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(Journal of Nutrition. 2000;130:1432S-1436S.)
© 2000 The American Society for Nutritional Sciences

Supplement

Role of Zinc in Plasma Membrane Function1

Boyd L. O’Dell

Department of Biochemistry, University of Missouri, Columbia, MO 65211


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 Alterations in the composition...
 REFERENCES
 
The concentration of plasma zinc is the generally accepted index of zinc status. Although low plasma zinc is an essential criterion of deficiency, alone it is inadequate. To supplement this index, we sought to determine the first limiting biochemical defect in animals fed zinc-deficient diets and concluded that the limiting function is associated with a posttranslational change in plasma membrane proteins. Among the signs of zinc deficiency in rats is a bleeding tendency associated with failure of platelet aggregation, a phenomenon that correlates with impaired uptake of Ca2+ when stimulated. Zinc-deficient guinea pigs exhibit signs of peripheral neuropathy, and their brain synaptic vesicles exhibit impaired Ca2+ uptake when they are stimulated with glutamate. Red cells from zinc-deficient rats show increased osmotic fragility associated with decreased plasma membrane sulfhydryl concentration. Both phenomena are readily reversed (2 d) by dietary zinc repletion. Volume recovery is dependent on Ca-dependent K channels and the sulfhydryl redox state. Both the impaired aggregation and calcium uptake of zinc-deficient platelets are corrected by in vitro incubation of blood with glutathione. Considering the fact that plasma membranes from several cell types show impaired function that is associated with a decreased rate of calcium uptake, it is postulated that a defect in calcium channels is the first limiting biochemical defect in zinc deficiency. The calcium uptake defect and consequent impaired second-messenger function likely results from an abnormal sulfhydryl redox state in the membrane channel protein.

KEY WORDS: • zinc status • biochemical defect • sulfhydryl redox state • calcium channels • osmotic fragility • rats


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
Alterations in the composition...
 REFERENCES
 
After years of searching for an adequate index of zinc status in adult humans, investigators have not found a more efficacious measure than plasma zinc concentration. Although plasma zinc is a valuable and essential criterion of zinc status, it is by itself inadequate, because there are other physiological factors that affect plasma zinc concentrations. Zinc plays many significant roles in metabolism and is a component of numerous metalloenzymes and transcription factors. As important as these zinc proteins are in metabolism, their concentrations and activities have not proved to be useful indicators of zinc status (Bettger and O’Dell 1993Citation ), and for a good reason. Because of their high affinity for zinc, metalloproteins are not the first biologically essential, zinc-dependent proteins to lose zinc when the extracellular medium is depleted, as occurs promptly when the dietary zinc intake is decreased. A goal of our laboratory has been to identify the first limiting biochemical defect that occurs during zinc deprivation, assuming that an estimate of this function would provide a valid index of zinc status. To be a useful index, a change in the biochemical indicator should occur before the appearance of gross signs of deficiency, and it should be relatively simple to measure.

This research goal led us to explore the functions of the plasma membrane in several different cell types. The plasma membrane is closely associated with the extracellular milieu, and at least in the case of the red cell, its zinc content decreases during zinc depletion and is readily restored on repletion. These changes in membrane zinc content are evident even though the measurable zinc concentration in the whole red blood cell remains unchanged (Bettger and Taylor 1986Citation , Johanning et al. 1989Citation , Johanning and O’Dell 1990Citation ). Decreased zinc concentration in the red cell membrane is associated with increased osmotic fragility of erythrocytes in rats (O’Dell et al. 1987Citation , Roth and Kirchgessner 1991Citation ) and pigs (Johanning et al. 1990aCitation ). The increased fragility is readily reversed in vivo by dietary repletion but not by in vitro zinc treatment (O’Dell et al. 1987Citation ). Erythrocytes from zinc-deficient rats also have an increased sensitivity to hemolysis induced by sodium dodecyl sulfate and melittin (Patterson and Bettger 1985Citation ). Erythrocyte fragility has been studied as an index of zinc status in humans (Woodhouse et al. 1996, 1998Citation ). In experimental subjects fed a purified, low zinc diet, there was increased osmotic fragility after depletion and return to normal on repletion. However, the response was slow. The biochemical defect involved in the response of red cells to osmotic stress is unclear, but it could involve the failure of synthesis of a critical membrane component or a posttranslational modification of a protein after normal synthesis.


