Brain, Vol. 125, No. 12, 2788-2789,
December 2002
© 2002 Oxford University Press
Book Review |
CHANNELOPATHIES OF THE NERVOUS SYSTEM
Department of Neurology, Addenbrooke’s Hospital, Cambridge, UK
CHANNELOPATHIES OF THE NERVOUS SYSTEM
Edited by Michael R. Rose and Robert C. Griggs
2001. Oxford: Butterworth-Heinemann
Price £60. pp. 347. ISBN 0750645075.
After war-years spent devising an airborne radar system for night fighters and serving Anti-Aircraft Command, respectively, Alan Hodgkin and his Cambridge pupil, Andrew Huxley, worked together on the physiology of the squid giant axon. The result of this collaboration between the physiologically inclined Hodgkin and the mathematically astute Huxley was a landmark paper, ‘A quantitative description of membrane current and its application to conduction and excitation in nerve’, published exactly 50 years ago in the Journal of Physiology. Their experimental work, drawing heavily on Cole’s voltage-clamp technique, was incorporated into a mathematical model of the generation of the action potential, based on the first of what have become called the Hodgkin–Huxley equations:
Ionic current = m3.h.GNa.(E-ENa) + n4.GK.(E-EK) + GL.(E-EL)
The flow of current across the membrane was described in this model by the movement of Na+ and K+ ions (as well as an additional ‘leak current’, L) flowing down their potential gradients (e.g. E-ENa) through channels of certain conductance (e.g. GNa) that could be separately opened and inactivated. In the case of Na channels, three ‘activation particles’ were required to be opened—and the inactivation particle not closed—for ion channels to pass (hence m3.h), and in the case of potassium channels, four activation particles had to be opened (hence n4). For this work, Hodgkin and Huxley received the Nobel Prize in 1963.
The Hodgkin–Huxley equations continue to inspire theorists of neuronal function; a recent article discusses ‘Global organization of bistable periodic solutions in the Hopf bifurcations in multiple-parameter space of the Hodgkin–Huxley equations’! But more importantly, Hodgkin and Huxley postulated the presence of ion channels in the membranes of nerve and muscle, a prediction that could not be tested until 1976 with a technical advance that earned its German inventors the Nobel Prize in 1991. Erwin Neher and Bert Sakmann’s patch-clamp technique consisted of applying tiny micropipettes to nerve or muscle cell membrane, allowing the current through individual ion channels to be resolved.
In the 1980s, molecular biology impacted on ion channel research. Shosaku Numa and colleagues from Japan led the way in a dazzling technological tour de force that saw the acetylcholine receptor, from the electric marine ray Torpedo, isolated, cloned and sequenced. Then, in a process that was soon applied to other channels, the receptor was synthesised and inserted into lipid bilayers, and then whole cells such as oocytes from the South African clawed frog (Xenopus). This allowed for a powerful and elegant fusion of molecular biology and physiology, with patch-clamp analysis of deliberately mutated forms of the acetylcholine receptor revealing each subunit’s function. The most recent triumph in understanding ion channels has been determining the three-dimensional structure of a bacterial potassium channel by X-ray crystallography.
As this glittering scientific story has played out, awareness has grown that defective ion channels might cause human disease. The first clues came in the 1960s with Elmqvist’s observation that muscle fibre miniature endplate potentials were reduced in biopsies from patients with myasthenia gravis and Bryant’s finding of reduced chloride conductance in muscle fibres from a myotonic goat. In the 1970s, a series of experiments, crucially the transfer experiments of Klaus Toyka, proved that myasthenia gravis was caused by an antibody in patients’ sera binding to the acetylcholine receptor. But it was not until the early 1990s that the first human inherited ‘channelopathy’ was discovered and the term coined. In 1991, Rojas showed that a single point mutation in the 
-subunit of the skeletal muscle sodium channel gene caused hyperkalaemic periodic paralysis and a few years later proof came that human myotonia congenita was—as predicted by Bryant—due to defects in the muscle chloride channel.
Now, 10 years later, knowledge of the channelopathies has exploded. It is a measure of progress that 33 authors (split evenly between the US and Europe) have filled 347 pages of condensed text in this new authoritative textbook on the field, edited by Michael Rose, from King’s, and Robert Griggs, from Rochester. Helpfully, the first 100 pages have been given over to the basic science of ion channels and techniques for assessing them in vitro and in vivo. Stephen Cannon’s description of ion channel physiology and Kerry Mills on the investigation of channelopathies in man are outstanding; whereas the important legacy of molecular biology to understanding of ion channels is less comprehensively surveyed. Stephen Waxman’s chapter on the plasticity of ion channel expression is a magisterial synthesis of idea and experiment.
