Table Of ContentContributors
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Mossaad Abdei-Ghany (415), Department of Molecular Medicine,
Cancer Biology Laboratories, Comell University College of
Veterinary Medicine, Ithaca, New York 35841
Barry E. Argent (231), Department of Physiological Sciences,
University Medical School, Framlington Place, Newcastle upon Tyne,
NE2 4HH, United Kingdom
Jorge Arreola (209), Center for Oral Biology in the Aab Institute of
Biomedical Sciences and Department of Pharmacology and
Physiology, University of Rochester School of Medicine and
Dentistry, Rochester, New York 14642
Kim E. Barrett (257), Department of Medicine, University of
California, San Diego, School of Medicine, San Diego, California
30129
Ted Begenisieh (209), Department of Pharmacology and Physiology,
University of Rochester School of Medicine and Dentistry, Rochester,
New York 14642
Dale J. Benos (389), Department of Physiology and Biophysics,
University of Alabama at Birmingham, Birmingham, Alabama 35294
S. Boese (283), School of Cellular and Molecular Biosciences, Division
of Physiological Sciences, University Medical School, Framlington
Place, Newcastle upon Tyne, NE2 4HH, United Kingdom
Hung-Chi Cheng (415), Department of Molecular Medicine, Cancer
Biology Laboratories, Comell University College of Veterinary
Medicine, Ithaca, New York 35841
Guy Droogrnans (327), KU Leuven, Laboratorium voor Fysiologie,
Campus Gasthuisberg, B-3000 Leuven, Belgium
Angela .F Dulhunty (59), Muscle Physiology Group, John Curtin
School of Medical Research, Canberra City, ACT 2601, Australia
XV
ivx srotubirtnoC
Randolph C. Eible (367), Department of Molecular Medicine, Cancer
Biology Laboratories, Cornell University College of Veterinary
Medicine, Ithaca, New York 35841
Stephan Frings (167), Insfitut ftir Biologische
Informationsverarbeitung, Forschungszentrum Jiilich, 52425 Jtilich,
Germany
Catherine M. Fuller (389), Department of Physiology and Biophysics,
University of Alabama at Birmingham, Birmingham, Alabama
49253
Sherif E. Gabriel (193), CF/Pulmonary Research and Treatment Center,
University of North Carolina, Chapel Hill, North Carolina 27599
Thomas Gensch (167), Insfitut f'tir Biologische
Informationsverarbeitung, Forschungszentrum Jiilich, 52425 Jtilich,
Germany
M. GlanviUe (283), School of Cellular and Molecular Biosciences,
Division of Physiological Sciences, University Medical School,
Framlington Place, Newcastle upon Tyne, NE2 4HH, United
Kingdom
Michael A. Gray (231,283), School of Cellular and Molecular
Biosciences, Division of Physiological Sciences, University Medical
School, Framlington Place, Newcastle upon Tyne, NE2 4HH, United
Kingdom
I. A. Greenwood (99), Department of Pharmacology and Clinical
Pharmacology, Cardiovascular Research Group, .tS George's Hospital
Medical School, Cranmer Terrace, London SW17 ,ERO United
Kingdom
Achim D. Gruber (367), Department of Pathology, School of
Veterinary Medicine Hannover, D-30559 Hannover, Germany
H. Criss Hartzell (3), Department of Cell Biology, Emory University
School of Medicine, Atlanta, Georgia 30322
Melissa W. .Y Ho (345), Laboratory of Signal Transduction, National
Institute of Environmental Health Sciences, Research Triangle Park,
North Carolina 27709
l-Iiroshi Kaneko (167), Institut fiir Biologische
Informationsverarbeitung, Forschungszentrum Jiilich, 52425 Jiilich,
Germany
srotubirtnoC xvii
James L. Kenyon (135), Department of Physiology and Cell
Biology/352, University of Nevada School of Medicine, Reno,
Nevada 89557
Steven J. Kleene (119), Department of Cell Biology, Neurobiology, and
Anatomy, University of Cincinnati, Cincinnati, Ohio 45267-0667
Akinori Kuruma (3), Laboratory for Developmental Neurobiology,
RIKEN Brain Science Institute, Wako-shi, Saitama 351-0198, Japan
W. A. Large (99), Department of Pharmacology and Clinical
Pharmacology, Cardiovascular Research Group, St. George's
Hospital Medical School, Cranmer Terrace, London SW17 ,ERO
United Kingdom
Derek R. Laver (59), School of Biomedical Science, Faculty of Health,
University of Newcastle NSW, 2308, Australia
Khaled Machaca (3), Department of Physiology and Biophysics,
University of Arkansas Medical Science, Little Rock, Arkansas 72205
Nael McCarty (3), Department of Physiology, Emory University
School of Medicine, Atlanta, Georgia 30322
James E. Melvin (209), Center for Oral Biology in the Aab Institute
of Biomedical Sciences, University of Rochester School of Medicine
and Dentistry, Rochester, New York 14642
Keith Nehrke (209), Center for Oral Biology in the Aab Institute
of Biomedical Sciences, University of Rochester School of Medicine