   Alterations in the composition of plasma membranes
TOP
 ABSTRACT
 INTRODUCTION
 Alterations in the composition...
REFERENCES
 
Numerous studies have shown that zinc deficiency alters the composition of the plasma membrane. There are changes in lipid content (Driscoll and Bettger 1997, Johanning and O’Dell 1989Citation ) and altered protein composition of the membrane skeleton extracted in low ionic strength buffer (Avery and Bettger 1991). Enzyme activities associated with the plasma membrane are depressed as well. The catalytic activities of Ca-ATPase and 5' nucleotidase in erythrocyte membranes from rats and pigs were decreased by zinc deficiency (Johanning et al. 1990bCitation ). The rate of zinc uptake by zinc-deficient rat erythrocytes was increased (Van Wouwe et al. 1991Citation ), but there was no effect of deficiency on the uptake of glycine by oocytes or preimplantation embryos (Peters et al. 1993Citation ). Alkaline phosphatase activity was decreased in erythrocyte membranes of young men fed diets marginally deficient in zinc (Ruz et al. 1992Citation ). The increased fragility of erythrocytes appears to result from a specific plasma membrane defect; however, the question remains: What is the defect and is it general in nature, i.e., does it affect function in other cell types?

Besides the increased red cell fragility observed in experimental animals, there are numerous other gross signs of zinc deprivation. Some of the common pathological signs of zinc deficiency observed in experimental animals are listed in Table 1Citation . The question to be addressed here is whether there is a common denominator for the diverse pathology. Consider first the bleeding tendency in pregnant rats at parturition. Associated with increased bleeding tendency in the rat, there is impairment of platelet aggregation (Gordon and O’Dell 1980Citation , Emery et al. 1990Citation ). Calcium uptake from the extracellular medium is essential for the initiation of platelet aggregation, and that function is limited in platelets from zinc-deficient rats. When platelets are stimulated with any of several agonists, such as ADP (O’Dell and Emery 1991Citation ), fluoride (Emery and O’Dell 1993Citation ) or thrombin (Xia and O’Dell 1995Citation ), aggregation and calcium uptake are impaired. Figure 1Citation presents a model of the mechanism by which zinc deficiency impairs platelet function. As indicated in the model, protein kinase C (PKC)2 is an essential enzyme for platelet aggregation. Although PKC concentration is not limiting in zinc-deficient platelets (Xia et al. 1994Citation ), it is a calcium-dependent enzyme whose activity is affected by the calcium concentration in its environment. All aggregating agents tested increased internal calcium concentration, and the uptake of external calcium was impaired in zinc deficiency.


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  		Table 1. Pathological signs of zinc deficiency

 


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  		Figure 1. Model of the mechanism by which zinc deficiency impairs platelet function. Aggregation in response to stimulation with ADP, thrombin or fluoride is depressed in zinc deficiency. This is the result of failure to take up extracellular calcium, which serves as a second messenger. The increase in cytosolic calcium stimulates the activity of PKC, an enzyme whose activity is essential for aggregation.

 
Another dramatic sign of zinc deficiency in chicks and guinea pigs is an abnormal gait and stance caused by peripheral neuropathy (O’Dell et al. 1990Citation , 1990aCitation ). Analogous to the impaired platelet function, brain synaptic vesicles prepared from zinc-deficient guinea pigs exhibit depressed calcium uptake compared with control animals. The calcium uptake defect was observed most dramatically when the vesicles were first depolarized with potassium and then stimulated with the neurotransmitter glutamate (Browning and O’Dell 1994Citation , 1995Citation ). Figure 2Citation summarizes data showing the effect of zinc status on glutamate-stimulated calcium uptake by synaptosomes prepared from guinea pig brain cortex.



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  		Figure 2. Calcium uptake by glutamate-stimulated brain cortical synaptosomes from zinc-deficient guinea pigs is decreased. Guinea pigs were fed a low zinc diet (-ZnAL), a zinc-adequate diet ad libitum (+ZnAL) or the adequate diet restricted to maintain body weight comparable to -ZnAL (+ZnRF). The glutamate stimulus was added to synaptic vesicles in a depolarizing medium (45 mmol/L K+). (Data from Browning and O’Dell 1994Citation .)

 
Both platelets and neurons are excitable cells that might be expected to exhibit comparable responses to depolarization and to cell agonists. Importantly, similar observations have been made with nonexcitable cells, i.e., fibroblasts grown in culture. When these cells were deprived of zinc by the use of a cell-impermeant chelator, the total zinc content of the cells was unchanged but their uptake of calcium was impaired (unpublished data).

