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. 2013 May 6;4(3):287–293. doi: 10.3945/an.112.003624

Impaired Calcium Entry into Cells Is Associated with Pathological Signs of Zinc Deficiency1,2

Boyd L O’Dell 3,*, Jimmy D Browning 4
PMCID: PMC3650497  PMID: 23674794

Abstract

Zinc is an essential trace element whose deficiency gives rise to specific pathological signs. These signs occur because an essential metabolic function is impaired as the result of failure to form or maintain a specific metal-ion protein complex. Although zinc is a component of many essential metalloenzymes and transcription factors, few of these have been identified with a specific sign of incipient zinc deficiency. Zinc also functions as a structural component of other essential proteins. Recent research with Swiss murine fibroblasts, 3T3 cells, has shown that zinc deficiency impairs calcium entry into cells, a process essential for many cell functions, including proliferation, maturation, contraction, and immunity. Impairment of calcium entry and the subsequent failure of cell proliferation could explain the growth failure associated with zinc deficiency. Defective calcium uptake is associated with impaired nerve transmission and pathology of the peripheral nervous system, as well as the failure of platelet aggregation and the bleeding tendency of zinc deficiency. There is a strong analogy between the pathology of genetic diseases that result in impaired calcium entry and other signs of zinc deficiency, such as decreased and cyclic food intake, taste abnormalities, abnormal water balance, skin lesions, impaired reproduction, depressed immunity, and teratogenesis. This analogy suggests that failure of calcium entry is involved in these signs of zinc deficiency as well.

Introduction

Many essential nutrients, particularly vitamins and trace elements, serve metabolic functions whose failure in case of deficiency leads to specific pathology. For example, vitamin B-6 deficiency causes convulsions in rats (1) and in human infants (2). This pathology results from the lack of pyridoxal phosphate, a cofactor of glutamate decarboxylase that catalyzes the formation of γ-aminobutyric acid, a regulator of neural activity. Essential trace elements perform similar functions, and their deficiencies result in pathological signs. This review identifies metabolic defects with specific pathology that result from nutritional deficiencies of zinc.

Zinc and other essential trace elements serve as components of proteins that catalyze or otherwise support critical metabolic functions. Such coordination complexes vary widely in stability, a property that depends on the binding energy between the metal ion and its protein binding site. Highly stable complexes that do not dissociate during the process of isolation are termed metalloproteins, and much less stable complexes, which cannot be isolated with the metal ion intact, are known as metal-protein complexes. Between these extremes there is a wide spectrum of stability, but all complexes may be involved in metabolic function. As is expected, the first specific pathology to be manifested usually results from a defective metabolic function that is dependent on a complex of low stability. The first limiting metabolic function and the first sign of incipient deficiency frequently differ among species, depending on the structure of the specific protein involved and the stability of the resulting complex. Although the thermodynamic stability of complexes plays an important role in their formation and dissolution, other factors, including the kinetics of dissociation and rate of protein synthesis, also play roles.

The primary purpose of this review is to describe specific signs of zinc deficiency and define so far as possible their causative metabolic defect. There are many known pathological signs, but the associated molecular defects have not been clearly defined. Emerging research identifies failure of calcium entry as the metabolic defect responsible for some signs of incipient zinc deficiency. This review presents research that associates calcium entry with some critical signs of pathology and speculates as to its relevance to other signs of pathology.

Zinc ions form complexes with a multitude of proteins, many of which perform essential metabolic functions. The zinc ion is a component of at least 300 metalloenzymes isolated from multiple species that catalyze >50 different physiologic reactions (3). Zinc metalloenzymes catalyze numerous reactions critical to metabolic functions (4) and most are very stable complexes with dissociation constants of ~10−9 M. For that reason, one would not expect them to lose zinc during incipient zinc deficiency. Few, if any, of the many known zinc metalloenzymes have been identified definitively with a specific pathology of zinc deficiency. There are examples of functional zinc complexes that readily lose activity. Thymulin, a serum thymic hormone, is a zinc-polypeptide complex with a dissociation constant of ~10−6 that loses zinc readily upon dietary deprivation of zinc (5, 6); in vitro zinc readily restores activity. Angiotensin-converting enzyme is another serum zinc complex that loses activity in zinc-deficient animals and whose activity is readily restored by the addition of in vitro zinc (7). Although the latter complex has high stability, it has a high rate of association and dissociation (8). The physical properties of these proteins and their intimate contact with the plasma contribute to their loss of zinc and activity. Nevertheless, there is no clear evidence that loss of their activities leads to overt signs of zinc deficiency pathology.