and Dentistry, Rochester, New York 14642
Bernd Nilius (327), KU Leuven, Laboratorium voor Fysiologie,
Campus Gasthuisberg, B-3000 Leuven, Belgium
Scott M. O'Grady (309), Departments of Physiology and Animal
Science, University of Minnesota, .tS Paul, Minnesota 55108
Catherine M. O'Reilly (231), Department of Physiological Sciences,
University Medical School, Framlington Place, Newcastle upon Tyne,
NE2 4HH, United Kingdom
Melissa Palmer-Densmore (309), Departments of Physiology and
Animal Science, University of Minnesota, .tS Paul, Minnesota 55108
Bendicht U. Pauli (367, 415), Department of Molecular Medicine,
Cancer Biology Laboratories, Cornell University College of
Veterinary Medicine, Ithaca, New York 35841
xviii srotubirtnoC
A. S. Piper (99), Department of Pharmacology and Clinical
Pharmacology, Cardiovascular Research Group, .tS George's Hospital
Medical School, Cranmer Terrace, London SW17 ,ERO
United Kingdom
Ilva Putzier (167), Institut ftir Biologische Informationsverarbeitung,
Forschungszentrum JiJlich, 52425 Jiilich, Germany
Zhiqiang Qu (3), Department of Cell Biology, Emory University
School of Medicine, Atlanta, Georgia 30322
J. Sayer (283), Department of Physiological Sciences, University
Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH,
United Kingdom
Roderick H. Scott (135), Department of Biomedical Sciences, Institute
of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen
AB25 2ZD, Scotland, United Kingdom
Stephen B. Shears (345), Laboratory of Signal Transduction, National
Institute of Environmental Health Sciences, Research Triangle Park,
North Carolina 27709
N. L. Simmons (283), School of Cellular and Molecular Biosciences,
Division of Physiological Sciences, University Medical School,
Framlington Place, Newcastle upon Tyne, NE2 4HH, United
Kingdom
G. Stewart (283), Department of Physiological Sciences, University
Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH,
United Kingdom
Bernard Verdon (231), Department of Physiological Sciences,
University Medical School, Framlington Place, Newcastle upon Tyne,
NE2 4HH, United Kingdom
Wolf-Michael Weber (41), Laboratory of Physiology, KU Leuven,
Campus Gasthuisberg, B-3000 Leuven, Belgium
John E Winpenny (231), Department of Physiological Sciences,
University Medical School, Framlington Place, Newcastle upon Tyne,
NE2 4HH, United Kingdom
Andrew C. Zygmunt (81), Masonic Medical Research Laboratory,
Department of Experimental Cardiology, Utica, New York 10531
Preface
For many years, chloride was neglected as a major ion in membrane transport
physiology, assumed simply to passively distribute across the plasma membrane in
accord with the prevailing membrane potential and ionic gradients. Cystic fibrosis
(CF) is a prime example of a situation in which early experiments noted defects
in chloride transport, but assumed they were secondary to defects in the transport
of a more important ion, Na +. However, the demonstration that chloride had an
important role in modulating neuronal excitability in the brain via the GABA and
glycine ligand-gated chloride channels was accompanied by an increased appre-
ciation for this ion. More recently, the identification of the C1C chloride channel
family and particularly the cystic fibrosis transmembrane regulator (CFTR) protein
has prompted an explosive increase in chloride channel research. The linkage of
these proteins to human disease, combined with the generation of appropriate
knockout mice, has dramatically increased awareness of the importance of C1-
transport. Despite this increasing research focus, chloride channels are not well
characterized at the protein and molecular level. This is partly due to the lack of
appropriate high-affinity probes that make isolation and purification difficult, as
available inhibitors have relatively low affinities. Furthermore, multiple conduc-
tance phenotypes have been recorded, suggesting that multiple channel families
exist.
The focus of the present volume is the subset of chloride channels that is sensitive
to Ca 2+. Calcium is the quintessential pluripotent regulator, and its concentration
in the cell is tightly controlled. Consequently, it might be predicted that a scheme
in which plasma membrane ion channels are regulated by calcium would permit
a level of regulation that may be particularly useful in electrically non-excitable
cells where channels would not be subject to dramatic voltage shifts. In fact, as
will become apparent to readers of the present volume, calcium-regulated chlo-
ride conductances (CaCCs) are nearly ubiquitous and occur in both nonexcitable
epithelial and endothelial cells, as well as in neurons and muscle.
