Giuliano Ciarimboli · Sophie Gautron Eberhard Schlatter E ditors Organic Cation Transporters Integration of Physiology, Pathology, and Pharmacology Organic Cation Transporters Giuliano Ciarimboli (cid:129) Sophie Gautron Eberhard Schlatter Editors Organic Cation Transporters Integration of Physiology, Pathology, and Pharmacology Editors Giuliano Ciarimboli Sophie Gautron Experimental Nephrology, Medical Clinic D French Institute of Health and University of Münster Medical Research Münster , Germany Neuroscience Institute of Biology Paris-Seine Eberhard Schlatter Paris , France Experimental Nephrology, Medical Clinic D University of Münster Münster , Germany ISBN 978-3-319-23792-3 ISBN 978-3-319-23793-0 (eBook) DOI 10.1007/978-3-319-23793-0 Library of Congress Control Number: 2015956344 Springer Cham Heidelberg New York Dordrecht London © Springer International Publishing Switzerland 2016 T his work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifi cally the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfi lms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. T he use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specifi c statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. T he publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. Printed on acid-free paper S pringer International Publishing AG Switzerland is part of Springer Science+Business Media (www.springer.com) This book is dedicated to the memory of Karl Julius Ullrich (1925–2010), former head of the Department of Physiology at the Max Planck Institute of Biophysics in Frankfurt am Main, Germany. Professor Ullrich was one of the founders of the renal transport physiology, especially with regard to the transport of organic anions and cations. Ullrich’s department stood out as a beacon of transport physiology. Many of his scholars were able to further increase knowledge of transport physiology. In this way, we would like to express our admiration and gratitude for his outstanding work. Pref ace Transport across the cell membrane is essential for vital processes like entry of nutrients into the intracellular compartment, delivery of cellular products to extra- cellular and intracellular destinations, and handling of metabolism waste products and toxic substances and is necessary to keep the intracellular milieu constant. Transport across cell membranes is mediated by a variety of different transport proteins. This book focusses on transporters for organic cations, which are not directly energy-dependent, such as organic cation transporters (OCTs), organic zwitterions/cation transporters (OCTNs), and multidrug extrusion proteins (MATEs). Because these transporters are polyspecifi c, they accept many different substrates of endogenous (e.g. choline, acetylcholine, histamine, and monoamine neurotransmitters) as well as of exogenous (e.g. drugs like metformin, quinine, cimetidine, and cisplatin) origin. S ince the cloning of the fi rst transporter for organic cations (rOCT1) in 1994, profound understanding of their structure, transport properties, and regulation has been obtained. In organs expressing these transporters at high levels, such as the intestine, liver, and kidney, transporters for organic cations play a pivotal role not only in absorption and in excretion of xenobiotics but also in their accumulation and toxicity. However, their expression is not restricted to organs typically involved in the transport of xenobiotics, but is found also in other tissues, such as the brain and reproductive organs. Recent studies with genetically modifi ed animals have helped to unveil novel physiological, pathophysiological, and pharmacological roles of transporters for organic cations. While there is no doubt about the pharmacological and toxicological implications of transporters for organic cations for the organism, their physiological functions had remained largely elusive. Moreover, gender- and species-specifi c differences in the expression and properties of these transporters as well as the role of single nucleotide polymorphisms on their function have become a focus of attention in physiology, pathophysiology, and medical care. This book presents current knowledge on the expression, physiological functions (see Chap. 1 by G. Ciarimboli), and regulation (see Chap. 5 by E. Schlatter and Chap. 6 by L.M. Aleksunes) of transporters for organic cations in various organs, on vii viii Preface their gender and species dependencies (see Chap. 9 by I. Sabolić, D. Breljak, and T. Smital), and on their role in pathophysiological situations. This overview should be of high interest for researchers and students in various areas of integrative, organ, cell, and molecular physiology and will contribute to delineate an integrative physi- ological interpretation of transporter function. A nother important aspect of the book is that it conjugates integrative transporter physiology with structural and molecular biology (see Chap. 2 by H. Koepsell and T. Keller), genetics (see Chap. 4 by M.V. Tzvetkov, N. Dalila, and F. Faltraco), pharmacology, and pathophysiology (see Chap. 3 by K. Inui and H. Motohashi and Chap. 8 by K. Tieu), offering an integration of the knowledge in these fi elds. The different chapters of the book present the state of the art of the research in these different fi elds. For this reason, the book addresses both expert readers and readers with a more general interest in understanding transporter function in physiology and pathophysiology. Hence, the book should also attract people interested in adap- tive mechanisms of the organism to conditions, such as salt intake, anxiety, and stress (see Chap. 7 by A. Orrico and S. Gautron). Since up to 40 % of the prescribed drugs are organic cations, this book will pro- vide important information on the involvement of transporters for organic cations in determining specifi c effects but also side effects induced by particular drugs, offering new approaches for a successful translation from physiology to clinical therapy. Finally, because of the expression of transporters for organic cations in plants, the role of these transporters for the environmental cycling of pharmaceuti- cal residues is also presented (see Chap. 1 0 by T. Eggen and C. Lillo). I n conclusion, we think that a book concentrating on the latest developments of integrative, organ, cell, and molecular aspects of function of transporters for organic cations will furnish an optimal platform to integrate the knowledge on these transporters and obtain a more comprehensive physiological understanding of their function. Münster, Germany Giuliano Ciarimboli Paris, France Sophie Gautron Münster, Germany Eberhard Schlatter Acknowledgements We would like to express our gratitude to the contributors to this book and to Springer Science+Business Media for enabling us to publish this book. We would like to thank the organizers of the congress of International Union of Physiological Sciences 2013 in Birmingham (UK) for giving us the opportunity to hold a symposium on organic cation transporters. By this occasion the idea of the book was born. G C would like to thank Frank Thevenod for the support in organizing the sym- posium on organic cation transporters, whose idea came up when visiting together with him. ix