Zinc is also a component of thousands of transcription factor proteins characterized as “zinc fingers” and related structures (4). The DNA binding proteins that have characteristic binding motifs, known as zinc fingers, twist, or rings are presumed to bind zinc, although only a few have been isolated and characterized as zinc metalloproteins (9). They also have high zinc stability, and there is no evidence that a zinc-dependent transcription factor becomes sufficiently limiting during incipient zinc deficiency to cause pathology.

Nevertheless, the pathological signs of zinc deprivation must result from a metabolic defect and likely result from malfunction of an essential zinc-protein complex. The putative complex would likely have low stability that contributes to the loss of zinc from, or failure to form, the complex when extracellular zinc concentration falls below normal limits. The zinc concentration in the cell cytosol is largely unchanged by zinc deficiency, but that of the blood plasma and the cell plasma membrane is decreased, suggesting that the first limiting function occurs in the plasma membrane (10). For that reason, one might expect the defective complex to exist in or be closely related to the cell plasma membrane. There are reports of a decrease in the zinc content of blood-formed elements in human zinc deprivation (6). The changes observed were small, 1 SD from the control mean, and may primarily reflect changes in plasma membrane zinc. Others (11) did not find a decrease in formed element zinc concentration in rodents, even when plasma zinc was substantially reduced.

Zinc deficiency pathology associated with defective calcium entry into cells

Recent results show that zinc deficiency impairs calcium entry in Swiss murine fibroblasts, 3T3 cells, when they are stimulated by growth factors (12, 13). Calcium commonly serves as a second messenger, and its entry is essential for many cell functions, including proliferation, differentiation, neuronal activity, immunity, and other functions (14). Signs of zinc deficiency that have been associated with impaired calcium uptake are listed in Table 1. The first sign of incipient zinc deficiency to be manifested differs among species.

Table 1.

Zinc deficiency pathology associated with defective cell calcium uptake

Gross pathology Species (Reference) Metabolic defect (Reference)
Impaired growth and cell proliferation Rat, pig, chicken, human, mouse cells (15–19) Decreased Ca entry when stimulated (12, 13)
Ataxia, low nerve conduction rate, impaired cognition and learning Guinea pig, chicken, rat, pig, human (27–31) Decreased Ca uptake by synaptic vesicles when stimulated (33, 34)
Excessive bleeding; impaired platelet aggregation Rat, human (37–40) Decreased Ca uptake by platelets stimulated to aggregate (41, 42)
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Impaired cell proliferation and growth

Impaired growth is a cardinal sign of zinc deficiency in all animal species studied. From the earliest studies, including in rats (15), pigs (16), chickens (17), and humans (18, 19), growth impairment has been reported as a preeminent sign of zinc deficiency. It is well established (20) that zinc deficiency in animals impairs DNA production in cells, but there is no evidence that the DNA synthetic mechanism per se is impaired. As described below, the primary metabolic defect in cellular DNA synthesis probably involves the signal for cell proliferation. This signal uses the second messenger for growth factors, i.e., calcium, and it lies upstream of the process for DNA synthesis (21).

Because the major component of an organism’s growth is cell proliferation, cell culture models have been used to elucidate the role of zinc in this process (22, 23). Those studies used 3T3 cells grown in a medium containing diethylenetriaminepentaacetate (DTPA)5 to induce severe zinc deficiency and showed that deficiency leads to drastically reduced cell proliferation as measured by DNA synthesis. By using a similar model involving a chelator, DTPA (12), as well as one without DTPA (13), we have shown that zinc deprivation impairs calcium entry into 3T3 cells when they are stimulated with polypeptide growth factors. Depressed calcium entry was associated with a low proliferation rate in both models: in severe zinc deficiency induced by DTPA and in mild deficiency without the chelator. In mild deficiency, calcium entry and proliferation were more dependent on the calcium concentration in the external medium. An increased and sustained concentration of free calcium in cells is required to initiate cell proliferation (20), which is effected primarily by opening a calcium channel in the plasma membrane. There are 2 recognized mechanisms for calcium entry, store-operated calcium entry (SOCE) and receptor-operated calcium entry (ROCE) (24, 25), and 2 known types of channel proteins, calcium release–activated calcium channel protein 1 (Orai1) and transient receptor potential canonical (TRPC) proteins (26). Orai1 serves only in SOCE and is highly specific for calcium; TRPC protein channels may be activated by both the SOCE and ROCE mechanisms. Swiss 3T3 cells possess both SOCE and ROCE mechanisms of calcium entry and both are impaired by zinc deficiency (13). Defective calcium entry explains the failure of zinc-deficient 3T3 cell to proliferate and may well explain the failure of DNA synthesis and growth associated with zinc deficiency in animals.

