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Department of Biochemistry, University of Missouri, Columbia, MO 65211
2To whom correspondence should be addressed.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • zinc status • osmotic fragility • sulfhydryl concentration • band 3 • zinc binding • rats
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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).
It has been postulated that the first limiting role is related to the
function of zinc in the plasma membrane of cells (Bettger and O'Dell 1993
). The concentration of zinc in the erythrocyte
membrane is decreased while that in the cytosol is not (Bettger and Taylor 1986
). Erythrocytes from zinc-deficient rats are
more subject to hypotonic hemolysis, i.e., osmotic fragility, than
normal, and the defect is reversed within 1 d by oral zinc
supplementation (O'Dell et al. 1987
). Platelets
(O'Dell and Emery 1991
, Xia and O'Dell 1995
) and synaptic vesicles prepared from brain cortex
(Browning and O'Dell 1994
) and hippocampus
(Browning and O'Dell 1995b
) from zinc-deficient animals
take up calcium at a slower rate than normal. The basis of this
apparent impairment of calcium channel function is unknown, but it may
relate to a protective function of zinc in the plasma membrane.
Many enzymes and ion channels in plasma membranes contain cysteine
residues that are essential for function. Among the thiol-containing
proteins found in plasma membranes are Na,K-ATPase (Lingrel and Kuntzweiler 1994
), Ca-ATPase (MacLennan et al. 1985
), 5'-nucleotidase (Zachowski et al. 1981
),
the anion exchanger, band 3, of erythrocyte membranes (Lux et al. 1989
), the water channel, aquaporin (Preston et al. 1993
, Zhang et al. 1993
), the voltage-gated
calcium channel (Murphy et al. 1990
), and the
N-methyl-D-aspartate
(NMDA)3
calcium channel (Reynolds 1990
). Sulfhydryl (SH)
reactive reagents and mild oxidation impair the functions of
Na,K-ATPase (Kirley et al. 1986
, Chan et al. 1977
), Ca-ATPase (Nicotera et al. 1985
), band 3
(Ojcius and Solomon 1988
), aquaporin (Preston et al. 1993
, Zhang et al. 1993
), the voltage-gated
calcium channel (Chiamvimonat et al. 1995
), and the
NMDA-calcium channel (Reynolds 1990
). Zinc deficiency
also impairs activity and function of Na,K-ATPase (O'Dell et al. 1990
), Ca-ATPase (Johanning et al. 1990
),
5'-nucleotidase (Johanning et al. 1990
), and functional
NMDA-calcium channels in synaptosomes (Browning and O'Dell 1995a
).
Whether the association of zinc status and impairment of membrane-bound
enzymes and ion channel proteins is related to the state of free SH
groups is not known, but there are models of such cause-and-effect
relationships. The enzyme, 
-aminolevulinate dehydratase, contains
both zinc and SH groups, the latter being essential for enzyme
activity. Zinc per se is not essential, but it is required for
protection of the thiols from air oxidation (Bevan et al. 1980
, Tsukamoto et al. 1979
). Zinc also protects
the SH groups of metallothionein from oxidation (Jacob et al. 1998
and cited references). Based on these models, it is
reasonable to postulate that zinc protects essential SH groups in
plasma membrane proteins. Erythrocyte ghosts are well-studied plasma
membranes and offer a good model to explore the relationship of zinc
status, membrane function, and membrane protein SH concentration. The
purpose of this study was to compare osmotic fragility of rat red blood
cells and the plasma membrane protein SH concentration during the
induction of zinc deficiency and repletion. Corollaries to this
objective were the measurement of thiol concentration in band 3 protein
and the zinc-binding affinity of erythrocyte membrane proteins.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Male rats of Wistar origin, weighing 120–140 g, were obtained from the
departmental colony. They were housed individually in suspended,
stainless-steel, wire-mesh cages in a room maintained at 22 ±
1°C and with a 12-h light-dark cycle. Rats were assigned to dietary
treatments for various lengths of time, as described for the individual
experiments below; the numbers of rats in each group of the respective
experiments are indicated in the Result section. The basal diet was
similar to the one used previously (O'Dell et al. 1983
), which was based on EDTA-treated soy protein. In the
present study the methionine supplement was 0.4% and the corn oil
level was 10%. Deionized water was consumed ad libitum. The
experimental protocol was approved by the Animal Care and Use
Committee, University of Missouri, Columbia.
