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Introduction
Fluctuations in cytosolic calcium
(Ca2+) concentrations act to modulate a vast array of physiological processes, including
neurotransmitter release, cell division, and muscle contraction. This control mechanism requires low cytosolic
Ca2+ levels under resting conditions alternating with transient increases in
Ca2+ upon activation. In cardiac muscle, transverse tubular
invaginations of the plasma membrane contact the membrane of the sarcoplasmic reticulum (SR)
Ca2+ stores to form dyadic junctions, establishing a structural framework for the external regulation of intracellular
Ca2+ release[1]. Two principal classes
of intracellular ion channels have evolved to facilitate the movement of
Ca2+ into the cytosol from intracellular stores: (i)
inositol 1,4,5-trisphos-phate receptors; and (ii) ryanodine receptors
(RyR)[2]. This review article will focus on cardiac (type 2)
RyR (RyR2), as increasing evidence emerges that RyR play a pivotal role in the development of cardiac arrhythmias and heart
failure. We will discuss classic and novel pharmacological
agents that may modulate these calcium release channels in
order to treat cardiac disease.
Ryanodine receptors (RyR)
RyR consist of large tetramers of RyR monomers,
comprised of a large regulatory domain protruding into the
cytosol and a much smaller transmembrane domain containing
the channel pore[3]. It is now well accepted that RyR2
channels exist as large macromolecular complexes comprised of
numerous regulatory subunits, including calmodulin (CaM),
the FK506-binding protein FKBP12.6 (also known as calstabin2), protein kinase A (PKA), CaM-dependent kinase
II, protein phosphatases 1 and 2A, phosphodiesterase,
junctin, triadin, and calsequestrin[4]. The gating behavior of
RyR can be regulated by many of these accessory proteins
(CaM, FKBP12.6, and PKA) as well as a variety of
endogenous ligands (Ca2+, ATP,
Mg2+)[5]. The physical and
functional association of RyR2 channels results in coordinated
gating behavior termed "coupled
gating"[6]. Coupled gating requires FKBP12.6 in the RyR2 macromolecular complex, and
allows clusters of channels to function as
Ca2+ release units that release calcium amounts that can be visualized as
Ca2+ sparks[7]. As the functional effects of the RyR2 accessory
subunits have been reviewed previously, this will not be the
focus of the present article[4,8].
The dysfunction of RyR2 has been implicated in
various diseases of the heart. A number of inherited mutations
in the RyR2 gene have been identified in patients with
exercise-induced ventricular arrhythmias and sudden cardiac
death[9_11]. Although initially most mutations were identified
in the amino terminus, central domain, and carboxy terminus,
more recent genetic data suggest that mutations may occur
throughout the channel protein[12]. In addition to these
relatively rare genetic arrhythmias, acquired RyR2 defects have
been implicated in the development of congestive heart
failure[13,14]. Clinical and experimental data suggest that in
failing hearts, the phosphorylation status of RyR2 is altered
due to chronic hyperactivity of
PKA[4,8,15]. The hyperphos-phorylation of RyR2 by PKA is associated with the loss of
the channel-stabilizing subunit FKBP12.6, which alters the
activation properties of RyR2 and increases the open
probability[13,16]. Moreover, it has been suggested that coupled
gating between RyR2 may be altered in the failing heart, which
might decrease systolic Ca2+ transients and/or cause a
diastolic Ca2+ leak[4,6]. The unwanted diastolic leak of
Ca2+ from the SR promotes the generation of arrhythmias and
anomalous contraction of the heart. Although some of the
mechanistic aspects of this concept have been debated in recent
articles, most authors agree that a diastolic SR
Ca2+ leak promotes arrhythmias and heart
failure[17,18]. Therefore, RyR have emerged as novel therapeutic targets for the treatment of
inherited arrhythmias and heart
failure[19].