Malfunction of the nervous system

Nervous system pathology is a sign of zinc deficiency in most mammalian species, but the pathology usually appears somewhat later than growth failure. Impairment of the peripheral nervous system is manifested by stiffness, hyperalgesia, and ataxia. These signs have been described in guinea pigs (27), chickens (28), rats (29), and pigs (30). Nerve conduction velocity in the sciatic nerve of both guinea pigs and chickens is decreased substantially and returns to normal upon zinc repletion. The effect of zinc deficiency on the central nervous system, particularly in the human, has been reviewed (31).

Glutamate serves as an important neurotransmitter in the central nervous system, and it has a function in the opening of calcium channels (32). Synaptic vesicles isolated from the guinea pig brain take up calcium when stimulated by glutamate, and the process is impaired by zinc deficiency (33,34). Neurotransmitter release is dependent on SOCE (35). Impaired calcium entry offers an explanation for the detrimental effect of zinc deficiency on the peripheral as well as on the central nervous system.

Although the nature of the calcium channel impairment by zinc deficiency is not known, genetic mutations in mice have demonstrated that brain calcium entry involves stromal interaction molecule 1 (STIM1) and Orai1 (36). These proteins are found in mouse brain, and they colocalize when neurons are treated with thapsigargin, a compound that stimulates SOCE. Malfunction of a calcium channel protein or proteins in nerve tissue is the probable basis of the pathology observed in zinc-deficient animals.

Blood loss and impaired platelet aggregation

At parturition, zinc-deficient rats exhibit excessive blood loss (37) and nonpregnant females show prolonged bleeding times from a minor wound (38). There is impaired aggregation of platelets in both rats (39) and humans (40) subjected to short-term zinc deprivation. Failure of rat platelets to aggregate when stimulated with ADP or thrombin is associated with reduced calcium entry, a process essential for aggregation (41, 42).

Platelets contain calcium channels that support both SOCE and ROCE. The sarco-/endoplasmic reticulum of platelets contains a high level of STIM1, the calcium-sensing protein that functions in SOCE. Modification of the STIM1 gene in mice impairs calcium entry as well as growth rate (43). Platelets from another mouse mutant that expresses an inactive form of Orai1 also show impairment of calcium entry (44). Platelets also contain TRPC-based calcium channels that support entry of calcium and other cations (45, 46). The analogy between genetic mutations and zinc deficiency in platelets supports the concept that they involve the same defective calcium channel proteins.

Pathological signs of zinc deficiency whose metabolic defect is by analogy due to defective calcium entry

There are numerous diseases in humans of genetic origin, as well as in mouse mutants, which result from the malfunction of STIM1 and Orai1, the proteins critical for activation of SOCE (47). Clinically, the lack of these proteins leads to immunodeficiency, congenital myopathy, and ectodermal dysplasias, diseases that mimic the signs of zinc deficiency. Genetically induced pathologies similar to those of zinc deficiency and other signs of deficiency that may involve impairment of calcium entry are described below.

In addition to the signs of zinc deficiency described in the section “Zinc Deficiency Pathology Associated with Defective Calcium Entry into Cells”, there are other pathological signs that may be explained by impaired calcium entry. However, calcium entry has not been studied directly in relation to these signs. Zinc deficiency signs for which no definitive metabolic defect has been determined are listed in Table 2.

Table 2.

Pathological signs of zinc deficiency possibly associated with defective cell calcium entry

Gross pathology Species (Reference) Metabolic defect (Reference)
Decreased and cyclic food intake Rat (48, 49) Food intake is dependent on Ca entry (12, 13)
Taste abnormalities Rat (53, 57), human (54) Taste receptor function and water balance require Ca influx (55, 56)
Osmotic fragility, abnormal water balance Chicken (58), rat (59) Decreased Ca entry inactivates the K channel and osmotic regulation (60)
Skin lesions, parakeratosis Rat (61),pig (16) Ca entry required for differentiation of keratinocytes (62–64)
Impaired reproduction, dystocia, low blood pressure Rat (37, 38, 65), human (66) Ca entry required for cell proliferation and muscle tone (7, 67)
Depressed immunity Mouse (68, 69), human (70) Ca entry required for thymocyte proliferation and differentiation (71–73)
Teratogenesis Rat (77–79) Ca entry required for cell proliferation and differentiation (12, 13)
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Decreased appetite and food intake