Experiment 1.
This experiment was designed to correlate osmotic fragility of erythrocytes with the SH concentration of their plasma membrane proteins. Groups of three rats were replicated in time, one fed free choice the basal, low-zinc diet (-ZnAL), which contained less than 1 mg Zn/kg diet, one fed free choice the control, adequate zinc diet (+ZnAL), which contained 100 mg of Zn/kg diet, and one fed the amount of control diet consumed the previous day by a -ZnAL pair-mate (+ZnPF). Rats were maintained on the three dietary regimens for 21 d, and tail blood was drawn to measure hemolysis and SH concentration. All rats then consumed the control diet ad libitum for 2 d, and blood was taken to repeat the fragility and SH measurements and for the determination of plasma zinc.
Experiment 2.
This experiment was designed to determine the time course of zinc depletion as measured by osmotic fragility and erythrocyte membrane SH concentration. One group of rats was fed the low-zinc diet and one pair-fed the control diet. Blood was collected at 3, 6, 9, 12, and 15 d.
Experiment 3.
This experiment was designed to extend the observations relating reduced SH concentration in the total membrane to a specific protein, band 3. Rats were maintained as in experiment 1 for 21 d, and blood was collected. Band 3 protein was isolated from erythrocytes of rats on all three dietary treatments for determination of SH content. In addition, erythrocyte ghosts were prepared from -ZnAL and +ZnPF rats for zinc-binding assays.
Preparation of erythrocyte membranes and of band 3 protein.
Approximately 5 mL of blood was drawn from the abdominal aorta of
ether-anesthetized rats using syringes and tubes that had been rinsed
with heparin [106 U/L of phosphate buffered saline (PBS)]
to serve as anticoagulant. Erythrocytes were separated from plasma by
centrifugation at 400 x g for 10 min at room
temperature. After removal of the buffy coat, they were transferred to
another tube and washed twice with 10 vol of PBS (150 mmol/L NaCl in 5
mmol/L phosphate, pH 7.4) and collected by centrifugation at
10,000 x g for 10 min at 4°C. At this stage they
were referred to as washed erythrocytes. Erythrocyte membranes or
ghosts were prepared as described (Johanning and O'Dell 1989
, Steck and Kant 1974
). Briefly, the washed
erythrocytes were lysed with 15 vol of 5 mmol/L of phosphate buffer (pH
8.0) and subsequently washed five additional times with the same lysing
buffer. Membranes were collected after each wash by centrifugation at
4°C for 10 min at 10,000 x g. This procedure yielded
approximately 1 mg of protein per mL of blood, as measured by the Lowry
method, using bovine serum albumin as standard. The membranes for the
zinc-binding assay were resuspended in an assay buffer (Tris-HCl, 10
and NaCl, 150 mmol/L, pH 7.4) and stored at -20°C for several
months.
Band 3 protein was prepared as described (Yamaguchi and Kimoto 1992
). Briefly, erythrocyte ghosts were prepared as described
above and then extracted with 9 vol of 0.1 mol/L NaOH for 30 min at
4°C. The insoluble fraction containing band 3 was collected by
centrifugation at 56,000 x g for 30 min at 4°C. The
protein was >95% pure by SDS-PAGE analysis.
Determination of membrane protein SH concentration.
The concentration of SH groups in the membrane proteins was measured
colorimetrically as described (Habeeb 1972
). Briefly,
1.5 mL of pH 8.0 buffer (0.08 mol/L sodium phosphate, 0.5 mg/mL of
Na2-EDTA, and 2% of sodium dodecylsulfate, SDS) was added
to each assay tube followed by 0.2 mL of membrane suspension containing
~120 µg of protein. After vortexing, 0.1 mL of
5,5'-dithio-bis(2-nitrobenzoic acid) (DTNB; 20 mg in 10 mL of 0.1 mol/L
sodium phosphate buffer, pH 8.0) was added, and the solution vortexed
again. Color was allowed to develop for 15 min at room temperature and
absorbance measured at 412 nm, using an equivalent concentration of
protein as the blank. The reagent blank was deducted from the total
absorbance. SH concentration was calculated from the net absorbance and
the molar absorptivity, 13,600 (mol/L)-1cm-1.
