Download THE CARDIAC ION CHANNELS: Relevance to Management of

Annu. Rev. Med. 1996. 47:135–48
Copyright © 1996 by Annual Reviews Inc. All Rights Reserved
THE CARDIAC ION CHANNELS:
Relevance to Management of Arrhythmias
Dan M. Roden, M.D., and Alfred L. George, Jr., M.D.
Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine,
Nashville, Tennessee 37232
KEY WORDS: ion currents, heart
ABSTRACT
The electrical activity of cardiac tissue is determined by the highly regulated
flow of ions across the cell membrane during the cardiac action potential. Ion
channels are pore-forming proteins through which these electric currents flow.
In this review, the ion currents that underlie the action potential are first
described. Then, the way in which expression of individual ion-channel genes
results in such ion currents is discussed. Finally, the concept that arrhythmias
may be due to abnormalities of structure, function, or number of ion channels,
or the way in which they respond to abnormalities in their environment (such as
acute ischemia), is reviewed. Further understanding of the molecular mechanisms underlying normal and abnormal cardiac electrophysiologic behavior
should allow the development of safer and more effective antiarrhythmic interventions.
INTRODUCTION
Ion channels are proteins that reside in the cell membrane. In response to
external stimuli, such as changes in potential across the cell membrane, ion
channels can form a pore, which allows movement of ions into or out of cells.
The integrated behavior of thousands of ion channels in a single cell results in
an ion current, and the integrated behavior of many ion currents makes up the
characteristic cardiac action potential. Thus, ion channels are the fundamental
building blocks that determine the electrical activity of cardiac tissue. Arrhythmias represent the end product of abnormal ion–channel structure, number, or
function. These abnormalities can be primary, or they may be due to other
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135
136 RODEN & GEORGE
factor(s) in the cell’s environment, such as acute ischemia, changes in circulating neurohormones, or intracellular calcium overload, which modify channel
function. Traditional approaches to the control of cardiac arrhythmias have
relied on drugs that alter this external milieu (e.g. beta-blockers), or drugs that
directly activate or, more commonly, block one or more ion current.
The first ion-channel gene was cloned in 1984. The succeeding decade has
seen the development of a new field of knowledge that relates an evolving
understanding of the physiology of individual ion currents to the molecular
mechanisms that underlie them. The implications of this new knowledge are
only now being appreciated. It contributes to our understanding of the molecular basis of abnormal electrophysiology in congenital diseases such as the long
QT syndrome, and in a wide range of common acquired diseases, such as
cardiac hypertrophy or ischemia. With this new knowledge comes the likelihood of improved diagnosis and the possibility of new antiarrhythmic therapies. In this review, the ion currents recorded in normal and abnormal cardiac
cells are first described. Then, the concept that individual pore-forming proteins, channels, underlie ion currents is discussed further. Finally, the cloning
of individual genes encoding ion-channel proteins and the way in which this
new molecular information can impact basic and clinical electrophysiology is
reviewed.
MULTIPLE ION CURRENTS UNDERLIE THE ACTION
POTENTIAL
The cardiac action potential is the record of voltage across a cardiac cell
membrane as a function of time (1). This transmembrane voltage is in turn
determined by the flow of individual ions across the cell membrane to form
ion currents. The initial application of voltage-clamp techniques to multicellular cardiac preparations allowed identification of major currents flowing during various portions of the cardiac action potential: A large inward sodium
current accounts for the rapid phase zero upstroke, and a balance between
inward currents (primarily calcium currents) and outward currents (primarily
delayed rectifier potassium currents) accounts for the plateau phase and ultimate repolarization (Figure 1). The magnitude of an individual ion current
may be dependent on many factors, such as the transmembrane potential (itself
determined by the magnitude of many ion currents), intracellular calcium, or
the presence of blocking drugs. Since the early 1980s, the patch-clamp technique, applied to single cells and to isolated patches of membrane, has been
used to further refine this picture. For example, we now appreciate that multiple subtypes of calcium current, with distinctive sensitivities to blocking
drugs, may be present in cardiac cells (2). Similarly, at least three types of
delayed rectifier potassium currents, IKs, IKr, and IKur, have been identified in
CARDIAC ION CHANNELS
137
Figure 1 The action potential and currents that underlie it. The current amplitudes are not drawn
to scale; the peak sodium current is much larger than any of the other currents shown here. Sodium
currents, calcium currents, and transient outward currents display inactivating behavior, that is,
during maintained depolarization they “turn off.” In contrast, delayed rectifiers (IKs, IKr, and IKur)
activate and remain activated as long as the membrane potential is depolarized. [Adapted by
permission from the Task Force of the Working Group on Arrhythmias (23).]