The extent to which the biophysical properties and mechanisms underlying
the regulation of these conductances have been elucidated forms the basis of the
present volume. Because the suponeX oocyte is highly amenable to electrophysio-
logical recording and has the advantage of expressing a large endogenous Ca 2+-
sensitive C1- current, the oocyte channel has perhaps been the most extensively
studied of any CaCC. It has both similarities to and differences from CaCCs found
xlx
xx Preface
in other systems, giving credence to the suggestion of multiple CaCC families.
The oocyte also expresses a C1- current that is inactivated by Ca .+2 Comparisons
between these two channels may result in some insights into fundamental mech-
anisms of Ca2+-based regulation. The CaCCs of neuronal and muscle cells have
also been studied extensively. In these tissues, C1- is used to both increase and
decrease membrane excitability, dependent on the distribution of C1- across the
membrane. For example, in cardiac tissue, voltage-dependent opening of mem-
brane and sarcoplasmic reticulum Ca +2 channels results in the participation of
CaCCs in membrane repolarization; conversely, in smooth muscle, activation of
CaCCs results in depolarization and opening of voltage-sensitive membrane Ca +2
channels, ultimately resulting in contraction. In sensory neurons, exit of C1- via a
CaCC is associated with depolarization and signal transduction; in other neuronal
types, increased CaCC activity is associated with repolarization and a reduction of
excitability. Consequently, the accurate measurement of intracellular C1- in cells
is crucial to understanding the role of the CaCC in that location.
In epithelia, the role of CaCCs may well be to augment fluid secretion evoked
by the actions of cAMP on CFTR. Because of this possible role, epithelial CaCCs
have come under increasing scrutiny as "alternative" channels to substitute for
defective or poorly functional CFTR in individuals with CE However, the role of
CaCCs in epithelial locations is controversial as exit of C1- from the cell is critically
dependent on driving force; opening a CaCC at the apical plasma membrane is
not the only way in which Ca +2 can influence C1- exit from the cell. Hence,
deciphering a clear role for CaCCs in epithelial cells has proved problematic and
is a focus of much research in epithelial tissues. However, in some epithelia,
notably those of the airway, there is now strong evidence for the presence of apical
membrane CaCCs, whereas in the gastrointestinal tract CaCCs are emerging as
important players in ion transport. In endothelial cells, CaCCs are thought to play
a role in stabilizing cell membrane potential, although other possibilities such
as influencing cell proliferation have also been proposed. One exciting aspect of
both epithelial and endothelial CaCC research is their identification as targets for
a novel intracellular regulator, inositol 3,4,5,6-tetrakisphosphate, suggesting that
these proteins may be subject to multiple layers of regulation.
Considerable progress has thus been made in identifying CaCCs and delineat-
ing their biophysical properties. However, the barrier to further characterization
has been the lack of molecular and protein information. Cloning these proteins has
proved to be a significant challenge. Recently, one family of proteins that seems
to function as CaCCs in a variety of heterologously expressing systems has been
cloned. This family, the CLCAs (chloride channel, calcium activated), consists of
membrane proteins that express some of the characteristics associated with other
CaCCs, e.g., sensitivity to the same blockers and activation by the same agonists.
However, these proteins are only beginning to be characterized in terms of their
electrophysiological properties and it is as yet uncertain if they are independent
Preface xxi
ion channels. An intriguing aspect of these proteins, however, is their potential role
in cell adhesion and tumor metastasis; they may truly be multifunctional proteins.
The picture that emerges of CaCCs is one of a diverse group of proteins, both
in terms of function and probable molecular identity. Despite this, there are cer-
tain points of commonality between the observed currents. However, one aspect of
chloride channel research that should be considered is whether the true physiologi-
cal role of these channels is to conduct C1-. Recent studies with CFTR have sug-
gested that the important physiological relevancy of this channel lies in its capacity
to conduct bicarbonate; similarly in this volume, the contribution of the CaCC of
skeletal muscle sarcoplasmic reticulum to phosphate transport is discussed. The
publication of the human genome, with those of other species well on the way
to completion, means that this is an exciting time to be involved in life science
research. The techniques of molecular biology have allowed the identification of
genes at a rate that would have been unthinkable even a few years ago. However,
in the field of CaCC research, considerable work remains to be accomplished,
most importantly identifying the molecular underpinning of the CaCCs in various
systems. The recent crystallization of a member of the C1C family of chloride
channels surely points the way to the future of CaCC research.
