Calcium ions (Ca2+) contribute to thephysiology andbiochemistry of organisms'cells. They play an important role insignal transduction pathways,[2][3] where they act as asecond messenger, inneurotransmitter release fromneurons, in contraction of allmuscle cell types, and infertilization. Manyenzymes require calcium ions as acofactor, including several of thecoagulation factors. Extracellular calcium is also important for maintaining thepotential difference acrossexcitable cellmembranes, as well as proper bone formation.
Plasma calcium levels in mammals are tightly regulated,[2][3] withbone acting as the majormineral storage site. Calciumions, Ca2+, are released from bone into the bloodstream under controlled conditions. Calcium is transported through the bloodstream as dissolved ions or bound to proteins such asserum albumin.Parathyroid hormone secreted by theparathyroid gland regulates theresorption of Ca2+ from bone,reabsorption in the kidney back into circulation, and increases in the activation ofvitamin D3 tocalcitriol. Calcitriol, the active form of vitamin D3, promotesabsorption of calcium from the intestines and bones. Calcitriol also plays a key role in upregulating levels of intracellular calcium, and high levels of this ion appear to be protective against cancers of the breast and prostate. The suppression of calcitriol by excessive dietary calcium is believed to be the major mechanism for the potential link between dairy and cancer. However, the vitamin D present in many dairy products may help compensate for this deleterious effect of high-calcium diets by increasing serum calcitriol levels.Calcitonin secreted from theparafollicular cells of thethyroid gland also affects calcium levels by opposing parathyroid hormone; however, its physiological significance in humans is in dispute.
Intracellular calcium is stored inorganelles which repetitively release and then reaccumulate Ca2+ ions in response to specific cellular events: storage sites includemitochondria and theendoplasmic reticulum.[4]
Characteristic concentrations of calcium in model organisms are: inE. coli 3 mM (bound), 100 nM (free), in budding yeast 2 mM (bound), in mammalian cell 10–100 nM (free) and in blood plasma 2 mM.[5]
| Age | Calcium (mg/day) |
|---|---|
| 1–3 years | 700 |
| 4–8 years | 1000 |
| 9–18 years | 1300 |
| 19–50 years | 1000 |
| >51 years | 1000 |
| Pregnancy | 1000 |
| Lactation | 1000 |
In 2022, it was the 277th most commonly prescribed medication in the United States, with more than 700,000 prescriptions.[8][9]
The US Institute of Medicine (IOM) establishedRecommended Dietary Allowances (RDAs) for calcium in 1997 and updated those values in 2011.[6] See table. TheEuropean Food Safety Authority (EFSA) uses the term Population Reference Intake (PRIs) instead of RDAs and sets slightly different numbers: ages 4–10 800 mg, ages 11–17 1150 mg, ages 18–24 1000 mg, and >25 years 950 mg.[10]
Because of concerns of long-term adverse side effects such as calcification of arteries and kidney stones, the IOM and EFSA both setTolerable Upper Intake Levels (ULs) for the combination of dietary and supplemental calcium. From the IOM, people ages 9–18 years are not supposed to exceed 3,000 mg/day; for ages 19–50 not to exceed 2,500 mg/day; for ages 51 and older, not to exceed 2,000 mg/day.[11] The EFSA set UL at 2,500 mg/day for adults but decided the information for children and adolescents was not sufficient to determine ULs.[12]
For US food and dietary supplement labeling purposes, the amount in a serving is expressed as a percent of Daily Value (%DV). For calcium labeling purposes, 100% of the Daily Value was 1000 mg, but as of 27 May 2016, it was revised to 1300 mg to bring it into agreement with the RDA.[13][14] A table of the old and new adult daily values is provided atReference Daily Intake.