heart cells from various species (3–6). IKs activates very slowly and is increased by β-adrenergic stimulation; IKr activates more rapidly and is blocked
by a number of available or investigational drugs (quinidine, E4031,
dofetilide); and IKur activates “ultra”-rapidly and is blocked by relatively low
concentrations of 4-aminopyridine. A third example is the transient outward
current, which is responsible for the rapid phase 1 repolarization seen in some
cells and which in many species consists of two separate currents (7, 8): ITO1
is activated by membrane depolarization (i.e. after phase 0), whereas ITO2 is
activated by increases in intracellular calcium. Sodium, calcium, and transient
outward currents share the property that they inactivate: At a given voltage, the
current first increases and then, with maintained voltage, its magnitude decreases. This behavior suggests distinct mechanisms are responsible for the
increase and the subsequent decrease (or inactivation) of these currents.
138 RODEN & GEORGE
Heterogeneity of Cardiac Action Potentials
The identification of multiple subtypes of individual ion currents provides an
explanation for the increasingly well-recognized heterogeneity of cardiac action potentials as a function of species, development, or disease. For example,
in a number of species, action potentials and ion currents recorded in neonatal
cells are quite different from those recorded in adult cells (9, 10), presumably
reflecting the presence of different ion currents at these time points. However,
virtually no information is available on developmental aspects of human electrophysiology. Regional differences in cardiac action potentials provide another example of physiologic heterogeneity. Action potentials recorded from
the sinus node and atrioventricular node lack a robust inward sodium current;
as a consequence, upstroke slope and impulse propagation are slower than in
other regions of the heart. Atrial action potentials are shorter than those recorded in the ventricle. One explanation may be the presence of a very prominent, large repolarizing current, activated by muscarinic agonists, in the
atrium. In the ventricle of many species (e.g. dog, guinea pig, human), there is
a gradient of action potential configuration and durations across the ventricle
wall (11). In addition, a distinctive group of cells (M cells) resembling those in
the conducting system has been identified in the midmyocardium. Conducting
system cells and M cells have the important characteristic that they prolong
markedly with slow stimulation, and an underlying mechanism, decreased IKs,
has been proposed (12). At slow rates, action potentials in these cells not only
may prolong markedly, they also may display discontinuities in repolarization
(early afterdepolarizations), which are thought to be involved in the genesis of
long QT-related arrhythmias (13). Another form of physiologic heterogeneity
that has recently been recognized is cell-cell variability, even within the same
chamber. For example, among human atrial cells, 29% are reported to display
only ITO, 13% display only a delayed rectifier (some combination of IKr, IKs,
and IKur), whereas the remaining cells exhibit both types (14). Thus, even
among neighboring cells different ion currents may be recorded.
Action Potentials in Diseased Tissues
Cardiac action potential configuration and duration may be altered in disease,
presumably as a consequence of disease-related changes in individual ion
currents. For example, action potentials are consistently prolonged when recorded from cardiac cells isolated from hypertrophied hearts (15). The underlying mechanism is a change in the balance between inward and outward
currents during the plateau, e.g. increased calcium current or decreased potassium current(s). Action potentials are also prolonged in ventricular myocytes
isolated from patients with congestive cardiomyopathy (16). The underlying
mechanism in this case appears to be a decrease in transient outward current.
CARDIAC ION CHANNELS
139
Similarly, action potentials isolated from the border zone of a myocardial
infarction (a region thought to be involved in the genesis of reentrant and
possibly other arrhythmias) display depressed ITO and sodium current (17).
Changes in individual ion currents have also been noted in animal models of
acromegaly, thyroid disease, or diabetes (18–20), and the mechanisms are
under intensive study. There are important implications of such disease-related
changes in individual ion currents. For example, drugs designed to block
individual currents will have less, or no, effect if the target current is absent
because of cardiac disease. In addition, it is important to recognize that the
magnitude of each ion current may be modulated by factors such as membrane
potential or intracellular calcium. Thus, a disease-related change in a single ion
current may, in turn, produce profound changes in the function of other ion
currents. Since the action potential represents the integrated behavior of many
currents, disease-related changes in one current may produce secondary
changes important for arrhythmogenesis. An example is IKr block: Rather than
merely prolonging the action potential (as would expected), block of this
current frequently results in early afterdepolarizations (an arrhythmogenic
event), likely the result, at least in part, of altered calcium current function (13,
21).