I thank several people who have been closely associated with the production
of this volume. The most important of these are the contributing authors; without
their willingness to consider the proposal and then to submit chapters of such
outstanding quality, this volume would not have been possible. I also thank two
long-suffering administrative assistants, Cathy Guy and PaWicia Matthews, who
have kept several projects on track during the compilation of this volume, as have
the current members of my laboratory, Sue Copeland and Toya Bishop. Mica Haley
and the staff at Academic Press were extremely patient and graciously answered
my numerous questions concerning publication of an academic book. Lastly, I
thank Dale Benos for persuading me that this topic was overdue for review in the
literature and inviting me to submit the original proposal to Academic Press.
Catherine Mary Fuller
Previous Volumes in Series
Current Topics in Membranes and Transport
Volume 23 Genes and Membranes: Transport Proteins and Receptors* (1985)
Edited by Edward A. Adelberg and Carolyn W. Slayman
Volume 24 Membrane Protein Biosynthesis and Turnover (1985)
Edited by Philip A. Knanf and John S. Cook
Volume 25 Regulation of Calcium Transport across Muscle Membranes
(1985)
Edited by Adil E. Shamoo
Volume 26 Na +-H + Exchange, Intracellular pH, and Cell Function* (1986)
Edited by Peter S. Aronson and Walter E Boron
Volume 27 The Role of Membranes in Cell Growth and Differentiation
(1986)
Edited by Lazaro J. Mandel and Dale J. Benos
Volume 28 Potassium Transport: Physiology and Pathophysiology* (1987)
Edited by Gerhard Giebisch
Volume 29 Membrane Structure and Function (1987)
Edited by Richard D. Klansner, Christoph Kempf, and Jos van Renswoude
Volume 30 Cell Volume Control: Fundamental and Comparative Aspects in
Animal Cells (1987)
Edited by R. Gilles, Arnost Kleinzeller, and L. Bolis
Volume 31 Molecular Neurobiology: Endocrine Approaches (1987)
Edited by Jerome E Strauss, III, and Donald .W Pfaff
Volume 32 Membrane Fusion in Fertilization, Cellular Transport, and Viral
Infection (1988)
Edited by Nejat Diizgiines and Felix Bronner
Volume 33 Molecular Biology of Ionic Channels* (1988)
Edited by William S. Agnew, Toni Claudio, and Frederick J. Sigworth
* Part of the series from the Yale Department of Cellular and Molecular Physiology
xxiii
xxiv Previous Volumes in Series
Volume 34 Cellular and Molecular Biology of Sodium Transport* (1989)
Edited by Stanley G. Schultz
Volume 35 Mechanisms of Leukocyte Activation (1990)
Edited by Sergio Grinstein and Ori D. Rotstein
Volume 36 Protein-Membrane Interactions* (1990)
Edited by Toni Claudio
Volume 37 Channels and Noise in Epithelial Tissues (1990)
Edited by Sandy I. Helman and Willy naV Driessche
Current Topics in Membranes
Volume 38 Ordering the Membrane Cytoskeleton Tri-layer* (1991)
Edited by Mark S. Mooseker and Jon S. Morrow
Volume 39 Developmental Biology of Membrane Transport Systems (1991)
Edited by Dale J. Benos
Volume 40 Cell Lipids (1994)
Edited by Dick Hoekstra
Volume 41 Cell Biology and Membrane Transport Processes* (1994)
Edited by Michael Caplan
Volume 42 Chloride Channels (1994)
Edited by William B. Guggino
Volume 43 Membrane Protein-Cytoskeleton Interactions (1996)
Edited by .W James Nelson
Volume 44 Lipid Polymorphism and Membrane Properties (1997)
Edited by Richard Epand
Volume 45 The Eye's Aqueous Humor: From Secretion to Glaucoma (1998)
Edited by Mortimer M. Civan
Volume 46 Potassium Ion Channels: Molecular Structure, Function, and
Diseases (1999)
Edited by Yoshihisa Kurachi, Lily Yeh Jan, and Michel Lazdunski
Volume 47 Amiloride-Sensitive Sodium Channels: Physiology and
Functional Diversity (1999)
Edited by Dale J. Benos
Previous Volumes in Series xxv
Volume 48 Membrane Permeability: 100 Years since Ernest Overton (1999)
Edited by David .W Deamer, Amost Kleinzeller, and Douglas M. Fambrough
Volume 49 Gap Junctions: Molecular Basis of Cell Communication in Health
and Disease
Edited by Camillo Peracchia
Volume OS Gastrointestinal Transport: Molecular Physiology
Edited by Kim E. Barrett and Mark Donowitz
Volume 51 Aquaporins
Edited by Stefan Hohmann, SCren Nielsen and Peter Agre
Volume 52 Peptide-Lipid Interactions
Edited by Sidney A. Simon and Thomas J. McIntosh