RyR pharmacology
The activity of RyR is regulated by multiple endogenous
proteins residing in the macromolecular channel complex as
indicated earlier. The focus of this review, however, will be
on exogenous pharmacological agents that have been shown
to interact with and modulate cardiac
RyR[20]. These agents may be classified according to their effect on the SR
Ca2+ release function (eg agonist or antagonist), or according to
the mechanism of RyR2 modulation (Tables 1, 2). One class
of agents modulates RyR2 primarily by altering gating of the
channel (ie the opening and closing of the ion-conducting
pathway), for example, by increasing the sensitivity to
Ca2+-induced activation of RyR2. A second group of molecules
acts by controlling the movement of ions through the pore
of the RyR2 channel, for example, by entering the pore and
physically obstructing ion passage. A third group of
compounds may alter RyR2 function by enhancing the
interaction between subunits within the RyR2 macromolecular
channel complex, or even between different RyR2 channel units
(ie enhancing coupled gating). Although none of these
compounds are currently used for the treatment of patients with
heart failure or arrhythmias, the emphasis of this review will
be on the potential therapeutic applications or
non-therapeutic side effects of RyR2 modulating agents. Based on
recent advances in our understanding of
Ca2+-handling
defects in heart failure and cardiac arrhythmias, one could
profile an ideal drug for the modulation of RyR2. Such
compounds would not interfere with systolic SR
Ca2+ release, as this would depress cardiac contractility. However,
inhibition of a diastolic SR Ca2+ leak would be desirable, as it is
likely to prevent arrhythmias and enhances SR
Ca2+ loading, which could improve contractility.
RyR2 agonists
Purine derivatives and related compounds This group
includes substances that have a similar sterical structure
based on a purine, carboline, carbazole, or imidazopyridine
ring, and are likely to act on the same molecular site.
Methylxanthine compounds, like caffeine and theophylline,
isolated from the leaves and beans of certain plants, activate
RyR2 by potentiating its sensitivity to the natural ligand
Ca2+. RyR2 is activated by millimolar concentrations of
caffeine, which causes a pronounced increase in the
sensitivity of RyR2 to Ca2+ such that the channels open at basal
(diastolic) Ca2+ levels[21]. At low caffeine concentrations,
caffeine increases the open probability of the RyR2 channel
by increasing the frequency of channel openings alone,
whereas at higher concentrations, it results from an increase
in both the open channel lifetime and the frequency of RyR2
openings[22]. Theophylline and other methylxanthines share
the mode of action of caffeine[23]. Although these effects are
readily observed in the experimental setting, it is unlikely
that RyR2 modulation will be important in the therapeutic
response to methylxanthines because their plasma
concentration (eg about 55 micromolar for theophylline) is lower
than the effective concentration
range[20]. Further compounds have been proposed to act in a similar manner to caffeine.
The imidazopyridine derivative, sulmazole, increases the
duration and frequency of RyR2 openings. Whereas the
EC50 for RyR2 activation by caffeine is between 0.2_1
millimolar, sulmazole displays much greater potency (400
µmol )[24,25].
Digitalis glycosides Digoxin is one of the cardiac
glycosides, a closely-related group of drugs that have
in common specific effects on the myocardium. These drugs
are found in a number of plants; digoxin is extracted from the
leaves of Digitalis lanata. At a therapeutic concentration
(~1 nm), digoxin increases the open probability of RyR2 by
decreasing the lifetime of the closed states of the
channel[26]. Digoxin appears to sensitize RyR2, as channel gating itself is
not modified at picomolar Ca2+ concentrations. The
activation of RyR2, which is clearly distinct from the canonical
Na+/K+-ATPase inhibiting action, might contribute to the
inotropic effects of digoxin and digitoxin. Such actions are
similar to those of caffeine and sulmazole, but digitalis
glycosides do not affect the RyR1
isoform[27]. Owing to its strong effects on
Na+/K+-ATPase, it is unlikely that digoxin will be
used clinically to modulate RyR2 in the heart.
Suramin Suramin is a polysulphonated naphtylurea,
originally developed for the treatment of trypanosomiasis
and is also used as an anticancer agent. In single channel
experiments, suramin (in micromolar concentrations)
increases the open probability of sheep cardiac RyR2
channels by stabilizing the open conformational
state[28]. Recently, it has been suggested that the complex changes in RyR2
activity may result from an interaction with CaM-binding
sites[29]. Thus, the suramin-induced potentiation of
Ca2+
release through RyR2 may involve a relief of CaM-induced
inhibition. It is unclear at present whether suramin has any
beneficial effects in animal models of heart failure.