Ion Currents as Targets of Antiarrhythmic Drug Action
The first drugs widely used for the management of cardiac arrhythmias, digitalis and quinidine, were introduced into therapy without there being knowledge of underlying cellular or molecular mechanisms of action. With the
identification of individual ion currents has come the ability to target specific
currents for suppression by new drugs. Further, detailed analysis of the dependence of drug block on factors such as membrane potential or stimulation
frequency has led to an ability to subclassify antiarrhythmic drug effects on
individual ion currents (22). Although classification schemes have some merit
in that drugs of a similar class may exert generally similar antiarrhythmic and
proarrhythmic effects, overlap among members of the same class is far from
complete (23). An evolving understanding of the molecular basis of the interaction between drugs and ion channels should allow greater understanding of
these subtle, but potentially clinically important, differences.
A major liability of currently available antiarrhythmic drug therapy is the
potential that drugs may provoke new arrhythmias rather than suppress them
(24). The mechanisms underlying many of these proarrhythmic syndromes
have been relatively well worked out. For example, in the Cardiac Arrhythmia
Suppression Trial (CAST), mortality among patients convalescing from a
myocardial infarction and treated with the potent sodium-channel blockers
encainide or flecainide was double that of patients treated with placebo (25). A
likely mechanism appears to be marked conduction slowing, with resultant
140 RODEN & GEORGE
increases in reentrant excitation, in the presence of the drugs and transient
myocardial ischemia. The results of CAST prompted drug development efforts
to move to action potential prolongation as an antiarrhythmic mode of action.
This class-III strategy is well supported by animal studies (26). However,
many new class-III drugs have the liability that they can, in occasional patients, produce marked action potential prolongation with resultant polymorphic ventricular tachycardia, the acquired long QT/Torsades de Pointes syndrome (13). It now appears likely that many of the newly developed class-III
antiarrhythmics that share this property also target IKr (27). Whether or not
this is the most appropriate molecular target to achieve the class-III goal of
action potential prolongation remains to be determined (see below); the identification of other ion currents controlling repolarization raises the possibility
that drugs that target other channels might be effective class-III antiarrhythmics, without the risk of Torsades de Pointes. Although this approach seems
attractive, it remains to be established that block of any ion channel can
provide truly safe and effective antiarrhythmic therapy. The only currently
available drugs shown to reduce mortality due to arrhythmias are beta-blockers (28) and, possibly, amiodarone (29); the former have no direct channelblocking effect and the latter blocks many channels and also exerts antiadrenergic actions.
INDIVIDUAL ION CHANNELS PRODUCE ION CURRENTS
The pioneering work of Hodgkin & Huxley postulated the existence of elementary channels that, under an external influence such as a change in membrane potential, would form a pore to allow ions to move across the cell
membrane (30). Over the subsequent three decades, advances in electrophysiology allowed inferences on the putative structure of ion channels. It was
postulated that the channel structure was likely a glycosylated protein, with
individual amino acid domains subserving important channel functions, such
as sensing voltage, acting as a selectivity filter in a permeation pathway across
the membrane to allow entry or egress of only selected ions, or binding drugs
or toxins (1). Thus, although the molecular structure of individual ion channels
remained unknown, the major features of that molecular structure had already
been inferred prior to the cloning of ion channels. Indeed, with the application
of the patch-clamp technique, it became possible in the early 1980s to describe
not simply the behavior of ion currents (the sum of the behaviors of many
individual ion channels), but, in fact, to observe the behavior of those single
channels (31). Since the isolation of a complementary DNA (cDNA) encoding
the electric eel sodium channel (32), literally dozens of ion-channel genes have
been described in a wide range of species. The cardiac sodium channel, L-type
calcium channel, and many potassium channels (of the Shaker, or Kv1.x,
CARDIAC ION CHANNELS
141
superfamily) share a common structural motif, presented in Figure 2. For the
potassium channels, the deduced amino acid sequence includes six membranespanning segments; four individual channel proteins are thought to coassemble
to form functional channels (33). The sodium- and calcium-channel gene
Figure 2 Structure of the human cardiac sodium channel. The human cardiac sodium-channel gene
SCN5A encodes a protein 2016 amino acids long. The protein consists of four homologous domains,
labeled I–IV. Each domain contains six putative transmembrane segments, designated S1–S6. The
protein folds upon itself to form a pore whose walls are lined by the S5–S6 loop of each of the four
domains, as indicated in the lower left. Regions that subserve important channel functions have been
identified by the site-directed mutagenesis approach described in the text, and several are indicated
here. For example, the S4 segment is thought to act as a voltage sensor because, in each of the four
domains, it is arranged in alpha helical fashion, with each third residue being positively charged.
