Editorial pubs.acs.org/CR
Introduction to Ion Channels and Disease
T
selectivity) often require precise stereochemistry, one might imagine that even subtle changes to their structures might cause them to fail and thereby cause devastating health consequences.14,19 As we shall see, that is indeed the case. However, we first consider how channel structures are determined, consider how the putative structures are tested, and then discuss what happens when they go awry. A key paradigm for understanding disease has been to determine the structures of the molecules in question, deduce how the molecules work, envision how they might fail, and develop a pharmacological/therapeutic strategy to mitigate the disease. One of the problems with this effort, as it relates to ion channels, is that membrane protein structures have been notoriously difficult to obtain. Joseph Robertson and colleagues describe several structure-determination methods, highlight some of the success stories in the field, describe how this work relates to ion channels, and offer some perspective on the barriers that need to be overcome. With ion channel structures in hand, theory and experiment are used to critically test or validate them. The theories need to predict, at the very least, the current−voltage relationships and ion selectivities that can be measured precisely using electrophysiological measurements. Aleksei Aksimentiev and coworkers describe the state-of-the-art in analytical theory and modeling/simulation of ion channel function. Much of this modern work is based on fundamental studies on the physics of ion transport by Robert Eisenberg and colleagues,20−24 on force fields for computer simulation by Bernie Brooks, Richard Pastor, and colleagues,25 and methods developed by Aleksei and his colleagues. Some channels alter their function in response to the binding of a ligand (e.g., a neurotransmitter). As such, ligand-gated ion channels allow for inhibitory and potentiating feedback control by other neurons. Thomas Grutter and colleagues describe the historical and modern aspects of research on this class of channels, describe the many families of them, illustrate how their dysfunction relates to well-known neurological diseases (e.g., Alzheimer’s, Parkinson’s, epilepsy, and neuropathic pain), and discuss efforts to develop targeted therapeutic agents against these diseases. In addition to discussing cardiac disease caused by the loss of channel gating, Jianmin Cui and colleagues touch upon other genetic-based mechanisms of ion channel diseases. For example, the disruption of normal cellular processes (e.g., proteins folding into their correct three-dimensional structures,26−28 trafficking of proteins to their targeted locations, and the turnover of proteins in cells29) can lead to a spectrum of diseases including cystic fibrosis (caused by a single-point mutation that results in the misfolding of a chloride-selective channel30), hypoglycemia in infants (due to the improper trafficking of subunits that comprise an ATP-sensitive K+-
he aim of this issue on Ion Channels and Disease is to briefly describe the historical development of the protein ion channel concept, the measurements used to determine how channels work at the molecular level, some consequences of their failure, and how channels (or biomimetic analogues of them) might prove useful in diagnosing and/or managing disease. This collection of reviews is meant to serve as a starting point for future discussions on this relatively new subject as it unfolds. Science is advanced by the interplay between accidental discovery, the ability to make precise measurements, theoretical modeling and prediction, and inspired guesswork. This paradigm is particularly well illustrated by the fitful progress in our understanding of how nerve and muscle cells work. For example, near the latter part of the 18th century, Luigi Galvani and colleagues noted that touching the muscle of a dead frog’s leg with a metallic object caused the latter to twitch.1 He correctly hypothesized that this remarkable effect was due to some form of animal electricity. However, Galvani and his contemporaries (including Alessandro Volta) were not in a position to determine the molecular basis of their observations. About a hundred years later, Santiago Ramon y Cajal, who used Golgi’s chemical stains to visualize the extensive nature of neural networks,2 correctly deduced that neurons were individual cells that made manifold interconnections with other neurons. This major advance in neuroanatomy notwithstanding, it took the novel ability to measure the weak electrical activity in nerves (during the late 1930s through the early 1950s) to grasp how they work. A series of elegant experiments demonstrated the presence of separate pathways for sodium influx and potassium efflux from cells (a stunning and highly thought-provoking result), as well as that spatial and temporal activity of these pathways could be altered by the transmembrane potential (see the seminal papers of Nobel Prize winners Hodgkin, Huxley, and others of this era in the book edited by Ian Cooke and Mack Lipkin3). Electrophysiological studies by Mueller, Rudin, and others4−7 showed that proteins from bacterial origin caused artificial membranes formed by lipids to exhibit ion-conducting and gating properties akin to nerve. In 1969, a simple theoretical calculation by Parsegian suggested that these ionic pathways are likely to be water-filled pores.8 Remarkably, it was only 14 years ago when Roderick MacKinnon and colleagues used their protein crystal structure of a potassium-selective ion channel to deduce how it works on the molecular level,9 a stunning achievement that was awarded the 2003 Nobel Prize in Chemistry. The review by Jan Behrends provides an interesting perspective on some of these and other historical aspects of ion channel research. We now know that, in addition to signal transmission in nerve10,11 and muscle contraction,12 ion channels are the basis of many cellular functions including brain activity, insulin secretion,13−15 water transport across membranes,16−18 etc. Because channels are so ubiquitous, and their functions (which include the binding of ligands or a high degree of ion © 2012 American Chemical Society
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diseases. It is my sincere hope that broader and deeper discussions on this interesting topic will ensue.