Is there a commonality between the defect in the red cell plasma membrane and that in the other cell types studied? Impairment of calcium uptake may well be the common thread. The hemolysis of red cells subjected to osmotic stress is the result of water uptake and the concomitant increase in volume. Volume recovery normally occurs via a mechanism that involves stretch activation of a membrane calcium channel, leading indirectly to activation of a Ca2+-dependent K+ channel and the attendant loss of potassium and water (Pierce and Politis 1990Citation ). This concept is depicted by the model presented in Figure 3Citation . It is important to note that an increase in intracellular calcium is required for activation of the potassium channel and that calcium uptake is required for volume recovery in the red blood cell. Although the rate of calcium uptake by erythrocytes in zinc deficiency has not been studied, impairment of the process by zinc deficiency would explain failure of volume recovery and the increased loss of hemoglobin. Also worthy of note is the evidence that sulfhydryl (SH) groups are essential for K+ and Cl- transport in sheep red cells (Lauf and Mangor-Jensen 1984Citation ).



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  		Figure 3. Model of the mechanisms involved in volume recovery of cells subjected to a hypotonic environment. In a normal cell, the movement of water and ions through the plasma membrane channels is at equilibrium. When placed in a hypotonic solution, water moves into the cell, and it is stretched, activating a calcium channel. Increased cytosolic calcium activates a potassium channel, which results in net extrusion of potassium and water. (Model based on results reviewed by Pierce and Politis 1990Citation .)

 
Because of the suggested relationship of osmotic fragility and the SH redox state of plasma membrane proteins, we measured osmotic fragility (hemolysis) of red cells from zinc-deficient and control rats as well as the SH concentration of red cell membranes from the same animals. As shown in Figure 4Citation , the two parameters were highly and inversely correlated (Xia et al. 1999Citation ). Hemolysis was increased to a significantly higher level in zinc-deprived rats than in control animals within 6 d after the consumption of a low zinc diet, and the SH concentration was decreased in the same time frame (data not shown). The changes in the degree of hemolysis and the concentration of membrane protein SH were readily reversed by dietary repletion. After the rats were fed the low zinc diet for 21 d, blood was collected; then, the rats were fed a zinc-adequate diet for 2 d, and again blood was collected. As shown in Figure 5Citation , dietary zinc repletion restored hemolysis to the control level. SH concentration was also restored to control level within 2 d of repletion (Fig. 6Citation ). These experiments show that decreased volume recovery (increased osmotic fragility) and low membrane SH concentration in zinc deficiency are highly correlated and that both are readily reversible in vivo. The ready reversibility of both defects in this system suggests that they are the result of posttranslational modification of a plasma membrane protein or proteins. It is worthy of note that the time required for depletion, ~6 d (Xia et al. 1999Citation ), is greater than that for repletion (1 d) (O’Dell et al. 1987Citation ). The explanation for this difference is not clear but probably relates to a "store" of zinc in the plasma membrane that is slowly depleted compared with the rate of repletion of zinc in the critical channel protein. This fact contributes to the greater value of fragility as an index than of plasma zinc concentration, which in rats drops markedly within 1 day after the consumption of a low zinc diet.



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  		Figure 4. Correlation of osmotic fragility (hemolysis) of red blood cells and plasma membrane protein SH concentration in zinc-deficient and control rats. A total of 48 rats were fed a low zinc diet (<1 mg/kg zinc) or a control diet (100 mg/kg zinc) for 21 d; then, hemolysis and membrane SH concentration were measured. The parameters were highly correlated (P < 0.003). (Data from Xia et al. 1999Citation .)

 


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  		Figure 5. Osmotic fragility of zinc-deficient red cells is readily reversed by dietary zinc repletion. Rats were fed a low zinc diet (<1 mg/kg zinc) and control diets (100 mg/kg zinc) for 21 d, and blood samples were taken via the tail vein; they were then fed the zinc-adequate diet for 2 d and blood was taken again. Hemolysis was significantly higher (P < 0.05) in deficient rats (-ZnAL) at 21 d and was returned to control values after 2 d of repletion. (Data from Xia et al. 1999Citation .)

 


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  		Figure 6. The low SH concentration in red cell membranes from zinc-deficient red cells is readily reversed by dietary zinc repletion. Membranes were prepared from the same blood used in Figure 5Citation , and the designations are the same. (Data from Xia et al. 1999Citation .)