This arrangement of the S4 segment of the 4th domain, spanning amino acids 1623–1645, is shown
in the lower right (each letter corresponds to a single amino acid). Another important region is the
linker at positions 1471–1523, joining domains III and IV. This small stretch of amino acids is critical
for normal sodium-channel inactivation; deletion of amino acids 1505–1507 [K(lysine)-P(proline)Q(glutamine)] produces the long QT syndrome. Two other recently identified mutations that can
also produce the syndrome are indicated. Sodium channel–blocking drugs probably bind to at least
residues in the S6 segment of domain IV. Tetrodotoxin, a specific sodium-channel toxin, binds with
high affinity to channels in brain and skeletal muscle, and with low affinity to those in heart muscle;
a key residue controlling this difference is the cysteine at position 373 in the heart channel (which
is an aromatic residue in the other channels). A β1 subunit associated with the sodium-channel protein
has been identified in heart and other tissues, but its role in modifying the function of the cardiac
sodium channel is not established. Calcium channels have a very similar topology to that indicated
here and are, in the heart, associated with ancillary subunits. Potassium channel proteins of the
Shaker superfamily have a topology very similar to a single one of the four domains; it is thought
that four Shaker proteins coassemble to form functional channels.
142 RODEN & GEORGE
products are roughly four times the size of the potassium channels and contain
four homologous domains each with the six membrane-spanning segment
motif. A single sodium- or calcium-channel gene product is sufficient to result
in a functional channel. Genes encoding proteins that seem to act as channels
but have little, or even no, homology to this common structural motif have also
been cloned (34).
THE IMPACT OF ION-CHANNEL GENE CLONING
The availability of genes that encode ion-channel proteins has allowed scientists in this area to ask questions that heretofore have been unaddressable. One
powerful tool has been injection of messenger RNA (mRNA) derived from
ion-channel genes into heterologous expression systems, commonly the oocytes of the frog Xenopus laevis, which then results in synthesis and transport
of channel protein to the cell membrane. Electrophysiologic testing in such
systems then reveals the functional features of the ion channels encoded by the
mRNA. The mRNA can then be mutated and the experiment can be repeated.
Comparison of currents encoded by wild-type and mutated RNA allows inferences on the role of individual regions or individual amino acids in important
ion-channel functions, such as drug binding, voltage sensing, or inactivation
(Figure 2).
A natural question raised by the cloning of multiple ion-channel genes is
the correspondence between currents observed in native myocytes and currents
encoded by individual cDNAs; in other words, which clones encode which
channels? Accumulating evidence strongly suggests that most ion channels are
actually complexes of multiple proteins, encoded by different genes. A
number of studies now suggest that different Shaker potassium-channel gene
products may coassemble to form ion channels with electrophysiologic characteristics typical of neither channel when expressed alone (35, 36). More
recently, ancillary subunits have been cloned for sodium, calcium, and potassium channels. These do not themselves encode ion channels when expressed
alone but highly modify level of expression or the activation or inactivation
characteristics of the target proteins to which they bind. The role of these
subunits in modulating channel function in individual cells types is under
intensive investigation. For example, expression of the rat brain sodium channel alone results in a slowly activating, slowly inactivating sodium current,
whereas coexpression of the channel with its β1 ancillary subunit results in a
current that activates and inactivates much more rapidly, like that observed in
native tissue (37). In contrast, the role of the β1 subunit in mediating expression of cardiac sodium channels seems much less clear, with some studies
suggesting the subunit serves little physiologic function (38). In the case of
Shaker potassium channels, β-subunits appear to play a role both in inactiva-
CARDIAC ION CHANNELS
143
tion as well as in determining overall current amplitude (39–41). The correspondence among individual ion currents, the ion-channel genes whose expression determines these currents, and the effects of commonly used antiarrhythmic drugs on those currents are presented in Table 1.
