Mysteries Unraveled by Channels Gone Awry

Ion Channels and Disease By Ashcroft Frances M. San Diego CA: Academic Press (2000). 481 pp. $75.00The controlled movement of molecules and other substances between cellular compartments is critical to the survival of cells, tissues, and the organism. This movement occurs through channels or pores that traverse the cell's plasma membrane or membranes of intracellular organelles. The regulated activity of specific membrane channels is critical to many essential physiological functions, including the initiation of secretion, maintenance of membrane excitability, stimulation of muscle contraction and control of osmolarity. Consequently, it should not be surprising that altered channel function can contribute to the development of a variety of disease states. This relevant and timely book provides an extensive and excellent overview of membrane channels and their potential involvement in disease.Modern biochemical methods have provided an avenue for the isolation and determination of the composition of many channel complexes. Channels are made up of protein subunits that form aqueous-filled pores that span the lipid bilayer. The opening and closing of many channels can be “gated” by particular physical or chemical stimuli while other channels are ungated and open at rest. For example, voltage-gated channels are opened or closed by membrane potential and can exhibit permeability to specific ions. In contrast, chemical signals operate ligand-gated channels. Binding of these chemicals opens channels with selective ionic permeability. Gene families exhibiting considerable amino acid homology encode different subunit isoforms composing voltage-gated and ligand-gated channels. Most recently, an inventory of the chromosomal location of the genes encoding channel protein subunits is underway.The basic biophysical properties of many voltage- or ligand-gated channels have been established only within the last few decades with the development of sophisticated electrophysiological measurement techniques. Ionic currents flowing through specific channels are commonly measured with patch-clamp techniques and the kinetic behavior of many channels has been established. The ability to express cloned channel proteins in cell systems amenable to these techniques has advanced our understanding of structure–function relationships. These studies have shown that the mutations in genes that cause specific changes in channel protein composition can lead to significant dysfunction in channel behavior. In fact, mutations in channel genes were identified in families with inherited neurological disease. These clinical phenotypes attributable to mutations that alter the behavior of membrane ion channels have been termed “channelopathies.” As the human genome continues to be determined, understanding the relationship between genetic regulation of ion channels and disease will become even more important in clinical arenas.In this book, the author has successfully undertaken the difficult task of presenting an overview of the sizable literature about membrane channels and their potential involvement in disease. Furthermore, in numerous instances, the author summarizes how the genetic dysfunction has provided exciting insight into structure–function relationships key to normal channel activity.Dr. Ashcroft has organized this book masterfully. The first five chapters provide an overview of pertinent background information including the basic properties of channels and the biophysical and molecular approaches commonly used to analyze channel function. This introductory information successfully provides the general reader with the vocabulary essential to understanding topics covered in later chapters without the burden of excessive detail. The remainder of the book is dedicated to discussions of selected ion channels and related topics. In most chapters, the basic properties of the channel(s) under discussion are highlighted, followed by a succinct summary of key structure–function studies, and a review of disease entities that can be attributed to alterations in this channel. Figures are appropriately intermingled throughout the text to reinforce salient points.A significant portion of the book is dedicated to a discussion of voltage- and ligand-gated channels with identified mutations known to contribute to the development of specific diseases. As an example, the author describes that mutations that change the composition of voltage-gated sodium or potassium channels in cardiac muscle cause a lengthening of the ventricular action potential, increased calcium current, and early after-depolarizations that initiate unwanted action potentials. These changes in membrane excitability result in long Q-T (LQT) syndrome, a rare cardiac disease that produces ventricular arrhythmia and potentially sudden death. This example is particularly important because it demonstrates that quite similar clinical phenotypes can be produced by mutations in different components of a single channel complex or by mutations in different channels within a common cell type. Also discussed are diseases such as hypokalaemic periodic paralysis, familial hemiplegic migraine and spinocerebellar ataxia type-6 that result from an altered composition (and consequent altered behavior) of voltage-gated calcium channels in skeletal muscle or CNS neurons. Mutations in voltage-gated chloride channels lead to the development of myotonia or depletion of extracellular volume and hypotension. Additional chapters focus on ligand-gated, receptor-channel complexes such as those gated by acetylcholine, glutamate, glycine, and GABA. Myasthenic syndromes are caused by mutations in skeletal muscle cholinergic receptors, and a rare form of epilepsy is attributed to a mutation in neuronal nicotinic receptor subunits. Many glutamate receptors exhibit marked calcium permeability, and overstimulation of these glutamate receptors is thought to be involved in a variety of neurodegenerative diseases or ischemic insults following a stroke. There is an extensive review of genetic mutations in chloride channels that cause altered function of epithelial cells in multiple tissues including the lung. These alterations underlie the etiology of cystic fibrosis, a very common and devastating disease in the United States and northern Europe.Dr. Ashcroft's coverage of the subjects is not limited to commonly recognized classes of voltage- or ligand-gated channels, but instead includes the general properties and the potential clinical roles of a wide variety of membrane channels. In addition, later chapters cover channels in nonexcitable cells, especially those cells critical to the immune response. Information is included about pores formed by antibiotics in bacterial membranes and how these channel-like pores have been used as model systems to understand basic channel behavior. Also included is a discussion of parasite pore formation in intracellular membranes as a means to escape from phagosomes and how “channel forming” venoms may form calcium channels in mast cell membranes allowing calcium influx, degranulation, and release of histamine. Thus, the reader really can begin to appreciate the broad nature of “channelopathy” as a major contributor to the development of disease phenotypes.In summary, Dr. Ashcroft has been very successful in meeting the stated task. 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. Furthermore, the author provides an excellent list of referenced books for those wishing a more detailed discussion of particular topics such as the biophysical properties of specific ion channels. I believe that this text also provides an 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.