Open main menu

Calcium in biology

  (Redirected from Ca2+)

Calcium ions (Ca2+) contribute to the physiology and biochemistry of organisms and the cell. They play an important role in signal transduction pathways,[1][2] where they act as a second messenger, in neurotransmitter release from neurons, in contraction of all muscle cell types, and in fertilization. Many enzymes require calcium ions as a cofactor, including several of the coagulation factors. Extracellular calcium is also important for maintaining the potential difference across excitable cell membranes, as well as proper bone formation.

Plasma calcium levels in mammals are tightly regulated,[1][2] with bone acting as the major mineral storage site. Calcium ions, 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 as serum albumin. Parathyroid hormone secreted by the parathyroid gland regulates the resorption of Ca2+ from bone, reabsorption in the kidney back into circulation, and increases in the activation of vitamin D3 to calcitriol. Calcitriol, the active form of vitamin D3, promotes absorption of calcium from the intestines and bones. Calcitonin secreted from the parafollicular cells of the thyroid gland also affects calcium levels by opposing parathyroid hormone; however, its physiological significance in humans is dubious.

Intracellular calcium is stored in organelles which repetitively release and then reaccumulate Ca2+ ions in response to specific cellular events: storage sites include mitochondria and the endoplasmic reticulum.[3]

Characteristic concentrations of calcium in model organisms are: in E. coli 3mM (bound), 100nM (free), in budding yeast 2mM (bound), in mammalian cell 10-100nM (free) and in blood plasma 2mM.[4]



Age-adjusted daily calcium recommendations (from U.S. Institute of Medicine RDAs)[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
Global dietary calcium intake among adults (mg/day)[6]

Dietary recommendationsEdit

The U.S. Institute of Medicine (IOM) established Recommended Dietary Allowances (RDAs) for calcium in 1997 and updated those values in 2011.[5] 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.[7]

Because of concerns of long-term adverse side effects such as calcification of arteries and kidney stones, the IOM and EFSA both set Tolerable 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.[8] 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.[9]

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.[10] A table of the old and new adult Daily Values is provided at Reference Daily Intake. The original deadline to be in compliance was July 28, 2018, but on September 29, 2017 the FDA released a proposed rule that extended the deadline to January 1, 2020 for large companies and January 1, 2021 for small companies.[11]

Health claimsEdit

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 and osteoporosis was later amended to include calcium and vitamin D supplements, effective January 1, 2010. Examples of allowed wording are shown below. In order to qualify for the calcium health claim, a dietary supplement much contain at least 20% of the Reference Dietary Intake, which for calcium means at least 260 mg/serving.[12]


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 preeclamsia was considered inconclusive.[13] 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.[14] Proposals for QHCs for calcium as protective against kidney stones or against menstrual disorders or pain were rejected.[15][16]

The European Food Safety Authority (EFSA) concluded that "Calcium contributes to the normal development of bones."[17] 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.[18] The EFSA also rejected claims for calcium and nails, hair, blood lipids, premenstrual syndrome and body weight maintenance.[19]

Food sourcesEdit

The United 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.[20]

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
almonds = 234 mg
collard greens = 232 mg
kale = 150 mg
goat milk = 134 mg
sesame seeds (unhulled) = 125 mg
nonfat cow milk = 122 mg
plain whole-milk yogurt = 121 mg
Food, calcium per 100 grams
hazelnuts = 114 mg
tofu, soft = 114 mg
beet greens = 114 mg
spinach = 99 mg
ricotta (skimmed milk cheese) = 90 mg
lentils = 79 mg
chickpeas = 53 mg
eggs, boiled = 50 mg
orange = 40 mg
human milk = 33 mg
rice, white, long-grain = 19 mg
beef = 12 mg
cod = 11 mg

Measurement in bloodEdit


Reference ranges for blood tests for calcium
Target Lower limit Upper limit Unit
Ionized calcium 1.03,[21] 1.10[22] 1.23,[21] 1.30[22] mmol/L
4.1,[23] 4.4[23] 4.9,[23] 5.2[23] mg/dL
Total calcium 2.1,[24][25] 2.2[22] 2.5,[22][25] 2.6,[25] 2.8[24] mmol/L
8.4,[24] 8.5[26] 10.2,[24] 10.5[26] mg/dL

The main methods to measure serum calcium are:[27]


The total amount of Ca2+ present in a tissue may be measured using Atomic absorption spectroscopy, in which the tissue is vaporized and combusted. To measure Ca2+ concentration or spatial distribution within the cell cytoplasm in vivo or in vitro, a range of fluorescent reporters may be used. These include cell permeable, calcium-binding fluorescent dyes such as Fura-2 or genetically engineered variant of green fluorescent protein (GFP) named Cameleon.