In contemporary molecular terms, the variability in cardiac action potentials
discussed above strongly suggests substantial variability (physiologic and
pathologic) in expression of individual ion-channel genes whose product proteins constitute individual ion-channel complexes. Thus, an emerging area of
study is the factor(s) regulating expression of individual ion-channel genes.
Regulation can be at multiple levels, e.g. gene transcription or mRNA editing
or stability. Little data are yet available on the molecular determinants of
normal and abnormal ion-channel expression; some studies do point to a role
for thyroid hormone, for intracellular cyclic adenosine 3′,5′-monophosphate
(cAMP), intracellular calcium, or membrane depolarization (42–44).
Table 1 Molecular genetics and drug block of cardiac ion currents
Currents
Inward
INa
ICa (L-type)
ICa (L-type)
Outward
ITO1 (volagegated)
ITO2 (C2+activated)
IKs
IKr
IKur
IKp
ICl
If (pacemaker
current)
IKl (inward
rectifier)
IK-Ach
Likely gene
Quinidine
Flecainide
Sotalol
Amiodarone
SCN5Aa (54)
L-type calcium
channela (55, 56)
—
++b
+c
++
+
++
+
Kv1.4 + Kv1.2a;
K4.2 (35, 57)
—
+
+
+
minK (58–60)
HERG (48, 52)
Kv1.5a (6, 61)
—
CFTR (62)
—
+
++
++
+
IRK family (63, 64)
+
++
Lidocaine
Verapamil
++
+
++
+
+
+
+
GIRK-CIR (65)
Inward and outward
Na-Ca exchanger Na-Ca exchanger (66)
a
Subunits that may be important for channel function have been identified. CFTR, Cystic fibrosis
transport regulator; IRK, inward rectifier—potassium; GIRK, G-protein-modulated IRK; HERG,
human eag-related gene; CIR, cardiac inward rectifier; —, no clone yet reported
b
++, clinically important channel-blocking action; sotalol and amiodarone also exert prominent
anti-adrenergic actions.
c
+, Channel-blocking action demonstrated; clinical importance uncertain.
144 RODEN & GEORGE
Ion Channels in Disease
One of the most exciting recent advances in the molecular physiology of ion
channels has been the identification of mutations in specific ion-channel genes
in some patients with the congenital long QT syndromes. It is now apparent
that lesions on at least four chromosomal loci can produce the long QT
phenotype (45). Mutations in ion-channel genes have been associated with two
of these chromosomal locations. A mutation in the gene on chromosome 3
encoding the cardiac sodium channel (termed SCN5A) appears to cause the
long QT syndrome in some patients (46), and a mutation in the gene on
chromosome 7 encoding the human eag-related gene (HERG) (whose expression seems to result in IKr) is responsible in others (47, 48). Loci have been
identified on chromosomes 4 and 11, but specific mutations in genes encoding
ion channels, or other proteins, have not yet been identified. In addition, other
families have been identified not linked to any of these four loci.
A candidate gene approach identified mutations in the sodium channel in
some affected families. First, families with the defect linked to a site on
chromosome 3 were found (45), and at the same time the cardiac sodium-channel gene was localized near this site (49). These findings allowed geneticists to
focus on this gene in these families, and mutations in the gene in affected
individuals were identified (46). One mutation is a 9-nucleotide deletion in the
linker between domains III and IV (Figure 2), a region of the protein important
for normal inactivation (50). When expressed in Xenopus oocytes, the mutant
channel activates and inactivates near-normally. However, with long pulses,
the mutant channel passes a small inward current whereas the wild type does
not (51). This aberrant behavior is due to a failure (about 3% of the time) of the
channel protein to remain closed during the plateau. This subtle change seems
sufficient to upset the normal balance between inward and outward currents
during the plateau to prolong the action potential. This is also consistent with
autosomal dominant inheritance, since only some sodium channels need be
abnormal to explain the defect. Recently, two other mutations in SCN5A have
been identified in other families (51a). Both are point mutations (see Figure 2);
the functional characteristics of these mutant channels have not yet been
reported.