Although as a general rule, dietary supplement labeling and marketing are not allowed to make disease prevention or treatment claims, the FDA has for some foods and dietary supplements reviewed the science, concluded that there is significant scientific agreement for a beneficial effect of dietary calcium on bone mineral density (along with vitamin D to facilitate its absorption), and published specifically worded allowed health claims. An initial ruling allowing a health claim for calcium dietary supplements andosteoporosis was later amended to include calcium andvitamin D supplements, effective 1 January 2010. Examples of allowed wording are shown below. In order to qualify for the calcium health claim, a dietary supplement must contain at least 20% of the Reference Dietary Intake, which for calcium means at least 260 mg/serving.[15]
In 2005, the FDA approved a Qualified Health Claim for calcium and hypertension in light of the evidence available at that time, with suggested wording "Some scientific evidence suggests that calcium supplements may reduce the risk of hypertension. However, FDA has determined that the evidence is inconsistent and not conclusive." Evidence for pregnancy-induced hypertension and preeclampsia was considered inconclusive.[16] The same year, the FDA approved a QHC for calcium and colon cancer, with suggested wording "Some evidence suggests that calcium supplements may reduce the risk of colon/rectal cancer, however, FDA has determined that this evidence is limited and not conclusive." Evidence for breast cancer and prostate cancer was considered inconclusive.[17] Proposals for QHCs for calcium as protective against kidney stones or against menstrual disorders or pain were rejected.[18][19]
TheEuropean Food Safety Authority (EFSA) concluded that "Calcium contributes to the normal development of bones."[20] The EFSA rejected a claim that a cause-and-effect relationship existed between the dietary intake of calcium and potassium and maintenance of normal acid-base balance.[21] The EFSA also rejected claims for calcium and nails, hair, blood lipids, premenstrual syndrome and body weight maintenance.[22]
TheUnited States Department of Agriculture (USDA) web site has a very complete searchable table of calcium content (in milligrams) in foods, per common measures such as per 100 grams or per a normal serving.[23][24]
| Food, calcium per 100 grams |
|---|
| parmesan (cheese) = 1140 mg |
| milk powder = 909 mg |
| goat hard cheese = 895 mg |
| Cheddar cheese = 720 mg |
| tahini paste = 427 mg |
| molasses = 273 mg |
| sardines = 240 mg |
| almonds = 234 mg |
| collard greens = 232 mg |
| kale = 150 mg |
| goat milk = 134 mg |
| sesame seeds (unhulled) = 125 mg |
| nonfatcow milk = 122 mg |
| plain whole-milkyogurt = 121 mg |
| Food, calcium per 100 grams |
|---|
| hazelnuts = 114 mg |
| tofu, soft = 114 mg |
| beet greens = 114 mg |
| spinach = 99 mg |
| ricottas (skimmed milk cheese) = 90 mg |
| lentils = 79 mg |
| chickpeas = 53 mg |
| rolled oats = 52 mg[25] |
| eggs, boiled = 50 mg |
| orange = 40 mg |
| humanmilk = 33 mg |
| rice, white, long-grain = 19 mg |
| beef = 12 mg |
| cod = 11 mg |
The amount of calcium inblood (more specifically, inblood plasma) can be measured astotal calcium, which includes both protein-bound and free calcium. In contrast,ionized calcium is a measure of free calcium. An abnormally high level of calcium in plasma is termedhypercalcemia and an abnormally low level is termedhypocalcemia, with "abnormal" generally referring to levels outside thereference range.
| Target | Lower limit | Upper limit | Unit |
| Ionized calcium | 1.03,[26] 1.10[27] | 1.23,[26] 1.30[27] | mmol/L |
| 4.1,[28] 4.4[28] | 4.9,[28] 5.2[28] | mg/dL | |
| Total calcium | 2.1,[29][30] 2.2[27] | 2.5,[27][30] 2.6,[30] 2.8[29] | mmol/L |
| 8.4,[29] 8.5[31] | 10.2,[29] 10.5[31] | mg/dL |
The main methods to measure serum calcium are:[32]
The total amount of Ca2+ present in a tissue may be measured usingAtomic absorption spectroscopy, in which the tissue is vaporized and combusted. To measure Ca2+ concentration or spatial distribution within the cellcytoplasmin vivo orin vitro, a range offluorescent reporters may be used. These include cell permeable, calcium-binding fluorescentdyes such asFura-2 or genetically engineered variant ofgreen fluorescent protein (GFP) namedCameleon.