 
If the primary defect is a change in the SH redox state, it should be reversible in vitro by a reduction process that does not directly involve zinc. To explore this possibility, we used glutathione (GSH) in the platelet model that is well established in our laboratory. First, it was shown that the SH redox state is changed in platelet membranes in the same manner as in erythrocyte plasma membranes (O’Dell et al. 1997Citation ). Blood was drawn from zinc-deficient and control rats into anticoagulant in the usual manner or into the anticoagulant providing 0.2 mmol/L GSH, and the platelets were promptly isolated. Figure 7Citation shows the effect of GSH treatment on aggregation and calcium uptake of platelets from zinc-deficient rats. In vitro, GSH restored both aggregation and calcium uptake to control values (control data not shown). The addition of GSH had no effect on the aggregation of platelets from control rats but decreased their uptake of calcium. These data support the concept that platelet function, aggregation and calcium uptake, as well as that of erythrocyte volume recovery, are dependent on the SH redox state.



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  		Figure 7. Correction of the platelet aggregation defect in zinc-deficient rats by in vitro treatment of blood with GSH. Rats were fed low or adequate zinc diets for 14 d, and blood was collected from the aorta into a syringe containing anticoagulants with and without 0.2 mmol/L added GSH. Washed platelets were prepared; aggregation and calcium uptake were stimulated with ADP. Platelets from zinc-deficient rats exhibited impaired aggregation and calcium uptake. but the responses of those collected in the presence of GSH were not different from those of untreated control animals. (Data from O’Dell et al. 1997Citation .)

 
There is evidence that a common denominator of zinc deficiency pathology is the impairment of calcium uptake when cells are stimulated by an extracellular signal, such as a hormone, mitogen or physical stimulus. The data suggest that the function of an SH-dependent calcium channel or channels fails when the zinc concentration in the plasma and extracellular environment is decreased, as occurs in zinc-deficient animals. This concept is illustrated by the model presented in Figure 8Citation . In this model of an SH-dependent calcium channel, a zinc ion is bound with relatively low affinity to an essential SH group. The binding affinity must be such that the zinc dissociates significantly when the free zinc concentration in the microenvironment drops to the level found in the extracellular fluids of zinc-deficient animals. As in the case of metallothionein (Jacob et al. 1998Citation ) and the enzyme delta-aminolevulinate dehydratase (Tsukamoto et al. 1979Citation ), in the absence of bound zinc, the SH group of critical plasma membrane proteins is readily oxidized to form a disulfide bond. The resulting disulfide bond may involve another SH group within the protein or a low-molecular-weight SH compound, such as GSH, not normally associated with the protein. According to this model, the first limiting biochemical function of zinc during the development of dietary zinc deficiency relates to a protective role of zinc against auto-oxidation rather than the absence of a catalytic role.



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  		Figure 8. Model of the mechanism by which zinc deficiency mediates the associated gross pathology. This model depicts an SH-dependent calcium channel in which a protective zinc ion is bound with low affinity to an essential SH group of the channel protein. Low zinc concentration in the microenvironment leads to dissociation of the zinc and subsequent oxidation (Ox) of the SH group to form a disulfide bond, inactivating the channel.

 


   FOOTNOTES
 
1 Presented at the international workshop "Zinc and Health: Current Status and Future Directions," held at the National Institutes of Health in Bethesda, MD, on November 4–5, 1998. This workshop was organized by the Office of Dietary Supplements, NIH and cosponsored with the American Dietetic Association, the American Society for Clinical Nutrition, the Centers for Disease Control and Prevention, Department of Defense, Food and Drug Administration/Center for Food Safety and Applied Nutrition and seven Institutes, Centers and Offices of the NIH (Fogarty International Center, National Institute on Aging, National Institute of Dental and Craniofacial Research, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute on Drug Abuse, National Institute of General Medical Sciences and the Office of Research on Women’s Health). Published as a supplement to The Journal of Nutrition. Guest editors for this publication were Michael Hambidge, University of Colorado Health Sciences Center, Denver; Robert Cousins, University of Florida, Gainesville; Rebecca Costello, Office of Dietary Supplements, NIH, Bethesda, MD; and session chair, Craig McClain, University of Kentucky, Lexington. Back

2 Abbreviations: GSH, glutathione; PKC, protein kinase C; SH, sulfhydryl. Back


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