Wikipedia

Calcium in biology

Calciumions (Ca2+) contribute to thephysiologyandbiochemistryof organisms'cells.They play an important role insignal transductionpathways,[2][3]where they act as asecond messenger,inneurotransmitterrelease fromneurons,in contraction of allmusclecell types, and infertilization.Manyenzymesrequire calcium ions as acofactor,including several of thecoagulation factors.Extracellular calcium is also important for maintaining thepotential differenceacrossexcitable cellmembranes,as well as proper bone formation.

Calcium is used in many nerves in thevoltage-gated calcium channelwhich is slightly slower than thevoltage-gated potassium channel.It is most notably used in thecardiac action potential.[1]

Plasma calcium levels in mammals are tightly regulated,[2][3]withboneacting as the majormineral storagesite. 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 hormonesecreted by theparathyroid glandregulates theresorptionof Ca2+from bone,reabsorptionin the kidney back into circulation, and increases in the activation ofvitamin D3tocalcitriol.Calcitriol, the active form of vitamin D3,promotesabsorptionof calcium from the intestines and bones.Calcitoninsecreted from theparafollicular cellsof thethyroid glandalso affects calcium levels by opposing parathyroid hormone; however, its physiological significance in humans is dubious.

Intracellularcalcium is stored inorganelleswhich repetitively release and then reaccumulate Ca2+ions in response to specific cellular events: storage sites includemitochondriaand theendoplasmic reticulum.[4]

Characteristic concentrations of calcium in model organisms are: inE. coli3mM(bound), 100nM(free), in budding yeast 2 mM (bound), in mammalian cell 10–100 nM (free) and in blood plasma 2 mM.[5]

Humans

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Age-adjusted daily calcium recommendations (from U.S. Institute of Medicine RDAs)[6]
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
Global dietary calcium intake among adults (mg/day)[7]
<400
400–500
500–600
600–700
700–800
800–900
900–1000
>1000

In 2021, calcium was the 243rd most commonly prescribed medication in the United States, with more than 1million prescriptions.[8][9]

Dietary recommendations

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The U.S. Institute of Medicine (IOM) establishedRecommended Dietary Allowances(RDAs) for calcium in 1997 and updated those values in 2011.[6]See table. The European 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]

Labeling

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For U.S. 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 May 27, 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.

Health claims

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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, and published specifically worded allowed health claims. An initial ruling allowing a health claim for calcium dietary supplements andosteoporosiswas later amended to include calcium andvitamin Dsupplements, effective January 1, 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]

  • "Adequate calcium throughout life, as part of a well-balanced diet, may reduce the risk of osteoporosis."
  • "Adequate calcium as part of a healthful diet, along with physical activity, may reduce the risk of osteoporosis in later life."
  • "Adequate calcium and vitamin D throughout life, as part of a well-balanced diet, may reduce the risk of osteoporosis."
  • "Adequate calcium and vitamin D as part of a healthful diet, along with physical activity, may reduce the risk of osteoporosis in later life."

In 2005, the FDA approved a Qualified Health Claim for calcium and hypertension, 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]

Food sources

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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
tahinipaste = 427 mg
molasses= 273 mg
sardines= 240 mg
almonds= 234 mg
collard greens= 232 mg
kale= 150 mg
goat milk = 134 mg
sesameseeds (unhulled) = 125 mg
nonfatcow milk= 122 mg
plain whole-milkyogurt= 121 mg
Food, calcium per 100 grams
hazelnuts= 114 mg
tofu,soft = 114 mg
beetgreens = 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

Measurement in blood

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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 calciumis a measure of free calcium. An abnormally high level of calcium in plasma is termedhypercalcemiaand an abnormally low level is termedhypocalcemia,with "abnormal" generally referring to levels outside thereference range.

Reference ranges for blood testsfor calcium
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]

  • O-Cresolphalein Complexone Method; A disadvantage of this method is that the volatile nature of the2-amino-2-methyl-1-propanolused in this method makes it necessary to calibrate the method every few hours in a clinical laboratory setup.
  • Arsenazo III Method; This method is more robust, but thearsenicin the reagent is a health hazard.

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 vivoorin vitro,a range offluorescentreporters may be used. These include cell permeable, calcium-binding fluorescentdyessuch asFura-2or genetically engineered variant ofgreen fluorescent protein(GFP) namedCameleon.