As access to an ionized calcium is not always available a corrected calcium may be used instead. To calculate a corrected calcium in mmol/L one takes the total calcium in mmol/L and adds it to ((40 minus the serumalbumin in g/L) multiplied by 0.02).[33] There is, however, controversy around the usefulness of corrected calcium as it may be no better than total calcium.[34] It may be more useful to correct total calcium for both albumin and theanion gap.[35][36]
Invertebrates, calcium ions, like many other ions, are of such vital importance to many physiological processes that its concentration is maintained within specific limits to ensure adequate homeostasis. This is evidenced by humanplasma calcium, which is one of the most closely regulated physiological variables in the human body. Normal plasma levels vary between 1 and 2% over any given time. Approximately half of all ionized calcium circulates in its unbound form, with the other half being complexed with plasma proteins such asalbumin, as well asanions includingbicarbonate,citrate,phosphate, andsulfate.[37]
Differenttissues contain calcium in different concentrations. For instance, Ca2+ (mostlycalcium phosphate and somecalcium sulfate) is the most important (and specific) element ofbone and calcifiedcartilage. In humans, the total body content of calcium is present mostly in the form of bone mineral (roughly 99%). In this state, it is largely unavailable for exchange/bioavailability. The way to overcome this is through the process ofbone resorption, in which calcium is liberated into the bloodstream through the action of boneosteoclasts. The remainder of calcium is present within the extracellular and intracellular fluids.
Within a typical cell, the intracellular concentration of ionized calcium is roughly 100 nM, but is subject to increases of 10- to 100-fold during various cellular functions. The intracellular calcium level is kept relatively low with respect to the extracellular fluid, by an approximate magnitude of 12,000-fold. This gradient is maintained through various plasma membranecalcium pumps that utilizeATP for energy, as well as a sizable storage within intracellular compartments. Inelectrically excitable cells, such as skeletal and cardiac muscles and neurons, membrane depolarization leads to a Ca2+ transient with cytosolic Ca2+ concentration reaching around 1 μM.[39] Mitochondria are capable of sequestering and storing some of that Ca2+. It has been estimated that mitochondrial matrix free calcium concentration rises to the tens of micromolar levelsin situ during neuronal activity.[40]
The effects of calcium on human cells are specific, meaning that different types of cells respond in different ways. However, in certain circumstances, its action may be more general. Ca2+ ions are one of the most widespreadsecond messengers used insignal transduction. They make their entrance into thecytoplasm either from outside the cell through thecell membrane via calcium channels (such ascalcium-binding proteins or voltage-gated calcium channels), or from some internalcalcium storages such as theendoplasmic reticulum[4] andmitochondria. Levels of intracellular calcium are regulated bytransport proteins that remove it from the cell. For example, thesodium-calcium exchanger uses energy from theelectrochemical gradient of sodium by coupling the influx of sodium into cell (and down its concentration gradient) with the transport of calcium out of the cell. In addition, theplasma membrane Ca2+ ATPase (PMCA) obtains energy to pump calcium out of the cell byhydrolysingadenosine triphosphate (ATP). Inneurons,voltage-dependent, calcium-selective ion channels are important forsynaptic transmission through the release ofneurotransmitters into thesynaptic cleft byvesicle fusion ofsynaptic vesicles.
Calcium's function inmuscle contraction was found as early as 1882 by Ringer. Subsequent investigations were to reveal its role as a messenger about a century later. Because its action is interconnected withcAMP, they are called synarchic messengers. Calcium can bind to several different calcium-modulated proteins such astroponin-C (the first one to be identified) andcalmodulin, proteins that are necessary for promoting contraction in muscle.