Corrected calciumEdit

As access to an ionized calcium is not always available a corrected calcium may be used instead. To calculate a corrected calcium in mmo/l one takes the total calcium in mmol/L and adds it to ((40 minus the serum albumin in g/L) multiplied by 0.2).[28]




Calcium regulation in the human body[30]







Calcium coordination plays an important role in defining the structure and function of proteins. An example a protein with calcium coordination is von Willebrand factor (vWF) which has an essential role in blood clot formation process. It was discovered using single molecule optical 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.[35]


Ca2+ ion flow regulates several secondary messenger systems in neural adaptation for visual, auditory, and the olfactory system. It may often be bound to calmodulin such as in the olfactory system to either enhance or repress cation channels.[36] Other times the calcium level change can actually release guanylyl cyclase from inhibition, like in the photoreception system.[37] 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.[38]

Cell type Effect
Endothelial cells ↑Vasodilation
Secretory cells (mostly) ↑Secretion (vesicle fusion)
Juxtaglomerular cell ↓Secretion[39]
Parathyroid chief cells ↓Secretion[39]
Neurons Transmission (vesicle fusion), neural adaptation
T cells Activation in response to antigen presentation to the T cell receptor[40]
Various Activation of protein kinase C
Further reading: Function of protein kinase C

Negative effects and pathologyEdit






Stomata closingEdit


Cellular divisionEdit


Structural rolesEdit





Cell signalingEdit


See alsoEdit


  1. ^ a b Brini, Marisa; Ottolini, Denis; Calì, Tito; Carafoli, Ernesto (2013). "Chapter 4. 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. 13. Springer. pp. 81–137. doi:10.1007/978-94-007-7500-8_4. ISBN 978-94-007-7499-5. PMID 24470090.
  2. ^ a b Brini, Marisa; Call, Tito; Ottolini, Denis; Carafoli, Ernesto (2013). "Chapter 5 Intracellular Calcium Homeostasis and Signaling". In Banci, Lucia (ed.). Metallomics and the Cell. Metal Ions in Life Sciences. 12. Springer. pp. 119–68. doi:10.1007/978-94-007-5561-1_5. ISBN 978-94-007-5560-4. PMID 23595672. electronic-book ISBN 978-94-007-5561-1 ISSN 1559-0836 electronic-ISSN 1868-0402
  4. ^ Milo, Ron; Philips, Rob. "Cell Biology by the Numbers: What are the concentrations of different ions in cells?". Retrieved 24 March 2017.
  11. ^ "Changes to the Nutrition Facts Panel - Compliance Date"
  12. ^ Food Labeling: Health Claims; Calcium and Osteoporosis, and Calcium, Vitamin D, and Osteoporosis U.S. Food and Drug Administration.
  13. ^ Qualified Health Claims: Letter of Enforcement Discretion - Calcium and Hypertension; Pregnancy-Induced Hypertension; and Preeclampsia (Docket No. 2004Q-0098) U.S. Food and Drug Administration (2005).
  14. ^ Qualified Health Claims: Letter Regarding Calcium and Colon/Rectal, Breast, and Prostate Cancers and Recurrent Colon Polyps -(Docket No. 2004Q-0097) U.S. Food and Drug Administration (2005).
  15. ^ Qualified Health Claims: Letter of Denial - Calcium and Kidney Stones; Urinary Stones; and Kidney Stones and Urinary Stones (Docket No. 2004Q-0102) U.S. Food and Drug Administration (2005).
  16. ^ Qualified Health Claims: Letters of Denial - Calcium and a Reduced Risk Of Menstrual Disorders (Docket No. 2004Q-0099) U.S. Food and Drug Administration (2005)
  17. ^ Calcium and contribution to the normal development of bones: evaluation of a health claim European Food Safety Authority (2016).
  18. ^ Scientific Opinion on the substantiation of health claims related to calcium and potassium and maintenance of normal acid-base balance European Food Safety Authority (2011).
  19. ^ Scientific Opinion on the substantiation of health claims related to calcium and maintenance of normal bone and teeth (ID 2731, 3155, 4311, 4312, 4703), maintenance of normal hair and nails (ID 399, 3155), maintenance of normal blood LDL-cholesterol concentrations (ID 349, 1893), maintenance of normal blood HDL-cholesterol concentrations (ID 349, 1893), reduction in the severity of symptoms related to the premenstrual syndrome (ID 348, 1892), “cell membrane permeability” (ID 363), reduction of tiredness and fatigue (ID 232), contribution to normal psychological functions (ID 233), contribution to the maintenance or achievement of a normal body weight (ID 228, 229) and regulation of normal cell division and differentiation EFSA Journal 2010;8(10):1725.
  20. ^ "Food Composition Databases Show Nutrients List". USDA Food Composition Databases. United States Department of Agriculture: Agricultural Research Service. Retrieved November 29, 2017.
  26. ^ a b Blood Test Results – Normal Ranges Archived 2012-11-02 at the Wayback Machine Bloodbook.Com
  31. ^
  35. ^ Jakobi AJ, Mashaghi A, Tans SJ, Huizinga EG. Calcium modulates force sensing by the von Willebrand factor A2 domain. Nature Communications 2011 Jul 12;2:385. [1]
  36. ^ Dougherty, D. P.; Wright, G. A.; Yew, A. C. (2005). "Computational model of the cAMP-mediated sensory response and calcium-dependent adaptation in vertebrate olfactory receptor neurons". Proceedings of the National Academy of Sciences. 102 (30): 10415–20. doi:10.1073/pnas.0504099102. PMC 1180786. PMID 16027364.
  37. ^ Pugh Jr, E. N.; Lamb, T. D. (1990). "Cyclic GMP and calcium: The internal messengers of excitation and adaptation in vertebrate photoreceptors". Vision Research. 30 (12): 1923–48. doi:10.1016/0042-6989(90)90013-b. PMID 1962979.
  38. ^ Gillespie, P. G.; Cyr, J. L. (2004). "Myosin-1c, the hair cell's adaptation motor". Annual Review of Physiology. 66: 521–45. doi:10.1146/annurev.physiol.66.032102.112842. PMID 14977412.
  40. ^ Levinson, Warren (2008). Review of medical microbiology and immunology. McGraw-Hill Medical. p. 414. ISBN 978-0-07-149620-9.

External linksEdit