One of the first zinc deficiency signs to be exhibited in growing animals is decreased and cyclic food intake (48, 49). Physiologically, food intake is mediated by myriad factors; deprivation of many essential nutrients results in loss of appetite. The effect of zinc deficiency, more than most, mirrors that of essential amino acid deprivation. The effects of both nutrients are early in onset and readily reversible. The lack of an essential amino acid largely prevents protein synthesis and hence cell proliferation. Consequently, there is an accumulation of unassimilated amino acids and their metabolites, and food intake drops quickly. It is restored promptly by administration of the missing essential amino acid (50). The effect of zinc deficiency is highly analogous. Diets high in protein and supplements of some amino acids, including methionine, phenylalanine, tryptophan, and threonine, accentuate the onset of decreased and cyclic food intake (48). Rats fed zinc-deficient diets, when given a choice, select a low-protein diet (51), and consumption of a low-protein diet essentially eliminates cyclic feeding. It is not clear which comes first in zinc deficiency, loss of appetite or failure to grow, but there is increasing opinion (48) that growth, i.e., cell proliferation, is the first to be depressed. Because zinc deficiency depresses cell proliferation, it is reasonable that unused amino acids and their metabolites are responsible for the depressed appetite. Mice with a defective Orai1 gene exhibit, among other pathologies, a decreased growth rate (52). Decreased and cyclic food intake associated with zinc deficiency may be explained by the failure of calcium entry and cell proliferation.

Taste abnormalities

Hypogeusia, or lack of taste acuity, occurs in rats and humans with relatively long-term zinc deprivation (53, 54). Zinc supplementation of hemodialysis patients improves their threshold of detection of salt, sucrose, and urea. A defect in SOCE channels in taste receptor cells, similar to that observed in mouse fibroblasts in culture (12, 13), would explain this type of taste abnormality (55, 56).

Rats fed a low-zinc diet for short time show a preference for an isotonic salt solution over that for water (57). This preference occurs in incipient zinc deficiency and is associated with the redistribution of body water, a sign described below. In zinc deficiency there is movement of extracellular water into the cells; this disequilibrium may well activate the salt preference. The water shift and related salt preference may involve a defect in calcium entry (see below). The lack of taste acuity in advanced zinc deficiency and the preference for salt solutions in incipient zinc deficiency appear to involve defective calcium entry at different locations; the former involves specifically taste receptors.

Abnormal body water distribution

Although zinc-deficient animals appear dehydrated, their total body water is normal. The dehydrated appearance is largely due to a shift of body water from extracellular to intracellular space (58). The shift is accompanied by increased cell size, as exemplified by increased hematocrit, and increased osmotic fragility of RBCs (59). Increased osmotic fragility of erythrocytes results from expanded cell volume due to the failure of potassium ion and water extrusion. The extrusion of potassium involves a stretch-activated, Ca-dependent K channel (60). When calcium entry is impaired, potassium extrusion fails and water is retained, resulting in enlarged cells that rupture readily when stressed with a hypotonic solution. Calcium entry into cells is essential for maintenance of water balance. In this regard, it is of interest that patients lacking genetic expression of Orai1 suffer from anhydrosis and decreased sweat production (47). The abnormal water distribution in zinc deficiency is consistent with the hypothesis of failure of cell calcium entry.

Skin lesions and abnormal keratogenesis

In relatively long-term zinc deficiency, alopecia and skin lesions are commonly described signs, and were first observed in rats (61) and later in all species studied. Parakeratosis, a lesion characterized by a buildup of nucleated epidermal cells in the striatum granulosum, first received special attention because it was a practical problem in swine husbandry (16). The lesion occurs due to the failure of keratinocyte differentiation, a process that requires the signal of calcium entry (62). As in the case of cell proliferation, an increased concentration of cytosolic free calcium is required to initiate in vitro differentiation of keratinocytes (63, 64). Adequate zinc is likely required for the increased calcium entry into keratinocytes. Mutant mice lacking Orai1 develop alopecia and Orai1-deficient patients have ectodermal dysplasias characterized by defects of the skin (47). The failure of cell calcium entry in zinc deficiency could explain the failure of cell differentiation and associated skin lesions.

Impaired reproductive function

The reproductive organs in both sexes of zinc-deficient animals are defective. Testicular development in male rats is retarded and accompanied by atrophy of the germinal epithelium (65). Similar pathology occurs in other species. Hypogonadism and depressed development of secondary sexual characteristics were observed in young men of low zinc status in Iran and Egypt (18, 66). These signs could result from limited cell proliferation in sexual organs and the consequent lack of hormone production. Growth and development of these organs involve cell proliferation and differentiation, processes dependent on calcium entry.