In the endothelial cells which line the inside of blood vessels, Ca2+ ions can regulate several signaling pathways which cause the smooth muscle surrounding blood vessels to relax.[citation needed] Some of these Ca2+-activated pathways include the stimulation of eNOS to produce nitric oxide, as well as the stimulation of Kca channels to efflux K+ and cause hyperpolarization of the cell membrane. Both nitric oxide and hyperpolarization cause the smooth muscle to relax in order to regulate the amount of tone in blood vessels.[41] However, dysfunction within these Ca2+-activated pathways can lead to an increase in tone caused by unregulated smooth muscle contraction. This type of dysfunction can be seen in cardiovascular diseases, hypertension, and diabetes.[42]
Calcium coordination plays an important role in defining the structure and function of proteins. An example a protein with calcium coordination isvon Willebrand factor (vWF) which has an essential role in blood clot formation process. It was discovered using single moleculeoptical tweezers measurement that calcium-bound vWF acts as a shear force sensor in the blood. Shear force leads to unfolding of the A2 domain of vWF whose refolding rate is dramatically enhanced in the presence of calcium.[43]
Ca2+ ion flow regulates several secondary messenger systems inneural adaptation for visual, auditory, and the olfactory system. It may often be bound tocalmodulin such as in the olfactory system to either enhance or repress cation channels.[44] Other times the calcium level change can actually releaseguanylyl cyclase from inhibition, like in the photoreception system.[45] Ca2+ ion can also determine the speed of adaptation in a neural system depending on the receptors and proteins that have varied affinity for detecting levels of calcium to open or close channels at high concentration and low concentration of calcium in the cell at that time.[46]
| Cell type | Effect |
|---|---|
| Endothelial cells | ↑Vasodilation |
| Secretory cells (mostly) | ↑Secretion (vesicle fusion) |
| Juxtaglomerular cell | ↓Secretion[47] |
| Parathyroid chief cells | ↓Secretion[47] |
| Neurons | Transmission (vesicle fusion),neural adaptation |
| T cells | Activation in response to antigen presentation to theT cell receptor[48] |
| Myocytes |
|
| Various | Activation ofprotein kinase C Further reading:Function of protein kinase C |
Substantial decreases in extracellular Ca2+ ion concentrations may result in a condition known ashypocalcemictetany, which is marked by spontaneousmotor neuron discharge. In addition, severehypocalcaemia will begin to affect aspects ofblood coagulation and signal transduction.
Ca2+ ions can damage cells if they enter in excessive numbers (for example, in the case ofexcitotoxicity, or over-excitation ofneural circuits, which can occur inneurodegenerative diseases, or after insults such asbrain trauma orstroke). Excessive entry ofcalcium into a cell may damage it or even cause it to undergoapoptosis, or death bynecrosis. Calcium also acts as one of the primary regulators of osmotic stress (osmotic shock). Chronically elevated plasma calcium (hypercalcemia) is associated withcardiac arrhythmias and decreased neuromuscular excitability. One cause of hypercalcemia is a condition known ashyperparathyroidism.
Someinvertebrates use calcium compounds for building theirexoskeleton (shells andcarapaces) orendoskeleton (echinoderm plates andporiferan calcareousspicules).
Whenabscisic acid signals the guard cells, free Ca2+ ions enter the cytosol from both outside the cell and internal stores, reversing the concentration gradient so the K+ ions begin exiting the cell. The loss of solutes makes the cell flaccid and closes the stomatal pores.
Calcium is a necessary ion in the formation of themitotic spindle. Without the mitotic spindle,cellular division cannot occur. Although young leaves have a higher need for calcium, older leaves contain higher amounts of calcium because calcium is relatively immobile through the plant. It is not transported through thephloem because it can bind with other nutrient ions andprecipitate out of liquid solutions.
Ca2+ ions are an essential component of plantcell walls andcell membranes, and are used ascations to balanceorganicanions in the plantvacuole.[49] The Ca2+ concentration of the vacuole may reach millimolar levels. The most striking use of Ca2+ ions as a structural element in algae occurs in the marinecoccolithophores, which use Ca2+ to form thecalcium carbonate plates, with which they are covered.
Calcium is needed to form thepectin in themiddle lamella of newly formed cells.
Calcium is needed to stabilize the permeability of cell membranes. Without calcium, the cell walls are unable to stabilize and hold their contents. This is particularly important in developing fruits. Without calcium, the cell walls are weak and unable to hold the contents of the fruit.
Someplants accumulate Ca in their tissues, thus making them more firm. Calcium is stored as Ca-oxalate crystals inplastids.
Ca2+ ions are usually kept at nanomolar levels in thecytosol ofplant cells, and act in a number of signal transduction pathways assecond messengers.