Membrane Transport Group, Department of Chemistry, The Faculties, The Australian National University, Canberra, Australian Capital Territory 0200, Australia
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ABSTRACT |
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The use of
electrophysiological and molecular biology techniques has shed light on
reactive oxygen species (ROS)-induced impairment of surface and
internal membranes that control cellular signaling. These deleterious
effects of ROS are due to their interaction with various ion transport
proteins underlying the transmembrane signal transduction, namely,
1) ion channels, such as
Ca2+ channels (including
voltage-sensitive L-type Ca2+
currents, dihydropyridine receptor voltage sensors, ryanodine receptor
Ca2+-release channels, and
D-myo-inositol
1,4,5-trisphosphate receptor Ca2+-release channels),
K+ channels (such as
Ca2+-activated
K+ channels, inward and outward
K+ currents, and ATP-sensitive
K+ channels),
Na+ channels, and
Cl channels;
2) ion pumps, such as sarcoplasmic
reticulum and sarcolemmal Ca2+
pumps,
Na+-K+-ATPase
(Na+ pump), and
H+-ATPase
(H+ pump);
3) ion exchangers such as the
Na+/Ca2+
exchanger and
Na+/H+
exchanger; and 4) ion cotransporters
such as
K+-Cl
,
Na+-K+-Cl
,
and
Pi-Na+
cotransporters. The mechanism of ROS-induced modifications
in ion transport pathways involves
1) oxidation of sulfhydryl groups located on the ion transport proteins,
2) peroxidation of membrane phospholipids, and 3) inhibition of
membrane-bound regulatory enzymes and modification of the oxidative
phosphorylation and ATP levels. Alterations in the ion transport
mechanisms lead to changes in a second messenger system, primarily
Ca2+ homeostasis, which further
augment the abnormal electrical activity and distortion of signal
transduction, causing cell dysfunction, which underlies pathological
conditions.
ischemia-reperfusion; muscle pathologies; thiol group; calcium homeostasis; membrane compartmentation; reducing and oxidizing agents
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INTRODUCTION |
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REACTIVE OXYGEN SPECIES (ROS), such as superoxide
radical anion (O2), singlet oxygen
(1O2),
hydrogen peroxide
(H2O2),
hydroxyl radical (· OH), and hypochlorous acid (HOCl), are
produced as by-products of oxidative metabolism, in which energy
activation and electron reduction are involved. Their production is
enhanced during inflammation, aging, radiation exposure, endotoxic
shock, and ischemia-reperfusion of heart, intestine, liver,
kidney, and brain. They have been implicated in various cell
dysfunctions (91, 126). This can be indicated by the protection
provided following treatments with free radical-scavenging enzymes (9,
54, 94, 104). The mechanisms of ROS action at the cellular level are
not well understood. It is obvious, therefore, that the understanding
of these mechanisms is important for developing therapeutic strategies
at cellular sites of dysfunction. In particular, the role of cell
membranes in compartmentation and transmembrane signal transduction
renders the changes in their properties the early events that are
associated with cell dysfunction. This review examines the
interaction of ROS with membrane phospholipids and proteins that
constitute ion transport pathways, i.e., ion channels, pumps,
exchangers, and cotransporters of both internal and surface membranes
in general and in muscles in particular.
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PRODUCTION, IDENTIFICATION, AND PATHOLOGIES OF ROS |
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The metabolic pathways that are known to produce ROS include
1) the xanthine (X)/xanthine oxidase
(XO) system, 2) the cyclooxygenase pathway of the arachidonic acid metabolic system,
3) the electron transport system of
mitochondria, 4) the activated
neutrophil system, and 5) the
amyloid protein system. The significance of the contribution of
each of these ROS sources is not well understood.
The superoxide radical anion O2 is
produced by the reduction of O2
using an electron that can be supplied by superoxide-generating NADPH
oxidase as follows
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(1) |
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(2) |
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(3) |
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(4) |
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(5) |
A flowchart of the major processes of ROS underlying pathologies is shown in Fig. 1. The pathologies that have been attributed to ROS-induced cell dysfunction include 1) cardiac stunning and arrhythmia (see Refs. 35 and 61); 2) skeletal muscle injury (see Refs. 130 and 151); 3) neurological conditions (see Refs. 91 and 126), e.g., neuronal damage in Parkinson's disease (see Ref. 27); 4) neurotoxicity (107); 5) Alzheimer's disease (see Refs. 6 and 171); 6) diabetes (see Ref. 123), apoptosis of T lymphocytes (see Ref. 37), and gastric mucosal injury (see Ref. 160); and 7) hypertension (156). Some of these effects can be suppressed by free radical scavengers (9, 54, 94, 104).
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In skeletal muscle, exercise increases the rate of ROS production (30, 130, 158). The enhancement of ROS production due to the increase in activity of mitochondrial electron carriers, low catalase concentrations, the sudden changes in oxygen supply and consumption, and the presence of high levels of myoglobin acting as a catalyst for the formation of oxidants is thought to cause skeletal muscle injury (see Ref. 130). The increase of free radicals in skeletal muscle and liver cells during exhaustive exercise is associated with a decrease in mitochondrial respiratory control, loss of sarcoplasmic reticulum (SR)/endoplasmic reticulum (ER) integrity, and increased levels of peroxidation products and lipid peroxidation. These effects are similar to those observed in vitamin E-deficient animals (30).
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ROS INTERACTION WITH ION TRANSPORT PATHWAYS |
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The interaction of ROS with ion transport pathways in muscles can be
deduced indirectly from changes in their membrane properties. Cosentino
et al. (29) demonstrated the role of
O2 in the mediation of
endothelium-dependent contraction. It has also been demonstrated that
H2O2
potentiates twitch tension in cardiac (84, 136) and skeletal muscles
(124, 136), and this induced tension can be decreased by catalase, a
specific enzyme that hydrates
H2O2
(136). The effects are usually characterized by amplification of
tension and tension oscillation, followed by spontaneous contractions
(84, 124). This effect of
H2O2 is not mediated via end effects on the myofilaments (111, 124). This
suggests that the signal transduction pathways are affected by ROS.
