Molecular Biology of Membrane Transport Disorders PDF
Preview Molecular Biology of Membrane Transport Disorders
Molecular Biology of Membrane Transport Disorders Molecular Biology of Membrane Transport Disorders Edited by Stanley G. Schultz University of Texas Medical School at Houston Houston, Texas Thomas E. Andreoli University of Arkansas College of Medicine Little Rock, Arkansas Arthur M. Brown Case Western Reserve University Cleveland, Ohio Douglas M. Fambrough The Johns Hopkins University Baltimore, Maryland Joseph F. Hoffman Yale University School of Medicine New Haven, Connecticut and Michael J. Welsh University of Iowa College of Medicine Iowa City, Iowa Plenum Press • New York and London LIbrary of Congress CatalogIng-In-PublIcatIon Data Molecular biology of membrane transport disorders / edited by Stanley G. Schultz ... let al.l. p. em. Includes bibl iographical references and index. 1. Membrane disorders. 2. Pathology, Molecular. I. Schultz, Stanley G. RDI i3.f"5855 1998 616.07--dc20 96-21633 CIP ISBN-13: 978-1-4612-8446-8 e-ISBN-13: 978-1-4613-1143-0 DOT: 10.1007/978-1-4613-1143-0 © 1996 Plenum Press, New York A Division of Plenum Publishing Corporation 233 Spring Street, New York, N. Y. 10013 Softcover reprint of the hardcover I st edition 1996 10987654321 All rights reserved No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise, without written permission from the Publisher Preface When the six of us gathered to start planning for what was to be the Third Edition of Physiology of Membrane Disorders, it was clear that since 1986, when the Second Edition appeared, the field had experienced the dawning of a new era dominated by a change in focus from phenomenology to underlying mechanisms propelled by the power of molecular biology. In 1985, detailed molecular information was available for only three membrane transporters: the lac permease, bacterial rhodopsin, and the acetylcholine receptor. During the decade that has since elapsed, almost all of the major ion channels and transport proteins have been cloned, sequenced, mutagenized, and expressed in homologous as well as heterologous cells. Few, if any, of the transporters that were identified during the previous era have escaped the probings of the new molecular technologies and, in many instances, considerable insight has been gained into their mechanisms of function in health and disease. Indeed, in some instances novel, unexpected transporters have emerged that have yet to have their functions identified. The decision to adopt the new title Molecular Biology of Membrane Transport Disorders was a natural outgrowth of these considerations. The seminal purpose of this volume, however, remains unchanged from, and is a logical extension of, that of its predecessor; namely, to provide a frame of reference for the understanding of the pathogenesis of clinical conditions that in volve derangements in membrane transport processes at the molecular level-a goal that ten years ago could only have been contemplated but that is now within our grasp. Accordingly, this volume is structured similarly to PMD but, because of length limitations, it focuses on areas where our understanding has advanced to the molecular level; no attempt has been made to du plicate sections of the Second Edition of PMD that are as timely today as they were when they were written. Stanley G. Schultz Thomas E. Andreoli Arthur M. Brown Douglas M. Fambrough Joseph F. Hoffman Michael J. Welsh v Contributors Robert J. Alpern • Department of Internal Medicine, The Jonathan Covault • Department of Physiology and Neuro University of Texas, Southwestern Medical Center, Dallas, biology, University of Connecticut, Storrs, Connecticut 06269 Texas 75235 Mark G. Darlison • Institute for Cell Biochemistry and Suresh V. Ambudkar • Department of Medicine, The Clinical Neurobiology, University Hospital Eppendorf, Uni Johns Hopkins University School of Medicine, Baltimore, versity of Hamburg, 20246 Hamburg, Germany Maryland 21218 David C. Dawson • Department of Physiology, The Univer Thomas E. Andreoli • Division of Nephrology and Depart sity of Michigan Medical School, Ann Arbor, Michigan 48109 ment of Internal Medicine, University of Arkansas College of Patricia V. Donnelly • Department of Pharmacology, Uni Medicine, Little Rock, Arkansas 72205 versity of Texas-Houston Medical School, Houston, Texas Yvonne L. O. Balba • Department of Pharmacology, Univer 77225 sity of Texas-Houston Medical School, Houston, Texas 77225 Mark Donowitz • Departments of Medicine and Physiol Krister Bamberg • Membrane Biology Laboratory, De ogy, GI Unit, The Johns Hopkins University School of Medi partment of Medicine, University of California, Los Angeles, cine, Baltimore, Maryland 21205 and Wadsworth VA Medical Center, Los Angeles, California William P. Dubinsky • Department of Integrative Biology, 90073 The University of Texas-Houston Medical School, Houston, Laurence Bianchini • Department of Biochemistry, Uni Texas 77225 versity of Nice, Nice, France Douglas M. Fambrough • Department of Biology, The Lutz Birnbaumer • Departments of Anesthesiology