Download ebook: Ion Channels and Disease: Channelopathies

Ion Channels and Disease: Channelopathies by Frances M. Ashcroft

Download Ion Channels and Disease: Channelopathies

Ion Channels and Disease: Channelopathies Frances M. Ashcroft
Language: English
Page: 481
Format: pdf
ISBN: 0120653109, 9781435601123
Publisher:

From The New England Journal of Medicine

This book reviews a wide variety of congenital and acquired conditions caused by abnormalities in ion-transport mechanisms. It starts with a description of relatively simple channels that respond to voltage changes or certain cellular metabolites by a conformational change that opens the pore. These channels are closed by a cytosolic loop that plugs the pore. The book continues with more complex channels composed of multiple subunits of the same composition and controlled by other subunits with a different composition. The complexity increases in a last group of ion channels that regulate more than one type of ion passage and form an intrinsic part of certain receptors or combine ion-channel activity with a transport function for more complex molecules. The last few chapters describe interesting roles of ion channels in cell-cell communication by mediating electrical impulses or exchange of nutrients or regulatory signals. There are examples of autoantibodies that interfere with the function of channels, cells that transport channels from one site to another, and cells that excrete ion channels to kill their target cells by ruining their membrane resistance.

These discussions are preceded by a comprehensive and up-to-date summary of molecular biology, biochemistry, electrophysiology, and molecular genetics. This might be superfluous for some readers, whereas others might prefer more extensive textbooks, but in any case, this survey clearly defines the basis for understanding subsequent chapters.

The strength of this very readable overview is that its focus is disease. There is a uniform style throughout the book. Starting with descriptions of a few disease states related to a particular ion channel, the authors provide a model of the channel based on protein composition and structure derived from molecular biologic, biochemical, and crystallographic data. The often complex channel responses to depolarization and hyperpolarization, binding of regulatory ligands, and certain toxins are then explained on the basis of the model. Mutations that cause abnormal channel control are discussed and form the basis of the description of the clinical phenotype. The result is a fascinating voyage through the human and, in a few cases, animal body, showing the molecular defects in ion channels in diseases ranging from diabetes mellitus, deafness, and myotonia to cystic fibrosis and migraine, and all placed by the author under the common denominator "channelopathy."

A nice illustration of the foregoing is the voltage-gated sodium channel in muscle fibers. This channel is activated by positively charged residues in the channel that sense a voltage change and respond by triggering a conformational change described as a "helical screw model," which opens the channel. Binding of an intracellular inactivation "ball" connected to the channel binds to the pore, blocks further passage of ions, and closes the channel. It is clear that mutations that change the composition of the voltage-sensing domains, the structure of the inactivation ball, or the size of the acceptor domain for the inactivation ball will interfere with channel function. The results of such mutations are changes in voltage dependence or the time course of channel inactivation, resulting in enhanced muscle excitability or paralysis; both conditions sometimes occur in a single patient.

The often complex material in this book is illuminated by pleasing examples of channel malfunction in everyday life. Eating too much of the Japanese delicacy fugu (puffer fish) increases the intake of tetrodotoxin, which plugs the voltage-gated sodium channel and can be fatal. Charybdotoxin in scorpion venom blocks the voltage-gated potassium channel. Certain goats with a defect in a skeletal-muscle chloride channel fall over every time a train passes their field. The gene that causes certain mutant fruit flies to shake their legs when anesthetized with ether codes for a voltage-gated potassium channel and is called "ether-a-go-go."

The book is richly illustrated with single-channel-current recordings of the relevant ion channels; hierarchical classification schemes for the relevant genes; tables listing locations of chromosomes, the distribution of various ion channels in tissue, mutations, and related protein abnormalities; and colored models based on crystal structures. There are a few tracings and listings meant for the insider, but in general, the illustrations contribute greatly to the clarity of the chapters. An extensive index helps readers locate all this information, and the bibliography is up to date, with references as recent as 1998. This book will help readers to review basic knowledge regarding muscle and neuronal activity, the functions of the kidney and the eye, and the intracellular events that make cells excrete water, activate signaling pathways, and prevent apoptosis.

Review

"...this volume is a gem of large proportion. The clear writing style, comprehensive coverage, up to date information and low cost mandate a most enthusiastic recommendation to any physician interested in the mechanisms of epilepsy."
-EPILEPSY RESEARCH (February 2001)
"The book is self-contained in the sense that it provides all the background knowledge necessary to understand the field. ...It manages to communicate complex ideas with clarity, precision and efficiency, and I personally enjoyed the sense of history that pervades the book, as well as the lucid style in which it is written."
-Blanche Schwappach, Universitate Heidelberg, in NATURE CELL BIOLOGY (September 2000)
"...a fascinating and accessible account of ion-channel diseases. Each chapter is illustrated with useful figures and diagrams...a very good introduction to the whole field of ion channels, and will be useful for researchers, clinicians and students. ...It is the favourite of several of my colleagues."
-Thomas J. Jentsch in NATURE (July 2000)
"This is a well documented and informative treatise on ion channels and associated pathologies. Experimental details are omitted without compromising clarity and understanding, making this an easy to read reference source... The audience is broad, ranging from advanced undergraduates to clinicians and researchers. The author reaches this large group with a balance among introductory scientific details, relevance, and completeness... Researchers will appreciate the full range of topics and extensive bibliography. Clinicians will find molecular explanations of pathologies such as retinitis pigmentosa, cystic fibrosis, and Charcot-Marie-Tooth Disease enlightening... This much needed book is informative, readable, and worth having."
-DOODY'S PUBLISHING REVIEWS (2000)
"This relevant and timely book provides an extensive and excellent overview of membrane channels and their potential involvement in disease. ...The book is well written and enjoyable to read. Given the rapid advance of knowledge in this field, the content is amazingly up-to-date. This book is an excellent overview text for the advanced undergraduate or beginning graduate student and would be beneficial to the ion channel researcher as well as established scientists whose expertise is in unrelated areas. ... I believe that this text also provides and excellent and essential source of information for clinicians wishing to better understand the relevance of "channelopathies" to the presentation of disease. Dr. Ashcroft has certainly hit the mark."
-Rodney L. Parsons, University of Vermont, in CELL

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