Early studies revealed that the effects of ROS on membrane properties
could be deduced from electrophysiological parameters of the membrane.
These include changes in membrane current and potential, ionic
gradients, action potential duration and amplitude, afterdepolarization, and spontaneous activity and loss of excitability (see Refs. 40, 166, 167).
The effects of ROS-generating systems on membrane potential are now well established. It has been demonstrated that X/XO as a ROS-generating system caused membrane depolarization and a decrease in the action potential amplitude and maximum rate of rise of action potentials in guinea pig ventricular myocardium (127). Delayed afterdepolarization and early afterdepolarization induced by t-BHP, DHF, and X/XO in guinea pig papillary muscle and canine ventricular myocytes have also been demonstrated (4, 5, 122). ROS-induced membrane depolarization has been attributed to inhibition of a Na+ current (11) or an inward K+ current (121), activation of an inwardly directed nonselective cation current (115, 152), and increase in a Ca2+ current that is associated with changes in intracellular Ca2+ concentration ([Ca2+]i). Similarly, the oscillation in [Ca2+]i has been implicated in arrhythmogenic afterdepolarization (113).
ROS-induced shortening of the action potential duration has been attributed to a possible increase in a delayed rectifying K+ current and decrease in activation of ATP-sensitive K+ (KATP) channels and Ca2+ currents (121, 146). Exogenous ROS-induced changes in the electromechanical function and metabolism in isolated rabbit and guinea pig ventricles shortened the duration of the action potential, indicating a decrease in the Ca2+ current and time-dependent outward current (50). More recently, Tokube et al. (169) reported biphasic changes in the action potential duration, with initial lengthening of the action potential due to a rapid decrease in whole cell K+ currents and subsequent shortening due to a decrease of whole cell Ca2+ current and increase in the single ATP-sensitive time-dependent outward K+ current.
In cardiac, smooth, and skeletal muscles the deleterious effects of ROS, produced by leaked electrons from the electron transport system of the mitochondria, are due to their interaction with various ion transport proteins underlying transmembrane signal transduction (Fig. 2). Figure 2 indicates that an important feature of ROS interaction with ion transport proteins is the modification in Ca2+ homeostasis that ultimately causes muscle pathologies.
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Ion Channels
Ca2+ channels.
L-TYPE VOLTAGE-SENSITIVE CA2+
CURRENTS.
L-type voltage-sensitive Ca2+
channels play an important role in
Ca2+ homeostasis in ventricular
myocytes. Hence numerous studies have been conducted to examine the
effects of ROS on these channels and to determine their contribution to
the alterations in Ca2+
homeostasis under adverse conditions (Table
1). It appears that the data for the
effects of ROS on current peak, amount of current, and kinetics of
L-type Ca2+ channels in
ventricular myocytes are conflicting. It has also been reported that
H2O2
has no influence on L-type Ca2+
current (100, 101). In contrast to the finding that ROS-induced reduction in peak current was associated with an increase in mean current due to slowing of the inactivation (26), Tokube et al. (169)
reported a decrease in the current peak with no changes in the
activation time course of this current. On the other hand, Cerbai et
al. (20), Matsuura and Shattock (115), and Moghadam and Winlow (119)
reported a decrease in L-type Ca2+
current. This decrease has been attributed to
Ca2+-induced channel inactivation
(see Ref. 115). The
H2O2-induced decrease in the inward Ca2+
current in cultured Lymnaea neurons is
dose dependent (119). There are data suggesting that overload due to
Ca2+ influx through the
voltage-gated Ca2+ channel can be
ruled out, since free radicals and
H2O2
inhibit the voltage-sensitive L-type
Ca2+ current (48, 50, 51, 121).
The inhibitory effects of HX/XO and DHF as ROS-generating systems were
reversed with SOD and catalase, suggesting that both
O2 and
H2O2
are effective (Table 1), whereas the effects of the cumene/XO
ROS-generating system were irreversible (48). Internal oxidative agents
used on ion channels also show that 4,4'-dithiodipyridine
[DTDP; a lipophilic sulfhydryl (SH)-oxidizing agent] and
thimerosal
{[(o-carboxyphenyl)thio]ethyl mercury sodium salt, a hydrophilic SH-oxidizing agent} inhibit the activity of cloned rabbit smooth muscle L-type
Ca2+ channels (23).
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K+ channels. CA2+-ACTIVATED K+ CHANNELS. The role of ROS in modulating ion channels has also been inferred from the use of ion channel blockers together with ROS-generating systems. The K+ channel blocker quinidine hydrochloride reduced Ca2+-dependent chemiluminescence products, indicative of oxygen radical production, in human eosinophils (143). They postulated that production of oxygen free radicals by the membrane-bound NADPH oxidase may be mediated by Ca2+-activated K+ (KCa) channels in human eosinophils and that this mechanism may underlie the role of eosinophils in the pathogenesis of allergic diseases. Relaxation evoked by nonneurogenic electrical field stimulation, via generation of free radicals, also modified Ca2+-dependent channels (1, 81, 186). In contrast to the H2O2-induced reversible inhibition [with DTT and reduced glutathione (GSH)] of KCa channels in the plasma membrane of bovine aortic endothelial cells (18), the large KCa channel in skeletal muscle from mouse is insensitive to as high as 50 mM H2O2 concentration (179). Differences in H2O2-induced modification in channel activity could be attributed to difference in tissue types. For example, it has been found that reducing agents decrease the activity of KCa channels in pulmonary, but not in ear, arterial smooth muscle cells of rabbit (128). The significance of H2O2 inhibition of KCa channels derives from the fact that disruption of Ca2+ homeostasis is mediated via depolarization of the membrane potential (see Table 3) (18).
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Na+ channels.