Volatile anesthetics Several halogenated compounds
affect SR Ca2+ release. The most extensively studied are
volatile anesthetics such as halothane, and its isomer
isoflurane. Halothane has been shown to increase SR
Ca2+ release at gas concentrations ranging from about 0.002% to
3.8% (v/v) in a Ca2+- and pH-dependent
manner[30,31]. At a physiological pH of 7.4, halothane increases RyR2 activity
at all Ca2+ concentrations without affecting channel
conductance[31,32]. Similar effects have been observed with isoflurane
and enflurane (2.5%_4%). A reduction of the pH from 7.4 to
7.1 causes maximum channel activation to occur at much
lower cytosolic Ca2+
concentrations[31]. Since the interaction of volatile anesthetics with RyR2 occurs at doses lower
than the minimum effective alveolar concentration (ie ~0.7%
for halothane and ~1.1% for isoflurane), their effects on RyR2
may produce negative inotropic effects and transient
vasoconstriction[33]. Negative inotropy may result from enhanced
diastolic Ca2+ release via RyR2, which reduces the levels of
Ca2+ in the SR available for the subsequent systolic
Ca2+ release. This in turn reduces the amplitude of the
Ca2+ transient and suppresses cardiomyocyte contractility.
4-Chloro-m-cresol The phenol derivative 4-chloro-
m-cresol (4-CMC) has been shown to increase the open
probability of RyR1 incorporated in planar lipid bilayers by
increasing both open lifetimes and
frequencies[34]. In contrast to caffeine, 4-CMC can modulate channel gating from
both the luminal and cytosolic sides of the channel. Whereas
there are myriad data concerning the actions of 4-CMC on
RyR1, relatively little is known about its action on the
cardiac RyR2 isoform. In cell lines expressing recombinant
RyR2, 4-CMC has been shown to enhance intracellular
Ca2+ release[35]. Although 4-CMC may modulate RyR2, the
significance of these pharmacological effects remains to be
further explored.
Peptide toxins Several peptide toxins isolated from
scorpion venoms have been shown to alter RyR2 activity, which
has raised the prospect that animal venom may represent a
unique source of selective modulators of intracellular
Ca2+ release channels[36]. Two peptides isolated from the
scorpion Pandinus imperator, imperatoxin A (IpTxa) and
imperatoxin I (IpTxi), are highly selective for RyR and show
no obvious activity with regard to other ion channels or
transporters[37]. IpTxa is a small peptide comprising of 33
amino acids with a molecular weight of approximately 4 kDa.
It specifically increases open probability of the RyR1 and
RyR3 isoforms by sensitizing these channels to cytosolic
Ca2+, but has little effect on RyR2. However, single channel
experiments have revealed that IpTxa induces the occurrence
of a subconductance state equivalent to ~30% of the full
conductance in all RyR isoforms, even though IpTxa has no
effect on RyR2 in ryanodine binding
assays[38]. IpTxi is a larger heterodimeric protein (~15 kDa) that consists of a large
subunit comprising of 104 amino acids covalently linked via
a disulfide bond to a smaller subunit of 27 amino
acids[39]. Single channel studies have demonstrated that IpTxi
inhibits both RyR1 and RyR2 with nanomolar affinity, although
these effects may be mediated via a lipid product of its
inherent phospholipase-2 (PLA-2)
activity[39]. In spite of these elegant electrophysiological
data, in vivo pharmacological experiments are needed to determine whether IpTx can
improve cardiac contractility in animals with heart failure.
Macrocyclic compounds The macrolide
immunosuppressant FK-506, also known as tacrolimus, can induce the
dissociation of FKBP12.6 from RyR2, thereby altering RyR2
gating. Rapamycin is another macrolide
immunosuppressant that can dissociate FKBP12.6 from the RyR2 channel
complex. In cardiac muscle, 0.1_10 µmol/L rapamycin
increases single channel open probability and decreases
channel conductance[40]. It has been speculated that the
former effect is the consequence of drug binding to
FKBP12.6, whereas the changes in channel conductance are the
consequence of FKBP12.6 dissociation from
RyR2[6,40]. Interference with the RyR2 subunit composition might be involved
in some effects of FK506, particularly in the development of
myocardial hypertrophy and heart failure, which has been
observed in some pediatric transplant
patients[41].