and Johns Hopkins University, Baltimore, Maryland 21218 Biological Chemistry, School of Medicine, and the Molecular Ursula A. Germann • Vertex Pharmaceuticals Incorpo Biology Institute, University of California at Los Angeles, rated, Cambridge, Massachusetts Los Angeles, California 90095 Michael M. Gottesman • Laboratory of Cell Biology, Na Mariel Birnbaumer • Departments of Anesthesiology and tional Cancer Institute, National Institutes of Health, Bethesda, Biological Chemistry, School of Medicine, and the Molecular Maryland 20892 Biology Institute, University of California at Los Angeles, Los Angeles, California 90095 Robert C. Griggs • Department of Neurology, University of Rochester, Rochester, New York 14642 Robert J. Bloch • Department of Physiology, University of Robert J. Harvey • Institute for Cell Biology and Clinical Maryland, School of Medicine, Baltimore, Maryland 21201 Neurobiology, University Hospital Eppendorf, University of Steven R. Brant • Departments of Medicine and Physiol Hamburg, 20246 Hamburg, Germany ogy, GI Unit, The Johns Hopkins University School of Medi Sandra Hoogerwerf • Departments of Medicine and Physi cine, Baltimore, Maryland 21205 ology, GI Unit, The Johns Hopkins University School of Med Thomas J. Burke • Department of Medicine, University of icine, Baltimore, Maryland 21205 Colorado Medical School, Denver, Colorado 80262 C. K. Ifune • Washington University School of Medicine, William B. Busa • Department of Biology, The Johns St. Louis, Missouri 6311 0 Hopkins University, Baltimore, Maryland 21218 Giuseppe Inesi • Department of Biological Chemistry, The William A. Catterall • Department of Pharmacology, Uni University of Maryland School of Medicine, Baltimore, versity of Washington, Seattle, Washington 98195 Maryland 21201 Marilyn M. Cornwell • Fred Hutchinson Cancer Research Laurinda A. Jaffe • Department of Physiology, University Center, Seattle, Washington 98195 of Connecticut Health Center, Farmington, Connecticut 06032 vii viii Contributors H. Ronald Kaback • Howard Hughes Medical Institute, John C. Parker • Department of Medicine, University of Departments of Physiology and Microbiology and Molecular North Carolina, Clinical Research Center, Chapel Hill, North Genetics, Molecular Biology Institute, University of Califor Carolina 27599 nia, Los Angeles, Los Angeles, California 90024 Ira Pastan • Laboratory of Molecular Biology, National Henry J. Kaminski • Department of Neurology, Case Cancer Institute, National Institutes of Health, Bethesda, Western Reserve University School of Medicine, Cleveland Maryland 20892 Veterans Affairs Medical Center, University Hospitals of Michael S. Phillips • Banting and Best Department of Cleveland, Cleveland, Ohio 44106 Medical Research, University of Toronto, C. H. Best Institute, Ronald S. Kaplan • Department of Pharmacology, College Toronto, Ontario M5G lL6, Canada of Medicine, University of South Alabama, Mobile, Alabama Jacques Pouyssegur • Department of Biochemistry, Uni 36688 versity of Nice, Nice, France Robert S. Kass • Department of Pharmacology, College of Christian Prinz • Membrane Biology Laboratory, Depart Physicians and Surgeons, Columbia University, New York, ment of Medicine, University of California, Los Angeles, and New York 10032 Wadsworth VA Medical Center, Los Angeles, California Victoria P. Knutson • Department of Pharmacology, Uni 90073 versity of Texas-Houston Medical School, Houston, Texas Louis Ptacek • Department of Neurology, Human Molecu 77225 lar Biology and Genetics, The University of Utah, Salt Lake Freddie Kokkie • Departments of Medicine and Physiol City, Utah 84132 ogy, GI Unit, The Johns Hopkins University School of Medi W. Brian Reeves • Division of Nephrology and Depart cine, Baltimore, Maryland 21205 ment of Internal Medicine, University of Arkansas College of Roger Lester • Department of Internal Medicine, Univer Medicine, Little Rock, Arkansas 72205 sity of Arkansas for Medical Sciences, and McClellan VA Robert L. Ruff • Departments of Neurology and Neuro Hospital, Little Rock, Arkansas 77205 science, Case Western Reserve University School of Medi Susan A. Levine • Departments of Medicine and Physiol cine, Cleveland Veterans Affairs Medical Center, University ogy, GI Unit, The Johns Hopkins University School of Medi Hospitals of Cleveland, Cleveland, Ohio 44106 cine, Baltimore, Maryland 21205 George Sachs • Membrane Biology Laboratory, Depart Jennifer Lippincott-Schwartz • Cell Biology and Metabo ment of Medicine, University of California, Los Angeles, and lism Branch, National Institute of Child Health and Develop Wadsworth VA Medical Center, Los Angeles, California ment, National Institutes of Health, Bethesda, Maryland 20892 90073 Maria M. Lopez-Reyes • Department of Pharmacology, John R. Sachs • Department of Medicine, State University University of Texas-Houston Medical School, Houston, of New York at Stony Brook, Stony Brook, New York 11794 Texas 77225 Henry Sackin • Department of Physiology and Bio David H. MacLennan • Banting and Best Department of physics, Cornell University Medical College, New York, New