Voltage-gated Na+ channels play an
important role in cell excitability and conductance. They vary in their
pharmacology and gating properties. There are few data on the effects
of ROS on whole cell Na+ currents
and no data on the unitary currents of single
Na+ channels (Table
6). Indirect findings support the view that this channel is not very sensitive to ROS. For example, potential measurements of skeletal muscle fibers revealed that neither the resting potential nor the action potential was affected in fibers treated with 1.5 mM
H2O2
for 30 min. This finding was taken to mean that the
Na+ channel was not blocked (124).
In experiments where the effect of SH-oxidizing agents on
Na+ was examined, it was shown
that DTDP induced no changes in expressed human cardiac
Na+ current (23), whereas other
reports suggest that SH-oxidizing agents do induce changes in this
channel. It has been reported that
Na+ channel inactivation is
inhibited by some oxidants such as chloramine-T, halazone, and HOCl
(177). Other oxidants such as
H2O2
produce a shift in
h, a kinetic
parameter of the inactivation process, without modifying channel
activation (133), whereas systems generating t-BHP (a substrate of glutathione
peroxidase), t-butoxy
(RO ·), or t-butylperoxy
(ROO ·) radicals caused a slow inactivation and progressive
decrease in Na+ current (11). This
effect of t-BHP was selective to
Na+ channels, since
Ca2+ and
K+ currents were unchanged. It is
for this reason that such changes in the
Na+ current have been proposed as
mechanisms for
H2O2-induced
alterations in the electrical and contractile behavior of isolated
cardiomyocytes (8).
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Cl channels.
The effects of ROS on Cl
channels have not been widely examined (Table 6). However, there is
evidence that Cl
channels
are sensitive to ROS. It has been previously shown that the
Cl
channel in the surface
membrane of bovine trachea (134) and the voltage-dependent
anion-selective channel in the mitochondrial outer membrane (190) are
regulated by an oxidation-reduction mechanism. Pharmacological and
biophysical studies also point to the presence of an
O2-sensing mechanism (GSH-GSSH) on
the small Cl
(SCl) channel
in the SR of skeletal muscle (95, 97). Recently, it has been reported
that the human skeletal muscle
Cl
current (hClC-1), as
expressed in Xenopus oocytes and in
human embryonic cells, is also modulated by SH-reactive compounds
(105). They suggested that the mechanism of
Zn2+-induced voltage-independent
nonreversible current inhibition, like that of
Cd2+,
Hg2+, and other SH-reactive
compounds, was mediated via binding to cysteine, histidine, or acidic
side chains present near the extracellular side of the membrane. It has
also been found that the ATP-sensitive SCl channel is modified by DTDP
and
H2O2
(95, 96, and unpublished observations).
Other channels. Ca2+ homeostasis could also be modified via nonselective ion channels. ROS have also been reported to activate a nonselective cation whole cell current in guinea pig ventricular myocytes (78). A Ca2+-activated nonselective cation channel has also been found to be modulated by SH reagents (92). However, ROS modulation of this channel has yet to be demonstrated. Recently, Koliwad et al. (93) reported that GSSH mediated cation channel activation in calf vascular endothelial cells during oxidant stress. The dependency, selectivity, and contribution of this channel to Ca2+ transport are not known.
Ion Pumps
Ion pumps and exchangers are less understood than ion channels, mainly due to the technical limitations of ion flux experiments, where ion transport is deduced from net transport due to influx and efflux processes. Recently, the whole cell voltage-clamp and patch-clamp techniques have been used for the measurement of a macroscopic Na+-K+ pump in isolated ventricular myocytes (153) and for the Na+/Ca2+ exchanger (24, 49). However, there are presently no techniques available for the recording of unitary currents of a single pump or exchanger protein equivalent to the unitary current recordings of a single-channel protein.SR and sarcolemmal Ca2+
pumps.
These pumps are important in muscle relaxation. For example, in smooth
muscles the relaxation is achieved by lowering
[Ca2+]cyt
via Ca2+ efflux at the plasmalemma
(Ca2+-ATPase and
Na+/Ca2+exchange)
as well as Ca2+ uptake via
Ca2+-ATPase in SR (159). The two
types of Ca2+ pumps in the
plasmalemma and SR are structurally and immunologically distinct and
are regulated differentially (56). Pharmacological probes also confirm
these distinctions. For example, thapsigargin, a plant-derived
sesquiterpene, inhibits the uptake pathway (109, 168) by binding to a
specific site of various
Ca2+-ATPase isoforms of SR and
ER but not to sarcolemmal
Ca2+-ATPase (109). The effects of
ROS on Ca2+ pumps have been
determined from modifications in 1)
vasoconstrictor peptide ANG II-induced contractions of artery rings by
cyclopiazonic acid, an SR Ca2+
pump inhibitor, 2)
Ca2+ transients,
3) acylphosphate levels of the
115-kDa sarco(endo)plasmic reticulum
Ca2+-ATPase (SERCA2b) pump protein
and 140- and 115-kDa pump proteins in the plasma membrane,
4) ATP-dependent azide-insensitive
oxalate-stimulated Ca2+ uptake,
5) phosphate-stimulated plasma
membrane
Ca2+-ATPase, and
6)
Ca2+-stimulated ATPase and
ATP-dependent Ca2+ accumulation
(Table 7). Both sarcolemmal and SR
Ca2+ pumps in cardiac and smooth
muscles are affected by ROS. Favero et al. (45) found that
H2O2
(1-80 mM) had no effect on the ATP hydrolysis of the SR
Ca2+-ATPase in skeletal muscle. By
contrast, ROS induced depression in the heart sarcolemmal
Ca2+-ATPase (86) and inhibition in
Ca2+-ATPase in the SR (55-57,
108, 140). The plasmalemmal Ca2+
pump is less sensitive to ROS than the SR
Ca2+ pump.