Severe zinc deficiency in female rats causes reproductive failure and production of nonviable offspring; parturition is accompanied by dystocia and excessive blood loss as discussed earlier (37, 38). The delayed and difficult parturition is accompanied by physiologic shock, expressed by low body temperature and low blood pressure. The bleeding tendency involves failure of platelet aggregation, which results from impaired calcium entry when the platelets are stimulated to aggregate (39, 40).

A similar metabolic defect in smooth muscle cells may well be responsible for loss of muscle tone in the uterus and vascular system. Store-operated calcium channels function in the regulation of smooth muscle contraction and tone, and Orai1 plays an essential role in calcium entry in aortic smooth muscle cells (67). Thus, impaired calcium entry into muscle cells could explain a major part of the female reproductive failure in zinc deficiency, including low blood pressure. Clinically, myopathy becomes apparent soon after birth in patients lacking STIM1 or Orai1 (47). Reproductive failure due to zinc deficiency in males involves lack of cell proliferation and in females loss of muscle tone, both of which depend on functional calcium entry.

Impaired immune function

Zinc deficiency results in low immune competence in several species, including humans, pigs, rats, and mice; mice (68, 69) and humans (70) have received the most research attention. Lymphopenia and reduced mass of the thymus in young animals are signs of zinc deprivation. The reduced number of thymocytes could be the result of decreased proliferation of precursor cells and/or the impaired maturation of precursor cells; both processes are dependent on calcium entry (71). Activation of T lymphocytes requires stimulation that induces calcium entry, an indispensable step for proliferation and acquisition of function (72). The circulating concentrations of the glucocorticoid corticosterone are elevated in zinc-deficient mice because of stress. The high corticosterone concentrations lead to apoptosis of thymocytes, lymphopenia, and thymic atrophy, signs that were prevented by adrenalectomy (reviewed in [73]). Other forms of stress have analogous effects. In growing rats, both zinc deficiency and pair-feeding cause elevated corticosterone concentrations as well as a reduced number of T cells per thymus, but T-cell numbers were not changed when expressed relative to body weight (reviewed in [74]).

The immunodeficiency of zinc deprivation is analogous to that of patients with nonfunctional Orai1 and STIM1. The stimulation of normal immune cells leads to calcium entry by Orai1-mediated calcium entry and proliferation of T cells (75). Mutations of Orai1 in human families have resulted in severe immunodeficiency due to defective T-cell activation that was associated with impaired calcium entry (76). Other patients develop combined immunodeficiency due to lack of STIM1. These proteins, which are critical for calcium entry, are important for the function but not development of T cells, B cells, mast cells, and macrophages. The impairment of calcium entry into immune cells could explain part of the detrimental effect of zinc deficiency on the immune system.

Congenital abnormalities and teratogenesis

Congenital malformations that result from lack of zinc were first observed in rats (77). This was followed by numerous studies (78, 79), some of which have been reviewed (80). Two hypotheses have been advanced to explain the detrimental effect of zinc deficiency on embryogenesis. One proposes that excessive apoptosis in critical areas of the embryo is responsible for the defects (79). This hypothesis suggests that high concentrations of reactive oxygen species (ROS) are involved in the apoptotic process. Zinc deficiency has long been recognized to result in excessive levels of free radicals (81), but there is no evidence that this phenomenon is related to failure of calcium entry. A more likely cause of the high ROS concentrations is the decreased concentration of intracellular metallothionein that results from zinc deficiency (82). Metallothionein functions as an effective scavenger of ROS (83).

The other explanation of teratogenesis is a failure of cell proliferation in specific areas during critical periods of embryonic development. This hypothesis is supported by the recurrent theme of this review, i.e., zinc deficiency impairs cellular calcium entry associated with decreased cell proliferation.

Concluding remarks

Several signs of zinc deficiency, including cell proliferation, nerve function, and platelet aggregation, are associated with impairment of calcium uptake in cultured fibroblasts and in cells from zinc-deficient animals. Calcium entry, which is essential for a sustained increase in cytosolic calcium, is required for multiple cell functions. If impaired calcium entry proves to be a first limiting metabolic function of zinc deficiency in humans, it offers a method for assessing zinc status. Blood platelets, which must take up calcium to initiate aggregation, offer an accessible tissue for such assessment.

Acknowledgments

Both authors read and approved the final manuscript.

Footnotes

5

Abbreviations used: DTPA, diethylenetriaminepentaacetate; Orai1, calcium release–activated calcium channel protein 1; ROCE, receptor-operated calcium entry; ROS, reactive oxygen species; SOCE, store-operated calcium entry; STIM1, stromal interaction molecule 1 (a calcium-sensing protein); TRPC, transient receptor potential canonical (protein).

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