Measurement of osmotic fragility.
The procedure was similar to that described earlier (O'Dell et al. 1987
) except that washed cells were used. A 100-µL
aliquot of a washed (twice with 10 vol of PBS) erythrocyte suspension
(0.10 hematocrit) was added to a series of tubes containing 2.5 mL of
saline solution (3.8 g/L; 64 mmol/L in 5 mmol/L phosphate buffer, pH
7.4). These tubes were allowed to stand at room temperature for 15 min,
centrifuged to pellet the cells, and the absorbance of the supernate
measured at 540 nm. Also included were control tubes that contained 8.5
or 0 g of NaCl/L to provide values for inherent and maximal
hemolysis, respectively.
Measurement of zinc binding.
Binding parameters were calculated by Scatchard analysis of saturation
binding assays using the Ligand program (Munson 1992
).
65Zn, specific activity 0.3 TBq (8 Ci)/mol, was added to
duplicate tubes containing 50 µg of membrane protein in 0.5 mL of
assay buffer. Graded concentrations, ranging from 5000 cpm (167 Bq) to
150,000 cpm (5kBq) were used. To measure nonspecific binding, zinc
sulfate (0.125 mmol/L final concentration) was added to duplicate tubes
containing the respective 65Zn concentrations. Tubes were
held at 5°C for 18 h and the membranes harvested by a
combination of centrifugation and filtration on a cell harvester
(Brandel, Gaitherburg, MD), according to the method of Rogart (1986)
. Glass fiber filters were pretreated with 0.1%
polyethyleneimine, and the buffer used to wash the filters contained
1 g of bovine serum albumin/L; both treatments were used to
decrease nonspecific binding of zinc to the filter.
Statistical analysis.
Osmotic fragility and SH data (experiment 1, Figs. 1 and
2
) were
analyzed by repeated measures analysis of variance, using the (GLM)
procedure of SAS. Time-course data (experiment 2, Figs. 4 and
5
) were
analyzed as a 2x5 factorial using GLM, with two levels of dietary zinc
and five time periods. Zinc status data (Table 1
)and band 3 SH data (experiment 3, Fig. 6
) were analyzed by one-way
analysis of variance. Post-hoc mean comparisons for the above were
completed using the LSMEANS component of GLM. Zinc-binding parameters
(experiment 3, Fig. 7
) and fragility/SH correlation data were analyzed
using the t-test (nonparametric) and linear regression components of
Microsoft Excel 97, respectively. Statistical significance was set at
P < 0.05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. Within 3 d of consuming
the low-zinc diet, the serum zinc concentration had decreased to 25%
of the level in pair-fed controls where it remained throughout the
trial (data not shown).
Osmotic fragility, as assessed by hemolysis in 3.8 g/L (64 mmol/L) of
saline, was significantly greater in erythrocytes from zinc-deficient
rats, and the abnormality was completely reversed within 2 d in
depleted rats that consumed the zinc-adequate diet (Fig. 1
).The SH concentration of erythrocyte membranes prepared from the same
blood was decreased by zinc depletion and returned to control levels
upon repletion (Fig. 2
).These indices of zinc status were inversely related (Fig. 3,
P < 0.001).
|
).As shown in Figure 5,
the SH concentration in the membranes followed a similar pattern except
that the SH concentration reached its nadir within 6 d and
remained constant thereafter.