Corrected calcium

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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 serumalbuminin 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]

Other animals

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Vertebrates

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Main article:Calcium metabolism

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 humanplasmacalcium, 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 asanionsincludingbicarbonate,citrate,phosphate,andsulfate.[37]

Calcium regulationin the human body[38]

Differenttissuescontain calcium in different concentrations. For instance, Ca2+(mostlycalcium phosphateand somecalcium sulfate) is the most important (and specific) element ofboneand 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 pumpsthat utilizeATPfor 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 situduring neuronal activity.[40]

Effects

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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 messengersused insignal transduction.They make their entrance into thecytoplasmeither from outside the cell through thecell membranevia calcium channels (such ascalcium-binding proteinsor voltage-gated calcium channels), or from some internalcalcium storagessuch as theendoplasmic reticulum[4]andmitochondria.Levels of intracellular calcium are regulated bytransport proteinsthat remove it from the cell. For example, thesodium-calcium exchangeruses energy from theelectrochemical gradientof 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 channelsare important forsynaptictransmission through the release ofneurotransmittersinto thesynaptic cleftbyvesicle fusionofsynaptic vesicles.

Calcium's function inmuscle contractionwas 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 Kcachannels 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 tweezersmeasurement 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]

Adaptation

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Ca2+ion flow regulates several secondary messenger systems inneural adaptationfor visual, auditory, and the olfactory system. It may often be bound tocalmodulinsuch as in the olfactory system to either enhance or repress cation channels.[44]Other times the calcium level change can actually releaseguanylyl cyclasefrom 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
Reference ranges for blood tests,showing calcium levels in purple at right

Negative effects and pathology

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Substantial decreases in extracellular Ca2+ion concentrations may result in a condition known ashypocalcemictetany,which is marked by spontaneousmotor neurondischarge. In addition, severehypocalcaemiawill begin to affect aspects ofblood coagulationand 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 traumaorstroke). Excessive entry ofcalciuminto 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 arrhythmiasand decreased neuromuscular excitability. One cause of hypercalcemia is a condition known ashyperparathyroidism.

Invertebrates

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Someinvertebratesuse calcium compounds for building theirexoskeleton(shellsandcarapaces) orendoskeleton(echinodermplates andporiferancalcareousspicules).

Plants

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Stomata closing

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Calcium GCaMP reporter in tomato pollen tube

Whenabscisic acidsignals 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.

Cellular division

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Calcium is a necessary ion in the formation of themitotic spindle.Without the mitotic spindle,cellular divisioncannot 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 thephloembecause it can bind with other nutrient ions andprecipitateout of liquid solutions.

Structural roles

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Ca2+ions are an essential component of plantcell wallsandcell membranes,and are used ascationsto balanceorganicanionsin 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 carbonateplates, with which they are covered.

Calcium is needed to form thepectinin themiddle lamellaof 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.

Someplantsaccumulate Ca in their tissues, thus making them more firm. Calcium is stored as Ca-oxalatecrystals inplastids.

Cell signaling

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Ca2+ions are usually kept at nanomolar levels in thecytosolofplant cells,and act in a number of signal transduction pathways assecond messengers.

See also

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References

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  2. ^abBrini, Marisa; Ottolini, Denis; Calì, Tito; Carafoli, Ernesto (2013). "Calcium in Health and Disease". In Astrid Sigel, Helmut Sigel and Roland K. O. Sigel (ed.).Interrelations between Essential Metal Ions and Human Diseases.Metal Ions in Life Sciences. Vol. 13. Springer. pp. 81–137.doi:10.1007/978-94-007-7500-8_4.ISBN978-94-007-7499-5.PMID24470090.
  3. ^abBrini, Marisa; Call, Tito; Ottolini, Denis; Carafoli, Ernesto (2013). "Intracellular Calcium Homeostasis and Signaling". In Banci, Lucia (ed.).Metallomics and the Cell.Metal Ions in Life Sciences. Vol. 12. Springer. pp. 119–68.doi:10.1007/978-94-007-5561-1_5.ISBN978-94-007-5560-4.PMID23595672.electronic-bookISBN978-94-007-5561-1ISSN1559-0836electronic-ISSN1868-0402
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