selective channel), and hypertension (due to abnormal turnover of Na+ channels). Ortrud Steinlein examines ion channel-based diseases of the brain and considers channel dysfunction caused by genetic disorders and acquired channelopathies (i.e., those caused by an individual’s immune system). She characterizes in detail several superfamilies of receptor channels (nicotinic acetylcholine, gamma-aminobutyric acid, and glycine receptors) and voltagegated sodium- and calcium-selective channels. Ortrud then discusses three major outcomes of channel dysfunction including paroxysmal movement disorders (e.g., Parkinson’s disease), various forms of epilepsies, and headache disorders (e.g., migraines). She briefly summarizes the impact of gene therapy on channelopathies and limitations the method currently faces. Channels are not solely located in nerve and muscle tissue. Because of its principal functions (i.e., homeostasis of fluid volume and ionic concentrations via the transport of water, small solutes, and ions), different parts within kidney cells are replete with many different channels and other ion transporters. Ivana Kuo and Barbara Ehrlich describe renal anatomy, proper renal function, and the hereditary and genetic mutations that cause dysfunction in this very complex organ (e.g., proteinuria, progressive loss of renal function, and hypertension). They also discuss the current pharmacological treatment strategies for these diseases. Marco Colombini reviews the properties and functions of three channels found in the outer membrane of mitochondria. These include the voltage-dependent anion channel (VDAC31), ceramide channels (composed of lipid, not protein), and Bax/ Bak. The mitochondrion is perhaps most well-known for generating most of the cell’s supply of adenosine triphosphate (ATP). However, because Bax/Bak is linked to programmed cell death, the organelle also has a significant role in a cell’s ultimate fate. In addition to its proper function (recycling damaged cells), apoptosis is linked to strokes, heart disease, cancer, viral diseases, and neurodegenerative diseases. Until now, we’ve considered ion channels that are produced in humans and some of the consequences of their dysfunction. However, there is also a class of pore-forming toxins secreted by bacteria that are considered as protein ion channels. These toxins are involved in a wide range of diseases (e.g., some forms of staph infections, cell death by anthrax infection, cholera, etc.). Ekaterina Nestorovich and Sergey Bezrukov review the biophysical properties of such channels and discuss various aspects of their toxicity. They also outline some novel approaches to block their virulent action, and there are other strategies to consider as well.32 This issue ends on an entirely different note. Instead of discussing solely channel-based diseases, Joseph Reiner and colleagues also review the relatively new field of using ion channels (and their biomimetic solid-state counterparts) as tools to detect and quantify biomarkers at low concentration and for sequencing DNA. The goals of these research efforts are to detect human diseases in their early stages and to determine whether therapeutic strategies are helpful, harmful, or simply ineffective for a given individual. If the latter measurement capability could be achieved (consider the impact the glucose meter has had on managing diabetes), it could usher in a new era of personalized medicine. As noted above, this issue should be viewed as a nucleation point in Chemical Reviews for further discourse of channel-based
John J. Kasianowicz
National Institute of Standards and Technology, Physical Measurement Laboratory, Semiconductor and Dimensional Metrology Division, CMOS Reliability & Advanced Devices Group, Gaithersburg, Maryland 20899, United States
AUTHOR INFORMATION Notes
Views expressed in this editorial are those of the author and not necessarily the views of the ACS. Biography
Dr. John J. Kasianowicz is a physical scientist and project leader in the Physical Measurement Laboratory at the National Institute of Standards and Technology (NIST). He earned a B.A. with distinction in Physics from Boston University and a M.A. in Physics and a Ph.D. in Physiology & Biophysics from SUNY at Stony Brook. His current research interests include ion channel structure−function, single molecule detection and characterization, single-molecule thermodynamics and kinetics, and the physics of polymer structure and transport. Dr. Kasianowicz pioneered the use of nanometer-scale pores for DNA sequencing and other analytical applications. Prior to his staff appointments at NIST, he was an Office of Naval Research postdoctoral fellow at the NIH and a National Academy of Sciences/National Research Council Research Associate at NIST. Dr. Kasianowicz is also a Fellow of the American Physical Society. He occasionally catches glimpses of the heavens through a wide range of fine telescopes.
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