Not only was the total membrane protein SH concentration decreased by
zinc deficiency, but the concentration in band 3 protein was decreased
to the same extent (Fig. 6
).Analysis of zinc-binding data (Fig. 7
)using the Ligand program was consistent with a single-binding site for
zinc. There was a tendency for decreased affinity (Kd, 3.5
vs. 1.4; P = 0.10) in the plasma membrane proteins from
zinc-deficient rats compared to those from pair-fed controls. There was
no difference in binding capacity (Bmax).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). The zinc concentration in the red
cell plasma membrane of zinc-deficient rats is decreased although that
of the whole cell is not changed measurably (Bettger and O'Dell 1993
). In the present study blood was drawn at the end of a
21-d depletion period and again from the same rats after 2 d of
zinc repletion, i.e., after consumption of the zinc-adequate diet for
2 d. Because of this short time interval and the fact that mature
erythrocytes do not synthesize protein, the prompt reversal shows that
the abnormality arises from a post-translational modification of
membrane proteins. That the modification is readily reversible by zinc
in vivo but not in vitro suggests that correction of the malfunction
requires not only zinc but another condition, such as a reduction of
disulfide bonds, i.e., reduction of cystine to cysteine residues. Since
the abnormality was not reversed by addition of zinc or glutathione in
vitro (O'Dell et al. 1987
), in vivo reversal probably
requires a metabolic process that promotes reduction in the presence of
zinc, perhaps a particular species of zinc.
The concept that a physiological concentration of zinc in the
micro-environment protects membrane proteins against post-translational
oxidation of SH groups to disulfides, leading to increased osmotic
fragility, is analogous to that used to explain zinc's function in
well-defined metalloproteins. Bevan et al. (1980)
and
Tsukamoto et al. (1979)
observed that removal of zinc
from -aminolevulinate dehydratase in the presence of oxygen caused
loss of enzymatic activity but not in its absence. Addition of zinc to
the oxidized form of the enzyme did not restore activity, but it did
restore activity after reduction of disulfide bonds in the enzyme. Zinc
protected essential SH groups at the active center of the enzyme. When
zinc is removed from metallothionein, the resulting apo-protein,
thionein, is extremely sensitive to oxygen, but it is quite stable when
its SH groups are complexed with zinc (Jacob et al. 1998
). The results presented here show a strong inverse
relationship between membrane SH concentration and osmotic fragility of
erythrocytes when zinc status varies; both parameters are affected by
zinc status but in opposite directions. The SH concentration of
membrane proteins decreased by zinc deficiency is rapidly reversed by
zinc repletion, in concert with the opposite change in osmotic
fragility. Both increased fragility and decreased SH concentration
occurred within 6 d after the rats consumed the low-zinc diet, and
in this experiment both returned to normal within 2 d of dietary
repletion. Changes in plasma zinc concentrations preceded change in
these parameters (data not shown), suggesting that the free-zinc
concentration in the membrane environment plays a key role in the
protection of membrane proteins from oxidation of essential SH groups.
The relative small decrease in SH concentration in total membrane protein, or in band 3, does not detract from its potential importance in malfunction. The functionally critical SH group(s) likely constitutes a very small proportion of the total SH groups measured in the whole membrane protein. In this regard it is important to note that the affected SH are revealed only after solubilization of the membranes with SDS; there was no observed difference in the SH concentrations of intact or unmasked membranes. Without SDS solubilization only 40% of the total SH groups were detectable (data not shown). Thus without solubilization the critical SH group(s) are masked to DTNB detection.
The loss of hemoglobin by erythrocytes exposed to hypotonic solutions
results from swelling and stretching due to water uptake. Volume
recovery and the prevention of hemolysis require the efflux of water
associated with efflux of K+ ions (Pierce and Politis, 1990
). Band 3 protein in erythrocyte membranes
catalyzes the exchange of inorganic anions and facilitates the movement
of water (Low 1986
). This 95k-Da protein makes up about
25% of the total membrane protein with ~106 copies per
cell. Band 3 contains six SH groups, and treatment of erythrocytes with
p-chloromercuribenzenesulfonate inhibits water flux by
reaction with one specific SH group of the six (Ojcius and Solomon 1988
). Toon et al. (1985)
found that
DTNB binds covalently to two sites on band 3 that are not bound by
another SH reagent, N-ethylmaleimide (NEM). DTNB inhibits
water transport by binding to another site with low affinity. Thus, the
water channel function of band 3 protein is impaired by thiol reagents
that bind one SH group; this SH may be involved in the osmotic
fragility of erythrocytes from zinc-deficient rats. While the decrease
in concentration of SH in band 3 protein is relatively small, the
change may well be sufficient to account for the impairment.