Medical Research, University of Toronto, C. H. Best Institute, York 10021 Toronto, Ontario M5G lL6, Canada Robert W. Schrier • Department of Medicine, University Otilia Mayorga-Wark • Department of Integrative Biol of Colorado Medical School, Denver, Colorado 80262 ogy, The University of Texas-Houston Medical School, Hous Joseph H. Sellin • Departments of Medicine and Integra ton, Texas 77225 tive Biology, The University of Texas-Houston Medical Orson W. Moe • Veterans Administration Medical Center, School, Houston, Texas 77030 Dallas, Texas 75216 Jai Moo Shin • Membrane Biology Laboratory, Depart Jami Montgomery • Departments of Medicine and Physi ment of Medicine, University of California, Los Angeles, and ology, GI Unit, The Johns Hopkins University School of Med Wadsworth VA Medical Center, Los Angeles, California icine, Baltimore, Maryland 21205 90073 Samir Nath • Departments of Medicine and Physiology, Joe Henry Steinbach • Department of Anesthesiology, GI Unit, The Johns Hopkins University School of Medicine, Washington University School of Medicine, St. Louis, Mis Baltimore, Maryland 21205 souri 63110 Lawrence G. Palmer • Departments of Physiology and Chung-Ming Tse • Departments of Medicine and Physiol Biophysics, Cornell University Medical College, New York, ogy, GI Unit, The Johns Hopkins University School of Medi New York 10021 cine, Baltimore, Maryland 21205 Contributors ix Michael J. Welsh • Howard Hughes Medical Institute, De Yilin Zhang • Banting and Best Department of Medical partments of Internal Medicine and Physiology and Bio Research, University of Toronto, C. H. Best Institute, Toronto, physics, University of Iowa College of Medicine, Iowa City, Ontario M5G lL6, Canada Iowa 52242 Piotr Zimniak • Departments of Internal Medicine and of Jeannie Yip • Departments of Medicine and Physiology, Biochemistry and Molecular Biology, University of Arkansas GI Unit, The Johns Hopkins University School of Medicine, for Medical Sciences, and McClellan VA Hospital, Little Baltimore, Maryland 21205 Rock, Arkansas 72205 C. H. Chris Yun • Departments of M<;:dicine and Physiol ogy, GI Unit, The Johns Hopkins University School of Medi cine, Baltimore, Maryland 21205 Contents 1. Membrane Traffic and Compartmentalization within the Secretory Pathway Jennifer Lippincott-Schwartz 1.1. Introduction ............................................................................... . 1.2. Compartmental Organization .................................................................. . 1.2.1. The Endoplasmic Reticulum. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. I 1.2.2. The Intermediate Compartment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 2 1.2.3. The Golgi Complex. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . .. 2 1.3. Characteristics of Transport Intermediates. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 3 1.3.1. Cargo Specificity: Bulk Flow versus Concentration. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 3 1.3.2. Morphological and Functional Characteristics of Transport Intermediates: Roles of Vesicles, Organelles, and Tubules ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 3 1.4. Molecular Mechanisms for Transport . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 5 1.4.1. Vesicle Formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 5 1.4.2. Membrane Targeting and Fusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 7 1.5. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 8 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 8 2. Cell Adhesion Jonathan Covault 2.1. Introduction ....... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. II 2.2. Early Studies of Cell Adhesion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. II 2.3. Cell Adhesion Molecular Families. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 12 2.3.1. Cadherins. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 13 2.3.2. Immunoglobulin (Ig)-Related CAMs ..................................................... 20 2.3.3. Integrins ............................................................................ 21 2.3.4. Selectins. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 22 2.4. Cell Adhesion Molecules Do More than Bind Cells Together . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 22 2.5. Cell Adhesion Processes Typically Involve Multiple CAMs .......................................... 22 2.5.1. Cell Junctional Complexes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 22 2.5.2. Leukocyte Adhesion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 23 2.5.3. Adhesion and Neural Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 25 2.6. Disorders of Cell Adhesion in Disease Processes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 30 2.6.1. CAM Involvement in the Intracellular Uptake of Viruses and Parasites. . . . . . . . . . . . . . . . . . . . . . . . .. 30 2.6.2. Altered Cell Adhesion and Cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 31 2.6.3. Disorders of Leukocyte Adhesion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 32 2.6.4. Disorders of Neural Development. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 32 2.7. Potential Therapeutic Modulation of CAM Activities ............................................... 33 2.8. Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 34 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 35 xi xii Contents 3. The Membrane-Associated Cytoskeleton and Exoskeleton Robert J. Bloch 3.1. Introduction ................................................................................ 47 3.2. Cytoskeletal-Membrane Interactions ............................................................ 47 3.2.l. Membrane Skeleton ................................................................... 47 3.2.2. Focal Adhesions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 55 3.3. Interactions of the Exoskeleton with the Plasma Membrane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 57 3.3.1. The Basal Lamina .................................................................... 57 3.3.2. Fibronectin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 59 3.3.3. Integrins as Receptors for Extracellular Proteins. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 59 3.3.4. Other Extracellular Matrix Receptors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 61 3.3.5. Membrane Domains and the Exoskeleton. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 62 3.4. Concluding Remarks ......................................................................... 62 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 63 4. Methods of Reconstitution of Ion Channels William P. Dubinsky and Otilia Mayorga-Wark 4.1. Introduction .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 73 4.1.1. Resolution-Reconstitution Approaches to Study Ion Channels. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 73 4.1.2. General Strategies for the Reconstitution ofIon Channels. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 74 4.1.3. Vesicles versus Bilayers .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 75 4.2. Characterization and Isolation of an Epithelial K Channel. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 75 4.2.1. Identifying the Ion Conductant in the Intact Tissue or Cell. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 75 4.2.2. Reconstitution of the Necturus Basolateral K Channel .................. ; . . . . . . . . . . . . . . . . . . .. 75 4.2.3. Characterization of the Reconstituted Basolateral K Channel. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 76 4.2.4. Purification of the Channel. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 80 4.3. Characterization ofIon Channels in Subcellular Membranes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 81 4.3.1. Tracheal Apical Membrane Permeabilities. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 81 4.3.2. A Tracheal Subcellular Membrane Anion Channel .......................................... 82 4.4. Confirmation of Ion Channel Activity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 82 4.4.1. Cystic Fibrosis Transmembrane Conductance Regulator. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 82 4.4.2. Protein Replacement Therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 83 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 83 5. Permeability and Conductance in Ion Channels: A Primer David C. Dawson 5.1. Introduction ................................................................................ 87 5.2. Measurable Properties of Ion Channels: Conductance and Permeability. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 87 5.2.l. Conductance: Ohm's Law .............................................................. 87 5.2.2. Permeability: Tracer Flows. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 89 5.2.3. The Flux-Ratio Equation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 90 5.2.4. Conductance/Permeability Relation ...................................................... 91 5.2.5. Ion Gradients, Electromotive Forces, and Reversal Potential .................................. 91 5.3. The Nemst-Planck Constant Field Channel. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 94 5.3.l. Conductance and Permeability. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 94 5.3.2. Equilibrium Selectivity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 95 5.3.3. Nonequilibrium Selectivity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 96 5.3.4. i-V Relations for the Nemst-Planck Channel. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 97 5.3.5. The Definition of Conductance: Slope vs. Chord. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 99 5.4. Channels that Bind Ions: Rate Theory Interpretations of Conductance and Permeability .................... 10 1 5.4.1. Beyond Nemst-Planck: Ion-Channel and Ion-Ion Interactions ................................ 10 1 5.4.2. Rate Theory and Flows ................................................................ 101 5.4.3. Single-Site, One-Ion Channel ........................................................... 102
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