Another telling witness to the expansion of knowledge on the channelopathies is that, in less than 10 years since the first mutation was identified, 43 mutations in the skeletal muscle chloride channel gene are now known to cause myotonia congenita; listing them takes as much page space in this book as the clinical description of the disease. These mutated genes have been synthesised and inserted into cell membranes, allowing their disturbed physiology to be minutely studied, in perhaps the most elegant of all pathophysiological analyses. Not all clinical mystery has disappeared though: the physiologists are still not able to explain the ‘warm up’ phenomenon of Thomsen’s disease or the extreme cold sensitivity of paramyotonia congenita.
The earliest channelopathies to be identified were skeletal muscle ion channel defects, causing various myotonias and periodic paralyses. At the same time, the pathogenesis of the congenital and acquired myasthenic syndromes was being worked out. Then ion channel gene defects came to be recognised amongst central nervous system diseases. The first of these to be unravelled, episodic ataxia type 1, was also the first human disease to be associated with a potassium channel defect. Shortly afterwards episodic ataxia type 2 was pinned down to a point mutation in the calcium channel, CACNA1A. An expanded CAG repeat in the open reading frame of the same gene causes spinocerebellar ataxia type 6, which although characteristically a chronic progressive disease, may be punctuated by episodic exacerbations of ataxia. More intriguingly still, other mutations in the same channel cause familial hemiplegic migraine, and still others produce a syndrome combining the features of familial hemiplegic migraine and episodic ataxia type 2. With the arrival of this rare form of migraine into the arena of channelopathies, joined by at least four inherited epilepsy syndromes (of which the prototype is autosomal dominant nocturnal frontal lobe epilepsy due to mutations in the neuronal nicotinic acetylcholine receptor), wider questions emerge: to what extent does ion channel dysfunction underlie sporadic epilepsy or migraine? Samuel Berkovic, and Peter Goadsby and Michel Ferrari, deftly negotiate these tantalising prospects. Furthermore, Sam Chong and John Hunter, as well as Paul Felts, make a strong case for the importance of ion channel dysfunction in the pathogenesis of pain syndromes and demyelinating diseases, respectively.
If there is a criticism of Rose and Grigg’s textbook, it is the omission of neurotoxins (other than an account of ciguatera poisoning). This is first of all rather ungrateful, as those studying ion channels owe a huge debt to assorted venomous animals. For instance, -bungarotoxin, from kait snake venom, binds almost irreversibly to the -subunit of the acetylcholine receptor, making it a crucial reagent for purifying the receptor and in assays of anti-acetycholine receptor antibodies. Subtypes of voltage-gated calcium channels are discriminated in the laboratory by toxins from the Conus family of fish-eating snails, and 
-agatoxin from the Sydney funnel web spider. Secondly, though, these toxins arguably cause as much morbidity as the inherited channelopathies. Snakebites cause 15–20 deaths a year in the US and several thousand worldwide; a proportion of these being due to neuromuscular blockade. Inexpertly cooked puffer fish claims up to 20 deaths a year in Vietnam alone, because of failure to inactivate tetrodotoxin (which has become a standard laboratory agent to block and label sodium channels). Not to forget the misery caused by the blockade of presynaptic voltage-gated and Ca2+-sensitive potassium channels by dendrotoxins from mamba snake venoms or the slowed inactivation of sodium channels by alpha-scorpion and sea anemone toxins. It is also a shame that Butterworth-Heinemann allowed no colour reproductions, as the impact of histology is lost in black and white. Not all of the figures and tables were produced with the quality one usually expects from this publisher. Perhaps also the editors might have disciplined the authors more, to reduce repetition.
These criticisms pall when contemplating what Rose and Griggs have achieved: a lucid and comprehensive account of a fast-evolving field. It is not the last word on the subject; that will be long in coming. For consider the editors’ concluding summary of the clinical hallmarks of channelopathies: syndromes of triggered episodes, lasting minutes to days, of positive neurological dysfunction, occurring at any age, with overlapping phenotypes and possibly accumulating fixed neurological damage. Just how many neurological diseases could be so described? Just as the generic ‘mitochondrial disease’ is now acceptable in a differential diagnosis, it will not be long before the soubriquet ‘channelopathy’ makes it to the bottom of long neurological lists.
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