Many drugs (e.g. biguanide antihyperglycemics, histamine H2 receptor blockers, platinum-based chemotherapeutics etc.) and toxins (e.g. MPP+, paraquat) are hydrophilic organic cations (OCs) that do not readily cross cell membranes by passive diffusion. Organic cation transporters play important roles in the disposition, efficacy and toxicity of these OC xenobiotics. These transporters are also likely to be involved in various physiological pathways through their uptake of endogenous bioactive amines. The plasma membrane monoamine transporter (PMAT) is a new polyspecific organic cation transporter first cloned and characterized in our laboratory. The physiologic substrates of PMAT are the monoamine neurotransmitters with serotonin (5- HT) being the most preferred substrate. PMAT also transports many structurally diverse cationic xenobiotics including the neurotoxin MPP+ and therapeutic drugs such as metformin. PMAT is highly expressed in the brain and the gastrointestinal tract, and has overlapping substrate specificity with organic cation transporters 1- 3 (OCT1-3). Our previous molecular and cellular work strongly supports a role of PMAT in 5-HT signaling pathways and in OC transport at barrier tissues including choroid plexus that forms the blood- cerebrospinal fluid (CSF) barrier. However, these studies are limited by their in vitro design, and the physiological function of PMAT and its in vivo significance in brain OC disposition remain undefined. We have recently created a novel PMAT knockout mouse model, which provides a unique resource to evaluate the roles and significance of PMAT in vivo. Using a chemical biology approach, we also identified a set of promising specific small molecule inhibitors for PMAT. More excitingly, the PMAT null mice exhibited physiological and histological abnormalities in the colon which could represent early signs associated with the development of inflammatory bowel disease. Because 5-HT is a key gut hormone known to be involved in the pathogenesis of inflammatory bowel disease, these observations suggest a protective role of PMAT against colitis likely through 5-HT mediated pathway. In this competing renewal application, we propose to use our novel animal model and unique chemical tools to investigate the physiological, pharmacological and pathological function of PMAT.
In Aim 1, we will further characterize and validate highly potent and selective small molecule inhibitors for PMAT.
In Aim 2, we will use our knockout animal model and specific chemical inhibitors to investigate the role of PMAT in mediating OC efflux at the blood-CSF barrier. Lastly, in Aim 3, we will investigate the pathogenic role of PMAT in the development of inflammatory response in the gut. The proposed studies will greatly enhance our understandings of the in vivo roles and significance of a novel organic cation transporter. These studies will shed new light on the determinants influencing brain disposition of OC drugs and toxins. Finally, our studies will elucidate the pathophysiologic role of PMAT in the gut and offer new insights into genetic factors influencing host susceptibility to inflammatory bowel disease.

Public Health Relevance

This project will determine how a specific transporter PMAT influences brain disposition of hydrophilic cationic drugs and neurotoxins, and whether PMAT plays a protective role against inflammatory bowel disease. Tools and knowledge generated from these studies have broad applications and far reaching implications in basic research, drug discovery and development, and disease prevention processes.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01GM066233-11
Application #
8665963
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Okita, Richard T
Project Start
Project End
Budget Start
Budget End
Support Year
11
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Washington
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
City
Seattle
State
WA
Country
United States
Zip Code
98195
Yin, Jia; Duan, Haichuan; Wang, Joanne (2016) Impact of Substrate-Dependent Inhibition on Renal Organic Cation Transporters hOCT2 and hMATE1/2-K-Mediated Drug Transport and Intracellular Accumulation. J Pharmacol Exp Ther 359:401-410
Wagner, David J; Hu, Tao; Wang, Joanne (2016) Polyspecific organic cation transporters and their impact on drug intracellular levels and pharmacodynamics. Pharmacol Res 111:237-46
Shirasaka, Yoshiyuki; Lee, Nora; Zha, Weibin et al. (2016) Involvement of organic cation transporter 3 (Oct3/Slc22a3) in the bioavailability and pharmacokinetics of antidiabetic metformin in mice. Drug Metab Pharmacokinet 31:385-388
Yin, Jia; Wang, Joanne (2016) Renal drug transporters and their significance in drug-drug interactions. Acta Pharm Sin B 6:363-373
Shirasaka, Yoshiyuki; Lee, Nora; Duan, Haichuan et al. (2016) Interspecies comparison of the functional characteristics of plasma membrane monoamine transporter (PMAT) between human, rat and mouse. J Chem Neuroanat :
Wang, J (2016) The plasma membrane monoamine transporter (PMAT): Structure, function, and role in organic cation disposition. Clin Pharmacol Ther 100:489-499
Yin, Jia; Duan, Haichuan; Shirasaka, Yoshiyuki et al. (2015) Atenolol Renal Secretion Is Mediated by Human Organic Cation Transporter 2 and Multidrug and Toxin Extrusion Proteins. Drug Metab Dispos 43:1872-81
Duan, Haichuan; Hu, Tao; Foti, Robert S et al. (2015) Potent and Selective Inhibition of Plasma Membrane Monoamine Transporter by HIV Protease Inhibitors. Drug Metab Dispos 43:1773-80
Lee, Nora; Duan, Haichuan; Hebert, Mary F et al. (2014) Taste of a pill: organic cation transporter-3 (OCT3) mediates metformin accumulation and secretion in salivary glands. J Biol Chem 289:27055-64
Adamsen, Dea; Ramaekers, Vincent; Ho, Horace Tb et al. (2014) Autism spectrum disorder associated with low serotonin in CSF and mutations in the SLC29A4 plasma membrane monoamine transporter (PMAT) gene. Mol Autism 5:43

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