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DRUG TRANSPORTERS AND NHERF PDZ PROTEINS

WALSH, DUSTIN R (2015) DRUG TRANSPORTERS AND NHERF PDZ PROTEINS. Master's Thesis, University of Pittsburgh. (Unpublished)

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Abstract

Drug transporters govern the absorption, distribution, and elimination of pharmacologically active compounds. Members of the solute carrier (SLC) and ATP binding- cassette (ABC) drug transporter family mediate cellular drug uptake and efflux processes, thereby coordinating the vectorial movement of drugs across epithelial barriers. To exert their physiological and pharmacological function in polarized epithelia, drug transporters must be targeted and stabilized to appropriate regions of the cell membrane (i.e., apical versus basolateral). Despite the critical importance of drug transporter membrane targeting, the mechanisms that underlie these processes are largely unknown. Several clinically significant drug transporters possess a recognition sequence that binds to PSD-95/Drosophila discs
large/ZO-1 (PDZ) proteins. PDZ proteins, such as the Na+/H+ exchanger regulatory factor

(NHERF) family, act to stabilize and organize membrane targeting of multiple transmembrane proteins including many clinically relevant drug transporters. These PDZ proteins are normally abundant at apical membranes, where they tether membrane-delimited transporters. NHERF expression is particularly high at the apical membrane in polarized tissue such as intestinal, hepatic, and renal epithelia, tissues important to drug disposition. Several recent studies have highlighted NHERF proteins as determinants of drug transporter function secondary to their role in controlling membrane abundance and localization. Mounting evidence strongly suggests that NHERF proteins may have clinically significant roles in pharmacokinetics and pharmacodynamics of several pharmacologically active compounds and may affect drug action in cancer and chronic kidney disease. For these reasons, NHERF proteins represent a novel class of post-translational mediators of drug transport and novel targets for new drug development.

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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
WALSH, DUSTIN Rdrw12@pitt.eduDRW12
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairNolin, Thomas Dnolin@pitt.eduNOLIN
Committee MemberEmpey, Philip Epempey@pitt.eduPEMPEY
Committee MemberPoloyac, Samuel Mpoloyac@pitt.eduPOLOYAC
Committee MemberFriedman, Peter Apaf10@pitt.eduPAF10
Date: 30 November 2015
Date Type: Publication
Defense Date: 6 October 2015
Approval Date: 30 November 2015
Submission Date: 21 November 2015
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 98
Institution: University of Pittsburgh
Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: Drug transporters, NHERF, PDZ, proteins
Date Deposited: 30 Nov 2015 14:30
Last Modified: 15 Nov 2016 14:30
URI: http://d-scholarship.pitt.edu/id/eprint/26399

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