H2O2
and O2 uncouple the hydrolytic
reaction of the plasmalemmal Ca2+
pump and inhibit the hydrolytic reaction of the SR
Ca2+ pump (55, 56, 102). Grover et
al. (57) studied interaction of ROS with the
Ca2+ pump in the SR from pig
coronary artery smooth muscle. It was found that 250 µM
(K0.5 = 74 µM)
H2O2
inhibited ANG II- and cyclopiazonic acid-induced contractions and
inhibited the increase in
[Ca2+]i
as well as the Ca2+-dependent
acylphosphate levels of the 115-kDa SERCA2b pump protein. They proposed
that
H2O2-induced
damage to the SR Ca2+ pump
diminishes the SR Ca2+ pool and
decreases the smooth muscle response to ANG II. Superoxide has similar
effects (57). Suzuki and Ford, (164) reported that, in SR of bovine
aortic smooth muscle, exogenous HX (0.1-100 µM; average 5 µM) + XO (10 U/ml) induced concentration-dependent inhibition of
Ca2+-ATPase. By comparison,
0.01-10 mM
H2O2
(50% inhibition at 1 mM) inhibited the
Ca2+-ATPase at 100 µM.
H2O2
also, in the presence or absence of 100 µM
FeSO4, significantly depressed the
SH content of L-cysteine. As far
as the effect of ROS moieties are concerned,
O
2 is the effective moiety, and
not
H2O2,
since the inhibition of the
Ca2+-ATPase is blocked by 100 U/ml
SOD but not by 20 mM mannitol or 100 µM desferrioxamine. The free
radical · OH produced irreversible inhibition of the
Ca2+-ATPase activity and SH
concentration, whereas
H2O2
had no effect on SH concentrations (164). However, other studies have
implicated 1O2
(102) and both O
2 and
H2O2
(56, 57, 86, 87), whereas Rowe et al. (140) implicated
H2O2
and · OH while the effectiveness of
O
2 was not ruled out.
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Na+-K+-ATPase
(Na+ pump).
Na+-K+-ATPase
is a membrane-bound enzyme composed of two subunits: an -catalytic
subunit with a relative molecular weight
(Mr) of
90,000-110,000 and a
-subunit with an
Mr of
40,000-60,000. The Na+ pump
is important for maintaining coronary tone. The pump transports three
Na+ and two
K+ per one ATP hydrolyzed against
their concentration gradients, generating internal negative charges.
The intracellular/extracellular concentrations in muscle cells are
typically 5-115/130 mM Na+
and 130/5 mM K+ (see Ref. 42).
There are several reaction steps in the function of the pump. The
hydrolytic and transport reactions of the pump can be uncoupled. For
example, treatment of inside-out erythrocyte vesicles with trypsin or
chymotrypsin uncouples the transport of
Na+ from the
Na+-K+-ATPase
(62). K+-activated
ouabain-sensitive
p-nitrophenylposphatase is associated with the hydrolytic step of the
Na+ pump. Conflicting effects of
ROS on Na+ pumps have been
reported (see Ref. 62). Some of these differences in ROS effects are
due to the methods used for ROS generation, in which different
individual ROS may not act via the same mechanism (Table
8). These differences could also arise from
resolution limitations of the flux experiments, which can be
overwhelmed by the back flux of ROS-enhanced activated
K+ channels.
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H+ pump. The H+ pump is important for preventing a drastic intracellular acidification and for charge balance and membrane polarization. Oxidant stress-induced pH changes in peritoneal macrophages have been attributed to modifications in the plasmalemmal H+-ATPase (see Ref. 14).
Adenine nucleotide translocator, phosphate carrier, and uncoupling
proteins.
These proteins are present in mitochondria. The phosphate carriers
catalyze the electroneutral exchange of phosphate for hydroxyl ion. The
adenine nucleotide carrier binds and transports adenine nucleotides,
whereas uncoupling proteins bind purine nucleotides but transport
H+,
OH, or
Cl
(see Ref. 137). The
effects of ROS on these protein transporters are not known. However, it
is very likely that they are affected by ROS. First, it is known that
in skeletal muscle and liver cells free radicals increase during
exhaustive exercise and this increase is associated with a decrease in
mitochondrial respiratory control (30). Second, ROS have deleterious
effects on mitochondrial metabolism (see Ref. 50) and are linked to a
leakage of electrons from mitochondria (see Ref. 91). Third, the
presence of the SH groups on the cysteine residues and the SH-induced
modification in permeation of phosphate,
Cl
, and
H+ (137) also suggest that ROS may
modify these transporters.
Ion Exchangers
Na+/Ca2+
exchanger.
The
Na+/Ca2+
exchanger couples the transport of three
Na+ to that of a single
Ca2+ in the opposite direction in
two consecutive, yet separate steps (see Ref. 28). The
Na+/Ca2+
exchanger, together with
Ca2+-ATPase of the ER/SR,
regulates Ca2+ levels that
underlie muscle contractility behavior under both normal and ischemic
conditions (see Ref. 13). In cardiac muscle the
Na+/Ca2+
exchanger contributes to force development, in particular, under glycosidic conditions (see Ref. 131). In smooth muscle, relaxation is
achieved partially via a decrease in
[Ca2+]cyt
efflux at the plasmalemma by means of the
Na+/Ca2+
exchanger (159). There is evidence suggesting that this exchanger is a
tetramer linked by disulfide bonds, and thus it is susceptible to
modification by oxidizing and reducing agents as well as ROS (see Refs.
19, 88, 129). However, both decreases (24, 34, 88) and increases in
Na+-dependent
Ca2+ uptake
(Na+/Ca2+
exchanger) (49, 135, 154) in both isolated and intact sarcolemmal vesicles have been reported (see Table 9).