RyR2 antagonists
Ruthenium red Ruthenium red, a water-soluble dye with
a structure that includes 14 amino groups, has been shown
to inhibit SR Ca2+ release in cardiac muscle. In planar lipid
bilayer experiments, micromolar concentrations of ruthenium
red dramatically decreases RyR2 open probability,
associated with long-term channel
closure[42]. At submicromolar concentrations, the major effect of ruthenium red is a
decrease in the lifetime of the open channel state, whereas at
higher concentrations (>1 µmol/L), the lifetime of the closed
channel is increased. Ruthenium red reduces the RyR2 single
channel current from both the cytosolic and luminal sides of
the channel. However, the dwell times of the block are longer
when ruthenium red is added to the luminal side. In addition,
luminal ruthenium red decreases the single channel current
without affecting channel open
probability[43]. Binding studies performed using recombinant RyR1 channels have
localized ruthenium red binding sites at residues 1861_2094 and
3657_3776[44]. On the basis of single channel studies, it has
been proposed that the drug-binding site is located within
the transmembrane domain, probably close to the channel
pore region, and ruthenium red cannot permeate through the
open channel[43]. Because ruthenium red is neurotoxic, it is
not an ideal candidate for drug development.
Dantrolene Dantrolene is a hydantoin derivative
commonly used for the treatment of the genetic disorder,
malignant hyperthermia, which is caused by inherited mutations
in RyR1 (Figure 1A). Importantly, dantrolene represents the
only drug targeting RyR that is currently approved for
clinical use. In skeletal muscle, 10_100 micromolar dantrolene
inhibits abnormal Ca2+ release from the
SR[45]. The inhibition of SR
Ca2+ release through RyR2 was also observed in
cardiac muscle, but the sensitivity to dantrolene was lower than
in the skeletal muscle. Recently, it has been demonstrated
that dantrolene can stabilize domain_domain interactions
within the RyR complex[46]. Taken together, these data
suggest that dantrolene might exert therapeutic effects in heart
failure by preventing an abnormal SR
Ca2+ leak, although this has not been investigated yet in experimental
models[19].
Ryanoids Ryanodine is a naturally-occurring plant
alkaloid isolated from plants of the genus
Ryania (Figure 1B). Because it binds with high affinity and specificity to
its receptor in the SR, RyR have been named after this compound.
Ryanodine is unusual in that it is a modulator of both gating
and ion translocating properties of RyR2. The
pharmacology of ryanodine has been described extensively in other
literature reviews[20,47,48], therefore we will focus on its action
on RyR2 and its potential application as a drug for the
treatment of cardiovascular disorders.
RyR2 possess both a high- and low-affinity binding site
for ryanodine, which contributes to the concentration-
dependent effects of ryanodine on the activity of RyR. At
nanomolar concentrations, ryanodine increases the open
probability of RyR2 without affecting the rates of ion
movement. At submicromolar concentrations, ryanodine
increases RyR2 open probability to almost 100% and it
induces a long-lasting subconductance state representing
~50% of the normal conductance
level[47]. Finally, at high micromolar concentrations, ryanodine causes the channel
to fully close, which accounts for an inhibitory effect on SR
Ca2+ release[49].
Derivatives of ryanodine, collectively called ryanoids,
display actions that do not conform to the canonical
ryanodine characteristics. For example, some ryanoids can
induce subconductance amplitudes far different from the
half-open state (ranging from 6%_75% of the maximum
amplitude)[47]. The duration of the subconductance states also vary
considerably among ryanoids. The unique features of certain
ryanoids could be considered when developing ryanodine
derivatives for heart failure therapy for which RyR2
specificity, low-level subconductance, and reversibility may
be desirable characteristics.
