttranslational Regulation of Organic Anion Transporters by Ubiquitination: Known and Novel. Med Res Rev 36:964-79
Xu, Da; Huang, Haozhe; Toh, May Fern et al. (2016) Serum- and glucocorticoid-inducible kinase sgk2 stimulates the transport activity of human organic anion transporters 1 by enhancing the stability of the transporter. Int J Biochem Mol Biol 7:19-26

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