The exchanger is also inhibited by the oxidizing agent HOCl (46, 88),
the SH-alkylating agent diamide (2, 24, 129), and SH-reducing agents
GSH and DTT (131). There is also evidence that SH-alkylating diamide stimulates
Ca2+/Na+
exchange (129). The nature of the inhibition or stimulation is not
clear. The stimulation of the
Na+/Ca2+
exchanger has been attributed to the increase in affinity to Ca2+, i.e., a decrease in
Km for
Ca2+ (135, 154) with no changes in
voltage dependency (154). The pathophysiological implication is that
such stimulation of
Na+/Ca2+
exchange by ROS may moderate the myocardial response to
ischemia-reperfusion injury (154). DiPolo and Beauge, (33)
proposed that the inhibition is due to a reduction in the affinity of
the exchanger to Ca2+. The
conflicting effects of ROS on the
Na+/Ca2+
exchanger may be partially due to the use of a different ROS-generating system and different parameters to deduce the exchanger activity (see
Table 9). For example, Kato and Kako (88) found that HOCl induced
inhibition whereas
H2O2
induced stimulation of the
Na+/Ca2+
exchanger.
H2O2-induced
Cl current is used as an
indicator of enhancement in the
Na+/Ca2+
exchanger (149). However, both Coetzee et al. (24) and Goldhaber (49)
obtained conflicting data, despite the fact that both used Ni2+ sensitivity of a membrane
current as a marker for the
Na+/Ca2+
exchanger. The conflicting effects of ROS on this exchanger are not due
to the ROS-generating system, since it has been found that
H2O2
and X/XO similarly enhanced this exchanger in ventricular myocytes,
causing Ca2+ overload and
triggering arrhythmia during reperfusion (49). The conflicting effects
may be due to differences in the exchanger mode during which the
effects of ROS were examined. There is evidence suggesting that
Ca2+ and
Na+ are translocated in separate
consecutive steps (see Ref. 89) and that the
Na+/Ca2+
exchanger may operate in reverse, i.e., efflux of
Na+ and influx of
Ca2+ during
ischemia-reperfusion when cytoplasmic concentration of Na+ is increased (54).
Furthermore, the exchanger is modulated by
Ca2+ and/or ATP, which
affect the exchange distribution between the active state and either of
two inactive states (see Refs. 66 and 67). Other regulatory mechanisms
may be involved, such as changes in lipid composition (106) and
H2O2
production via insulin-NADPH oxidase interaction (88).
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Na+/H+
exchange.
The isoforms of the
Na+/H+
exchanger are present in various epithelial and muscle cells. They play
important physiological roles, such as regulation of intracellular pH,
cell volume, and reabsorption of NaCl and
NaHCO3. There is little
information on the effects of ROS on these exchangers in epithelial
cells. ROS have been implicated in the increased activity of the
cellular
Na+/H+
exchanger that is activated by phosphorylation in vascular myocytes from hypertensive rats (156). It has also been reported that exposure
of human neutrophils to 100 nM
N-formyl-methionyl-leucyl-phenylalanine activated the amiloride-sensitive
Na+/H+
exchanger, leading to an increase in intracellular pH from 7.22 to 7.8 (157). The ROS-generating system X/XO inhibited this transport system
in isolated myocytes of rat heart and in sealed sarcolemmal vesicles of
bovine heart (184), and the inhibition was reversed with catalase and
SOD and, therefore, indicated that
H2O2
and O2 were the effective
moieties. The effect of ROS on the
Cl
/HCO
3
exchanger is unknown.
Ion Cotransporters
Cation-Cl transporters.
The electroneutral transporters have important physiological roles,
such as regulatory volume decrease and transepithelial salt transport
(see Ref. 120). Their activity depends on the presence of all the
transported ions. However, they differ pharmacologically with respect
to the identity and stoichiometry of the transported ions. There is
little direct or indirect information on the effect of ROS on these
transporters.
Other cotransporters.
NA+-PI
COTRANSPORT.
H2O2
and O2 inhibited the
Na+-Pi
transport system in isolated myocytes of rat heart and in sealed
sarcolemmal vesicles of bovine heart (184). Furthermore, this
ROS-induced inhibition was reversed with catalase and SOD. The effect
of ROS on
Na+-HCO
3
and
K+-HCO
3
cotransporters is unknown.
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THE PRIMARY TRANSPORT PATHWAY AS A TARGET FOR ROS |
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ROS-induced changes in membrane properties are considered early events in response to oxidative stress. However, the molecular mechanism(s) for ROS action on ion transport pathways is not known. Hypothetically, the effects of ROS can be caused via direct effects on ion transport proteins. Ion channels that have been thought to be a prime ROS target include a 106-kDa Ca2+-release channel (162, 185), DHPR and RyR Ca2+-release channels (125), and K+ channels (94, 104). It has been reported that the direct effect of H2O2 on KATP channels in skeletal muscle is mediated via oxidation of the channel protein (179). It has to be noted that the concentration of H2O2 used by Weik and Neumcke (179) greatly exceeded those reported in studies where the effect was thought to be indirect (50, 123). Tokube et al. (169) suggested that ROS directly affected the KATP channel by binding to the ATP-binding site, causing a decrease in the sensitivity of the channel to ATP in the range of 0.2-2 mM, without affecting ADP or glibenclamide binding sites. Indirect effects of ROS on ion transport pathways are mediated via membrane phospholipids. There are several examples where changes in ion transport have been attributed primarily to changes in membrane phospholipids. It has been argued that ROS caused peroxidation of membrane phospholipids and that this led to changes in the KATP channel (63) and the Ca2+-Mg2+-ATPase (see Table 7).
The data in Tables 1-9 show that the concentrations of ROS-induced
changes are different for ion channels, pumps, and exchangers. It
appears that the inhibitory concentrations for ion pumps are less than
those required for ion channel inhibition. Thus ion pumps are more
sensitive to ROS than ion channels. However, it is not known which of
the ion pumps is the primary target. Attempts have been made to
determine the primary ion pathway that is affected by ROS from the
IC50 of individual ROS. The data
in Tables 7 and 8 show that Ca2+
uptake is more sensitive to
H2O2
than ouabain-sensitive Rb+ uptake.
However, Rb+ uptake is more
sensitive to O2 than
Ca2+ uptake (42). These findings
suggest that the primary ion pump that is affected by ROS depends not
only on the type of pump but also on the individual ROS.
