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In Renal Organic Cation Secretion Bethzaida Multidrug And Toxin Extrusion's (MATE) Role in Renal Organic Cation Secretion Item Type text; Electronic Dissertation Authors Astorga, Bethzaida Publisher The University of Arizona. Rights Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author. Download date 01/10/2021 03:57:28 Link to Item http://hdl.handle.net/10150/205470 1 The Role of Multidrug And Toxin Extrusion (MATE) in Renal Organic Cation Secretion Bethzaida Astorga A Dissertation Submitted to the Faculty of the PHYSIOLOGICAL SCIENCES GRADUATE INTERDISCIPLINARY PROGRAM In Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY In the Graduate College THE UNIVERSITY OF ARIZONA 2011 2 THE UNIVERSITY OF ARIZONA GRADUATE COLLEGE As members of the Dissertation Committee, we certify that we have read the dissertation prepared by: Bethzaida Astorga entitled: The Role of Multidrug And Toxin Extrusion (MATE) in Renal Organic Cation Secretion and recommend that it be accepted as fulfilling the dissertation requirement for the Degree of Doctor of Philosophy _______________________________________________________________________ Date: 11/29/11 Stephen H. Wright _______________________________________________________________________ Date: 11/29/11 Nathan J. Cherrington _______________________________________________________________________Date: 11/29/11 William H. Dantzler _______________________________________________________________________ Date: 11/29/11 Nicholas A. Delamere _______________________________________________________________________ Date: 11/29/11 Alexander Simon Final approval and acceptance of this dissertation is contingent upon the candidate’s submission of the final copies of the dissertation to the Graduate College. I hereby certify that I have read this dissertation prepared under my direction and recommend that it be accepted as fulfilling the dissertation requirement. ________________________________________________ Date: 11/29/11 Dissertation Director: Stephen H. Wright 3 STATEMENT BY AUTHOR This dissertation has been submitted in partial fulfillment of requirements for an advanced degree at the University of Arizona and is deposited in the University Library to be made available to borrowers under rules of the Library. Brief quotations from this dissertation are allowable without special permission, provided that accurate acknowledgment of source is made. Requests for permission for extended quotation from or reproduction of this manuscript in whole or in part may be granted by the head of the major department or the Dean of the Graduate College when in his or her judgment the proposed use of the material is in the interests of scholarship. In all other instances, however, permission must be obtained from the author. SIGNED: Bethzaida Astorga 4 ACKNOWLEDGEMENTS To all of the faculty members that made the last 7 years in the Physiological Science Program interesting, ‘in a good way’. To the members of my committee, Dr. Nathan Cherrington, Dr. William Dantzler, Dr. Nick Delamere, Dr. Alex Simon and Dr. Stephen Wright. A special thanks to Dr. Dantzler, who always took time to be a second mentor to me. Dr. Scott Boitano for always making it to all the graduate student activities and for facilitating so many connections in the field. Dr. Cindy Rankin for always encouraging me to continue on and for helping me decide to continue my education with the Physiological Sciences Graduate Program. Also, Dr. Heddwen Brooks for introducing me to many people in the world of renal physiology and for being a role model for ‘women in science’. Dr. Tom Pennabaker for teaching me immunohistochemistry and for always being willing to help me on the microscope. To all my fellow graduate students and colleagues that made my time in graduate school so special. Thank you to Dr. Ryan Pelis who always made things in the lab fun and ‘doable’; and for his continued mentorship. Dr. Yod Dangpraprai who was there to commiserate with me and to always point out the positive (and for listening to my political rants). Mark Morales, who deserves at least 50% of this degree for helping me with so many of my experiments and for listening to me complain for hours on end when things were not working. Theresa Wunz, who took the role of lab manager to a whole new level with her ‘no-nonsense’ attitude. She taught me almost everything I know about cell culture, keeping an orderly lab notebook and most importantly how to be the “squeaky wheel”. Xiaohong Zhang made everything about molecular biology look and sound easy, and while I will never be as good as she is at it, I certainly appreciate all the time she spent explaining her tricks to me. Thank you to Kristen Evans for being a good friend and a great lab technician. And finally a very special thank you to (soon to be Dr.) Laura Wright and Lori Cole who I met in this program and who are now my lifelong friends. To those I met while in Los Angeles at the University of Southern California, thank you so much for your continued friendship and for a great year in the Programs in Biomedical & Biological Sciences (PIBBS). Thank you to Dr. Alicia McDonough and Dr. Alan Yu for kindly taking me into your labs and for your continued support. Thank you to University of Arizona (Bear Down!) for making me proud to be a Wildcat! And to the Physiological Sciences Graduate Program for taking me back after my ‘sabbatical’ at the University of Southern California. Especially, Holly Lopez for ‘taking care of business’. Finally to my family, Elizabeth Astorga, Dad (Octavio Astorga) and Grandmother (Manuela Orozco) for being patient and for not asking me “So, how long before you graduate?”, anymore. I could not be more grateful to my Mother, Evadina Lomerson, whose prayers “for me to finally finish!” always brightened up my day (especially while writing this dissertation). To my Grandfather, Manuel Orozco, whose own sacrifices have always been a source of motivation, pride, strength and ambition. Also, to my incredible husband, Kevin Yarbrough, who has not only listened and consoled me but also encouraged and been proud of me. His support has been invaluable. And last but certainly not least, Dr. Stephen Wright, who has guided me in this long and at times frustrating journey. I’ve learned things about science, life, academia, obscure Sci-fi novels and movies, the 60’s and 70’s and membrane protein kinetics that I am certain I could not have learned anywhere else. In the summer of 2004 I walked into his lab thinking that “I would give research a try”, 7 years later I am leaving with great memories, friendships and with the certainty that it would not have been this fun and unique anywhere else. Thanks Steve. 5 TABLE OF CONTENTS LIST OF FIGURES ...................................................................................................................... 9 LIST OF TABLES ...................................................................................................................... 11 ABSTRACT ................................................................................................................................ 12 CHAPTER 1: INTRODUCTION ............................................................................................... 14 1.1 Background .............................................................................................................. 14 1.2 Organic Cations ....................................................................................................... 14 1.3 Cellular Physiology of Renal OC Secretion ............................................................ 16 1.4 Basolateral OC Transport – the OCTs ..................................................................... 18 1.4.1 Molecular Characteristics of OCT1 and OCT2 ....................................... 18 1.5 Apical OC Transport – the MATEs ......................................................................... 21 1.5.1 Molecular Characteristics of MATEs ...................................................... 23 1.5.2 MATE Protein Structure & Function ....................................................... 25 1.6 Kinetics & Selectivity of MATE transporters.......................................................... 27 1.7 Role of MATEs in Renal OC Secretion - Specific Aims ......................................... 30 1.8 Predictive Models: Use of Pharmacophores ............................................................ 31 1.9 Competitive Exchange Diffusion ............................................................................. 35 ORGANIZATION OF CHAPTERS ........................................................................................... 36 CHAPTER 2: MATERIALS AND METHODS ........................................................................ 37 2.1 Chemicals ................................................................................................................. 37 2.2 Cell Culture and Stable Expression of hMATE1 & hMATE2-K ............................ 37 2.3 Transport by hMATE1- & hMATE2-K Expressing CHO cells .............................. 38 2.4 Real-Time Quantitative-PCR ................................................................................... 38 2.5 Immunohistochemistry ...........................................................................................
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