Local anesthetics Several charged local anesthetics are
known to inhibit RyR2 channels. These include both tertiary
amines (eg procaine, tetracaine, and lidocaine), as well as
quaternary amines (eg QX572 and
QX314)[50]. Although procaine and tetracaine (Figure 1C) are both effective at low
millimolar concentrations, procaine appears to be more
selective for RyR2 compared to RyR1. Single channel studies
have revealed that both drugs decrease the RyR2 open
probability by stabilizing a closed conformational
state[51]. Single channel studies of RyR2 have revealed 2 different modes of
action of local anesthetics. Tetracaine and procaine
decreased the channel open probability by stabilizing a closed
state of the channel without affecting its unitary
conductance[51]. In contrast, lidocaine (Figure 1D) and quaternary
amines appear to induce voltage-dependent channel blockade, characterized by reduced conductance without
changes in the open probability. This voltage-dependent
inhibition is also observed in the presence of millimolar
concentrations of procaine or tetracaine, in the presence of 2
µmol/L ryanodine[51]. Interestingly, tetracaine has been
shown to prevent arrhythmogenic spontaneous SR
Ca2+ release events, presumably by reducing aberrant diastolic RyR2
openings[52]. Moreover, tetracaine also potentiates systolic
Ca2+ release due to enhanced diastolic SR
Ca2+ filling (due to decreased
Ca2+ leak from the SR)[53]. Thus, compounds such
as tetracaine may have a therapeutic benefit in the
prevention of cardiac arrhythmias and contractile dysfunction in
heart failure.
1,4-Benzothiazepines The pharmacological agents
discussed earlier modulate RyR2 by directly altering channel
gating or ion translocation. Recently, an additional
mechanism for regulating RyR2 channels has been
described[54,55]. It was shown that the 1,4-benzothiazepine derivative JTV519
(also known as K201, Figure 1E) stabilizes the interaction of
RyR2 with the endogenous inhibitory subunit
FKBP12.6[54-56]. The FK506-binding protein FKBP12.6 has previously been
shown to stabilize a closed conformational state of the RyR2
channel, thereby decreasing the open
probability[57]. In addition, JTV519 may enhance coupled gating between RyR2
channel complexes by increasing the binding of
FKBP12.6[6]. Based on observations that FKBP12.6 binding to RyR2 is
decreased in patients and animals with heart failure, the
therapeutic role of JTV519 was assessed in disease models.
In animal models of heart failure and myocardial infarction,
JTV519 has been demonstrated to improve contractile
function and prevent the development of adverse left ventricular
remodeling[54,56]. Because these therapeutic effects were not
observed in FKBP12.6-deficient mice, it was concluded that
these effects are dependent on the enhanced interaction of
FKBP12.6 with RyR2[56]. Furthermore, it has been proposed
that JTV519 may prevent cardiac arrhythmias that arise from
delayed afterdepolarizations, initiated by a SR
Ca2+ leak through FKBP12.6-depleted
RyR[58,59]. JTV519 prevented catecholaminergic ventricular tachycardias in FKBP12.6
haploinsufficient mice, but not in FKBP12.6-deficient mice,
again indicating that the enhanced binding of FKBP12.6 to
RyR2 constitutes the therapeutic mechanism of this
1,4-benzothiazepine derivative (Figure
2)[19,60]. Although these animal studies are very promising, it remains to be seen
whether or not JTV519 becomes a useful clinical drug in the
treatment of cardiac arrhythmias and heart failure.
Conclusion
In this article, we provided a general overview of
therapeutic approaches and pharmacological agents that are
known to modulate RyR in the heart. Some of these
compounds modulate channel gating, whereas others regulate
ion translocation. The recent emergence of RyR2 as a critical
defect in the pathogenesis of heart failure and triggered
cardiac arrhythmias has spurred interest in developing novel
therapeutic agents based on these channels. Although it is
imperative that effective therapeutic agents do not interfere
with systolic SR Ca2+ release (as this would depress cardiac
contractility), the inhibition of a diastolic SR
Ca2+ leak would be desirable as it likely prevents arrhythmias and enhances
SR Ca2+ loading (thus improving contractility). Most of the
classic RyR2 modulating drugs, however, display
unacceptable side effects or lack long-term efficacy. The recently
described 1,4-benzothiazepine JTV519, however, acts via a
different mechanism, namely by allosteric modification of
protein-protein interactions within the channel complex.
Interestingly, this drug selectively targets diastolic SR
Ca2+ leaks without affecting systolic
Ca2+ release. Finally, these studies suggest that drugs that modify other subunits within
the RyR2 macromolecular complex may also provide
therapeutic benefits in patients with heart failure or arrhythmias.
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