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MECHANISMS OF ROS-INDUCED MODIFICATIONS |
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Figure 3 shows the possible molecular targets underlying ROS effects on ion transport mechanisms. These molecular targets include 1) membrane phospholipids, 2) membrane proteins, 3) regulators of ion transport mechanisms, or 4) a combination of these targets.
|
Oxidation of SH Groups
The majority of studies of ROS effects on ion transport assume that ROS-induced stimulation (e.g., Ref. 12) or inhibition (e.g., Ref. 18) are mediated via modifications in SH groups of the transport proteins (see Tables 1-9). The interaction of ROS with ion transport proteins is viewed as being consistent with a thiol-disulfide redox state model and thus explains the widespread ROS-induced cellular dysfunction (85). The evidence for SH groups of the ion transport pathways as the site(s) for ROS action is discussed in ROS mimic SH-oxidizing agents and SH-reducing agents reverse ROS action.ROS characteristics.
ROS are capable of reaching SH groups embedded in the membrane. For
example,
H2O2
can readily cross the cell membrane and be converted to · OH
via the Fenton reaction, with consequent oxidizing of the SH groups.
This SH oxidation produces intermolecular cross-links that underlie
ROS-induced protein oligomers (70, 80, 88). The physical changes in the
structure of the channel and pump proteins modify the function of the
transporting proteins and/or the availability of regulatory
sites on these proteins. It has been proposed that
H2O2
modifies the redox state of the channel protein in such a way that
oxidation of the cysteines involved in the "ball" and
"chain" mechanism that gate the channel occurs (173). Jamme et
al. (80) suggested that, during exposure to ROS-generating systems, the
Na+-K+-ATPase
forms cross-links without the isoforms of the 90-kDa -catalytic subunit and thus modifies the affinity and accessibility to the regulatory sites on this pump. Physical changes that modify ion transport mechanisms could also be brought about via ROS-induced changes in the properties of the phospholipids. The affinity or the
accessibility of the ATP and ouabain binding sites could be modified by
alteration in membrane integrity and fluidity during ROS-induced lipid
peroxidation.
ROS mimic SH-oxidizing agents. It has been found that the SH-oxidizing agents H2O2 or DTNB prevent Ag+ contractions and Ag+ inhibition of E-C coupling in single skeletal muscle fibers from R. temporaria or R. catesbeiana and that these effects were reversible with the SH-reducing agents (125). The RyR Ca2+-release channels can also be enhanced by ROS and SH-oxidizing agents that induce Ca2+ release (Table 1 and Refs. 76, 145, 170, 188).
The oxidation state of ion transport proteins does not simply favor an active state, and the reduced state does not favor an inactive state. For example, oxidization of SH groups by DTNB reversibly increased the activity of maxi-KCa channels in rabbit pulmonary and ear arterial smooth muscle cells (128), whereas oxidation induced inhibition of this channel that could be activated with GSH in equine tracheal myocyte (178). SH oxidation with DTNB and thimerosal also inhibited KCa channels (18) and the ATP-regulated K+ channel in pancreaticSH-reducing agents reverse ROS action. ROS-induced changes that have been reported to be reversed with SH-reducing agents, e.g., DTT, include 1) H2O2-induced increase in Po of RyR in both cardiac and skeletal muscle (46, 124), 2) H2O2-induced decline in activity of Ca2+-activated K+ channels (18), 3) H2O2-induced depression in the Ca2+ pump (86, 87), 4) UV-C-generated · OH and peroxyl (ROO ·)- or H2O2-induced inhibition of Na+-K+-ATPase (80, 85), and 5) H2O2-induced inhibition of the Na+/Ca2+ exchanger (88). Cysteine block of ROS-induced inhibition of the SR Ca2+ pump also suggests the involvement of SH groups (164). In addition, ROS-induced mechanical dysfunction, due to impairment of Ca2+-ATPase, is prevented by SH-reducing DTT (38, 39, 46). It is assumed that SH-modifying agents act on ROS-induced disulfide by dissociating the H2O2-induced disulfide-linked RyR protein complex (45). However, the possibility that DTT has its own effect cannot be ruled out. Cai and Sauvé (18) suggested that oxidation of KCa channels by H2O2 forms disulfide bonds that differ from those induced by SH oxidation with DTNB and thimerosal.
Localization of the SH groups for ROS action.
Localization of the SH groups on which ROS action occurs is achieved by
using SH-modifying agents that differ in their pharmacological properties. The studies in which the poorly membrane-permeable thimerosal and the charged DTNB oxidizing agents were used suggest that
H2O2
inhibits KCa channels by
interacting with SH groups that are localized on the cytoplasmic side
of the channel (see Ref. 18). On the other hand, rose bengal, a
ROS-generating system that reverses the blocking effect of ryanodine
(see Ref. 185), has an action that suggests a competition between ROS
and ryanodine on a binding site that contains some SH groups.
N-(7-dimethylamino-4-methyl-3-coumarinyl)maleimide labeling of cysteine indicates that this binding site (its oxidized SH
groups keep the RyR in the active state) is embedded in the membrane
away from the cytoplasmic side of the membrane (124). It is not known
whether such differences in the localization of SH groups, cytoplasmic
vs. internal, may account for differences in the proposed mechanisms of
ROS action. The differences in the sensitivity of ion transport
pathways to ROS-generating systems may be due to preferential binding
of ROS to the SH groups of amino acids in the transport proteins (61).
There is also evidence that indicates the presence of different sites
underlying ROS-induced modifications in ion transport pathways. The
opposite effects of
H2O2
(inhibition) and DTDP (activation) on the gating of the SCl channel
suggest that these oxidizing agents have different binding sites on the
channel protein. Krippeit-Drews et al. (100, 101) reported that DTNB
inhibited both Ca2+ and
KATP currents, whereas
H2O2
had no effect on the Ca2+ current
while it enhanced the KATP
current. These data point to the presence of another mechanism, other
than SH oxidization, that may also be responsible for modulating ion
channels. The presence of such different mechanisms may explain the
opposite effects of
H2O2
(12) and of
1O2
and O2 radicals (69)
observed on the RyR Ca2+-release
channel. There is also evidence that the SH group modulating ATP-sensitive channels may be close to the ATP binding site. ATP inhibition of the K+ channel
prevents the irreversible inhibitor NEM from reaching critical SH
groups (179). Similarly, ATP inhibition of the SCl channel prevents the
oxidizing agent DTDP from activating the channel (unpublished
observations).