The efflux of water in the volume recovery process requires the efflux
of K+, a process associated with an increase in cytosolic
calcium (Pierce and Politis 1990
). This suggests that
calcium uptake is involved in the process via calcium-activated
K+ channels. Calcium uptake is impaired by zinc deficiency
in other membrane systems. Platelet malfunction, including impaired
aggregation and the associated decrease in calcium uptake, occurs in
zinc-deficient rats (O'Dell and Emery 1991
, Xia and O'Dell 1995
). Relative to the present discussion, it is
significant that platelet membranes from zinc-deficient rats also have
a decreased concentration of SH groups, and deficient platelet function
is restored to normal by incubation of blood with glutathione in vitro
(O'Dell et al. 1997
). Calcium uptake is impaired also
by zinc deficiency in another membrane system, namely brain synaptic
vesicles (Browning and O'Dell 1994
, 1995a
). Adequate-free
zinc in the plasma membrane environment protects critical SH groups in
calcium channels of other cells (Chiamvimovat et al. 1995
), giving credence to the concept that zinc exerts a
general effect in the protection of plasma membrane proteins against
autoxidation.
The zinc-binding affinity of membrane proteins would be expected to
decrease with loss of SH groups as occurs in zinc deficiency. Zinc
binds with highest affinity to cysteine residues and with decreasing
affinities to histidine and carboxylic amino acid residues. Removal of
an SH ligand from tetrahedral binding sites that also involve ligands
of lower affinity would decrease total binding affinity without
necessarily decreasing the total number of binding sites. Oxidation of
SH groups could also lead to a change in protein conformation, thereby
resulting in loss of binding sites and affinity. The data presented
here suggest that the binding affinity is decreased, without a change
in the number of binding sites. The Kd of control membranes
was ~1 µmol/L, a value that appears to be in a physiologically
significant range. This Kd value differs substantially from
that obtained for human erythrocyte membranes (Brandao-Neto and Bell 1994
). The latter workers, using a displacement assay,
found two binding sites with dissociation constants of 14.6 and 103
µmol/L in erythrocyte membranes that had been stored frozen.
In conclusion, there is a strong negative relationship between osmotic fragility and concentration of SH groups in the proteins of erythrocyte membranes from rats of different zinc status. The decrease in total membrane SH concentration of zinc-deficient rats is reflected in a major membrane protein, band 3. It appears that one of the first systems to fail in zinc deficiency is the loss of critical SH groups in proteins of the red blood cell plasma membrane, a defect that is readily reversible in vivo. The increased osmotic fragility of zinc-deficient erythrocytes probably results from impairment of water transport, calcium uptake, or both. Either or both of these processes may be affected the SH redox state, but the precise metabolic defect is unknown.
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FOOTNOTES |
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2 Abbreviations used: DTNB,
5,5'-dithio-bis(2-nitrobenzoic acid); GLM, general linear models; NEM,
N-ethylmaleimide; NMDA,
N-methyl-D-aspartate; PBS, phosphate-buffered
saline; SDS, sodium dodecyl sulfate; SH, sulfhydryl or thiol group;
-ZnAL, low-zinc diet fed free choice; +ZnAL, adequate zinc diet fed
free choice; +ZnPF, adequate-zinc diet pair-fed.
Manuscript received September 11, 1998. Initial review completed November 3, 1998. Revision accepted December 21, 1998.
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;
-ZnAL, replete 2 d, 
; +ZnPF, 21 d, 
; +ZnPF replete
2 d, 
; +ZnAL, 21 d, 
; +ZnAL, replete 2 d, 
. The
variables were correlated, P < 0.001;
r = 0.550. Y = -0.28X + 81.6.