The studies of families with congenital long QT syndrome linked to chromosome 7 used a similar candidate gene approach. Interestingly, until these
studies were accomplished, a cDNA encoding IKr, a common target for antiarrhythmic drug block, had not been isolated. HERG was first isolated to chromosome 7 (52), and then families with the long QT syndrome linked to
chromosome 7 were identified (45). Mutations in the gene were found in
affected individuals (47), strongly suggesting that the channel would be defective in the long QT syndrome. Since the topology of the encoded protein
CARDIAC ION CHANNELS
145
seemed to resemble a Shaker-like channel, it was assumed that the lesion
would be a decrease in a potassium current, with resultant action potential
prolongation. It was only then that wild-type HERG was expressed in Xenopus
oocytes and shown to strongly resemble IKr (48). Some of the reported mutations are single amino acid substitutions and may result in an abnormal, but
functional, protein. Others seem to be much more severe and are likely to
result in nonfunctional proteins. Since the HERG gene product, like members
of the Shaker superfamily, probably assembles as a multimeric ion channel,
the presence of even a single abnormal gene product might be sufficient to
completely disrupt channel function. This dominant-negative effect could then
account for decreased IKr in families linked to chromosome 7 and would also
be consistent with the autosomal dominant pattern of inheritance.
The tight linkage of a lesion in a gene important for expression of IKr and
the congenital long QT syndrome then naturally raises the question of whether
IKr is an appropriate target for antiarrhythmic drug block. Certainly, the characteristic toxicity of IKr blockers is long QT-associated polymorphic ventricular tachycardia (Torsades de Pointes) very similar to that seen in the congenital
long QT syndrome. It might be argued that in the diseased heart, IKr block
might be beneficial (perhaps with a smaller risk of long QT-associated arrhythmias), but this notion remains to be proven; a large multicenter trial is
currently under way that will test this for at least one drug, dofetilide. Because
action potential prolongation produces a range of desirable electrophysiologic
effects (26), the identification of lesions in IKr in the congenital long QT
syndromes suggests that drugs that block other channels to accomplish action
potential prolongation might be safer. The cloning of genes that encode individual ion-channel proteins may allow such a directed drug development
strategy to go forward.
Recognition that abnormal electrophysiology can result in defined abnormalities in ion-channel gene structure or gene regulation then raises the natural
question of whether or not therapy specifically targeted at defined lesions can
be undertaken. For example, blockers of abnormally functioning sodium channels in chromosome 3 patients might be highly effective but would not be as
useful in other forms of the congenital long QT syndrome. In patients with an
IKr lesion, some intervention that promoted coassembly of normal HERG gene
products (derived from an unaffected parent) and excluded expression of abnormal HERG gene products would be more desirable. It has been suggested
that the high incidence of sudden death in the dilated cardiomyopathies may be
related in part to action potential prolongation due to defective ITO (53). In this
case, therapy aimed at promoting expression of ITO might result in action
potential shortening. Such therapy could be a drug whose action is to promote
expression of new ITO channels, or a gene that encodes a repolarizing current.
146 RODEN & GEORGE
A danger with this strategy is excessive action potential shortening, which
could be highly arrhythmogenic, especially if it were heterogenous.
Cellular electrophysiology is now moving away from the description of
action potential abnormalities to a more molecular approach to the understanding of these abnormalities. It is the great hope that the identification of
such molecular lesions will make way for the development of new gene or
drug therapies to correct them. The way in which the behavior of many
ion-channel gene products results in the action potential reinforces the concept
that interfering at the level of the single gene may have unpredicted consequences due to secondary perturbations in the behavior of other, functionally
normal channels. Thus, a major challenge for contemporary electrophysiology
is to continue to develop new molecular information and, at the same time, to
integrate it toward a better understanding of the mechanisms underlying normal and abnormal electrophysiology at the cellular and whole heart levels.
ACKNOWLEDGMENTS
This work was supported in part by grants from the United States Public
Health Service (HL49989, HL46681, NS32387). Dr. Roden is the holder of
the William Stokes Chair in Experimental Therapeutics, a gift from the Daiichi
Corporation. Dr. George is a Lucille P. Markey Scholar.
Any Annual Review chapter, as well as any article cited in an Annual Review chapter,
may be purchased from the Annual Reviews Preprints and Reprints service.
1-800-347-8007; 415-259-5017; email: [email protected]
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