Other SH-modulated transport proteins.
Some of the ion channels that are modulated by SH reagents have also
been modulated by ROS in accordance with the SH hypothesis. One would
expect that all ion channels and pumps that are modulated by
SH-reducing and SH-oxidizing agents would also be modulated by ROS and
the oxidation-reduction state in vivo. However, it should not be
assumed that ROS would act in a manner similar to SH-oxidizing agents.
As indicated above, there is evidence, contrary to such similarities,
pointing to different mechanisms of actions. Some of the ion channels
that are modulated by SH reagents, and not yet examined for ROS
effects, include fast transient K+
(IK(A))
channels (141), diphtheria toxin channels (116), and reduced human
skeletal macroscopic Cl
current (hClC-1) (105).
Changes in Ca2+ Homeostasis
Intracellular Ca2+ is an important second messenger system, and various cells maintain Ca2+ homeostasis. ROS-induced functional abnormalities in cardiac muscle are thought to be linked to an increase in [Ca2+]cyt (see Refs. 49 and 51), which has been confirmed with the fura 2 technique (16, 63). The broad effects of ROS can also be explained in terms of changes in the Ca2+ second messenger system. In cardiac tissue, the elevation of cytosolic Ca2+ (Ca2+ overload) is linked to various functional abnormalities, e.g., contractile dysfunction and ventricular arrhythmia, associated with ROS-induced tissue damage during ischemiareperfusion (51). ROS-induced changes in [Ca2+]cyt homeostasis of muscles in general could be mediated via depression in sarcolemmal Ca2+-ATPase, inhibition in SR Ca2+-ATPase (Table 7), modification in the gating of SR Ca2+-release channels (Table 2), changes in the Na+/Ca2+ exchanger (Table 9), or nonspecific Ca2+ leakage across membranes (see Ref. 161). The changes in Ca2+ homeostasis need not be directly due to ROS-induced modifications in Ca2+ pathways but may also arise indirectly via modifications in other ion pathways. Cai and Sauvé (18) have argued that H2O2 may modulate agonist-induced Ca2+ influx, activating nitric oxide synthase, which metabolizes L-arginine to citrulline and nitric oxide, indirectly via depolarization in the membrane potential due to H2O2-induced inactivation of KCa channels. The role of HOCl in increasing intracellular Ca2+ homeostasis (46) is partly due to its effects on both the sarcolemmal Na+/Ca2+ exchanger (88) and the Na+-K+-ATPase (103, 114). In fact, some Ca2+ pathways are ruled out as a cause for changes in Ca2+ homeostasis. For example, the irreversible free-radical-induced decrease in Ca2+ currents in ventricular myocytes suggests that cellular Ca2+ overload during reperfusion is unlikely to be due to an increase in the sarcolemmal Ca2+ influx via voltage-gated Ca2+ channels (48). Regarding the contribution of other Ca2+ pathways to changes in Ca2+ homeostasis, Elmoselhi et al. (43) found that the Ca2+ pump contributing to the IP3-sensitive pool was damaged by H2O2 and OLipid Peroxidation
In addition to the direct effects of ROS on ion channels and pumps underlying the transmembrane signaling mechanism (see Ref. 181), ROS alter compartmentation and ionic homeostasis, via membrane phospholipids, leading to alteration in membrane function (16). It is important to distinguish between two possible consequences of ROS-induced lipid peroxidation. The first possibility is that ROS-induced lipid peroxidation leads to a nonspecific leak of some pathway in the lipid itself, which consequently results in a modification of Ca2+ homeostasis. The second possibility is that ROS-induced lipid peroxidation modifies the physical properties of phospholipids in such a way that some proteins of ion channels, pumps, exchangers, and/or associated proteins that regulate these transport pathways are altered. The first possibility can be ruled out, since there is overwhelming evidence suggesting that ROS induce specific effects on ion transport pathways (see Tables 1-9). The second possibility cannot be ruled out, as it does not exclude the possibility of direct ROS effects on proteins of the ion transport pathways. There is evidence for ROS-induced membrane peroxidation that causes membrane malfunction. Guerra et al. (58) found that anti-lipoperoxidant partially prevented DHF-induced reduction in the DHP binding sites and that the protectant thiourea (an · OH scavenger) prevented lipoperoxidative damage (80). It has also been demonstrated that the Na+/Ca2+ exchanger is sensitive to lipid composition (10) and is enhanced by increasing cholesterol content (106). Similarly, the Na+-K+-ATPase is activated by fatty acids, acylglycerols, and related amphiphiles (79). It has also been reported that membrane lipid peroxidation by t-BHP modified the physiological automaticity by impairing cellular metabolic functions and damaging lipid membrane structure and ion channel proteins (147).The mechanism of ROS-induced membrane peroxidation involves biochemical
changes that alter the physical properties and inactivate membrane-bound enzymes that regulate membrane permeability. Indeed, loss of endothelial cells, which are a major source of
reperfusion-generated free radicals, has been found to be associated
with increased formation of lipid peroxidation products, such as
malondialdehyde and lipid peroxides (see Ref. 98). There is evidence
that lipid peroxidation subsequently leads to alterations in
Ca2+ homeostasis (see Ref. 63).
For example, t-BHP augments and subsequently attenuates Ca2+
currents in rabbit sinoatrial node and nodal isolated cells. Modification by t-BHP of
Ca2+ homeostasis has also been
deduced from an increase in resting tension (122). Therefore, lipid
peroxidation has been invoked as a mechanism underlying some diseases.
For example, Butterfield et al. (17) reported that -amyloid peptide
free radical fragments initiated synaptosomal lipoperoxidation that has
been implicated in Alzheimer's disease.
Oxidative Phosphorylation and ATP Levels
In endothelial cells there is evidence showing that ATP levels decline under conditions of oxidative stress or H2O2-induced inhibition of glucose-dependent pathways of ATP synthesis (68). Obviously, ATP-sensitive, e.g., KATP channels, or ATP-modulated transport pathways, e.g., Ca2+ and Na+ pumps, are likely to be modified if the ATP levels are significantly reduced either 1) directly via ROS-induced effects on the metabolism of ATP production or 2) indirectly via ROS-induced splitting of the ATP to ADP and phosphate (see Ref. 169). It has been reported that H2O2 inhibits the glycolytic pathway and oxidative phosphorylation (72), causing an increase in the activity of the KATP channel (50, 123). However, the relationship between a decrease in ATP levels and cellular dysfunction is not clear (148). There is evidence showing that cytotoxicity is not coupled to ATP levels. For example, desferrioxamine, an iron chelator, and allopurinol and oxypurinol (XO inhibitors) prevent H2O2 cytotoxicity but not a decrease in ATP levels in pulmonary endothelial cells (172). Similarly, after ischemia the ATP level recovers on reperfusion, whereas Na+-K+-ATPase and the glycoside binding sites continue to decrease (see Refs. 82 and 90).At the ion channel level, the X/XO- and
H2O2-induced
increase in the
Po of
KATP channels recorded in the
cell-attached configuration results from a reduction in ATP level due
to irreversible inhibition of oxidative phosphorylation and glycolysis
rather than to a reduction in the channel sensitivity to ATP (51).
However, observations similar to those found in the cell-attached
configuration (51) and in the inside-out configuration (32) have been
attributed to a direct effect on the ATP sensitivity of the channel,
thus ruling out inhibition of oxidative phosphorylation and glycolysis (169). These differences are thought to be due to
1) differences in
Mg2+ concentration levels, which
affect KATP channels (169), and 2) differences in ROS-generating
systems, i.e., X/XO producing O2
(169) and
H2O2/FeCl2
producing · OH (32).
Changes in pH
It is known that oxidant stress can modify some pH regulatory mechanisms (see Ref. 14). Subsequently, this causes changes in intracellular pH, which can influence various ion transport mechanisms, such as inactivation of enzymes, damage to Na+-K+-ATPase (90), and modification of Ca2+-release channels (110, 139) and sarcolemmal Cl ![]() |
ROS AS SECOND MESSENGERS IN ION TRANSPORT PATHWAYS |
---|
Recent reports suggest that ROS, or at least
H2O2,
may function as second messenger systems. It has been proposed that
H2O2 modulates a complex of heme-linked NADPH oxidase protein coupled to
K+ channels that function as an
oxygen sensor mechanism in airway chemoreceptors of small lung
carcinoma cell lines (176). Closure of this
K+ channel induces membrane
depolarization and enhances Ca2+
influx that could cause the release of transmitters or modification of
spike duration and frequency (176). It is assumed that, for H2O2
to play a second messenger role, a specificity to
H2O2
modulation must be achieved, as well as sufficient concentrations of
H2O2 accumulated, before it is destroyed by
H2O2
scavengers in a highly reduced cellular environment, e.g., the presence
of 1 mM GSH (see Refs. 83, 173, 189). Another channel that is modulated
by ROS in a second messenger manner is the SCl channel. Pharmacological and biophysical studies indicate the presence of an
O2-sensing mechanism (GSH-GSSH) on
the SCl channel protein (95) that is also modulated by
H2O2
(unpublished observations). It remains to be seen whether the
O2-sensitive
K+ channel of the arterial
chemoreceptor that is modified by low PO2 (47) is
sensitive to ROS. It has been reported that an anion channel allows
· O2 permeation into
human amnion cells, which consequently causes increases in
1) cytosolic pH, 2)
[Ca2+]cyt,
and 3) release of arachidonate (74).
The interaction of ROS with other second messenger systems could also
lead to changes in Ca2+ levels,
e.g.,
H2O2-induced
activation of phospholipase A2 and arachidonic acid metabolic pathways (21, 22).
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CONCLUSIONS |
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![]() ![]() ![]() ![]() ![]() |
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The well-accepted ROS-induced cardiac dysfunction during ischemia and perfusion, cardiomyopathies, neurotoxicity, inflammation, and aging involves the disruption of various ion transport pathways underlying electrophysiological functions. ROS modify ion transport mechanisms either directly via ion transport pathway proteins and/or ion transport regulatory proteins or indirectly via peroxidation of membrane phospholipids. The nature and sequence of events that lead to the disruptions of these ion transport pathways are not fully understood. ROS-induced modification of SH groups on ion transport proteins leads to changes in the homeostasis of Ca2+, a major second messenger system, and perhaps other cytosolic factors. The order of potency and the primary mechanism of cell dysfunction for individual ROS are yet to be determined. The potency of individual ROS and the ion transport mechanism that they primarily affect depend on various factors that include types of tissue. It is obvious, therefore, that such understanding is important for the development of specific drugs for individual ion transport proteins. ROS scavengers, e.g., superoxide dismutase and catalase, thiol-disulfide modifying agents, and Ca2+ channel modulators, are the bases for therapeutic approaches in free radical-induced ischemic and reperfusion myocardial injury. The cloning of ion transport protein isoforms, utilization of specific antibodies and molecular probes, and direct mutations of specific sites, will enable us to characterize the SH-oxidization sites and enhance our understanding of the structure-function relation for individual transport proteins.
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ACKNOWLEDGEMENTS |
---|
I thank Roger McCart for numerous discussions, suggestions, and critical reading of the manuscript. I also acknowledge Drs. Gunasegaaran Karupiah and Mal Rasmussen for commenting on the manuscript.
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FOOTNOTES |
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This research work was supported by National Health and Medical Research Council of Australia Project Grant 970122.
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