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Calcium in biology

Calcium ions (Ca2+) contribute to the physiology and biochemistry of organisms' cells. They play an important role in signal transduction pathways,[2][3] 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.

Calcium is used in many nerves in the voltage-gated calcium channel which is slightly slower than the voltage-gated potassium channel. It is most notably used in the cardiac action potential[1]

Plasma calcium levels in mammals are tightly regulated,[2][3] 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.[4]

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.[5]

Humans edit

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 1 million prescriptions.[8][9]

Dietary recommendations edit

The U.S. Institute of Medicine (IOM) established Recommended 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 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.[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 edit

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 at Reference Daily Intake.

Health claims edit

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 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]

The European 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 edit

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.[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
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
ricottas (skimmed milk cheese) = 90 mg
lentils = 79 mg
chickpeas = 53 mg
rolled oats = 52 mg[25]
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 blood edit

The amount of calcium in blood (more specifically, in blood plasma) can be measured as total 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 termed hypercalcemia and an abnormally low level is termed hypocalcemia, with "abnormal" generally referring to levels outside the reference range.

Reference ranges for blood tests for 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 the 2-amino-2-methyl-1-propanol used 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 the arsenic in the reagent is a health hazard.

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 calcium edit

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 serum albumin 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 the anion gap.[35][36]

Other animals edit

Vertebrates edit

In vertebrates, 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 human plasma 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 as albumin, as well as anions including bicarbonate, citrate, phosphate, and sulfate.[37]

 
Calcium regulation in the human body[38]

Different tissues contain calcium in different concentrations. For instance, Ca2+ (mostly calcium phosphate and some calcium sulfate) is the most important (and specific) element of bone and calcified cartilage. 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 of bone resorption, in which calcium is liberated into the bloodstream through the action of bone osteoclasts. 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 membrane calcium pumps that utilize ATP for energy, as well as a sizable storage within intracellular compartments. In electrically 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 levels in situ during neuronal activity.[40]

Effects edit

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 widespread second messengers used in signal transduction. They make their entrance into the cytoplasm either from outside the cell through the cell membrane via calcium channels (such as calcium-binding proteins or voltage-gated calcium channels), or from some internal calcium storages such as the endoplasmic reticulum[4] and mitochondria. Levels of intracellular calcium are regulated by transport proteins that remove it from the cell. For example, the sodium-calcium exchanger uses energy from the electrochemical 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, the plasma membrane Ca2+ ATPase (PMCA) obtains energy to pump calcium out of the cell by hydrolysing adenosine triphosphate (ATP). In neurons, voltage-dependent, calcium-selective ion channels are important for synaptic transmission through the release of neurotransmitters into the synaptic cleft by vesicle fusion of synaptic vesicles.

Calcium's function in muscle 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 with cAMP, they are called synarchic messengers. Calcium can bind to several different calcium-modulated proteins such as troponin-C (the first one to be identified) and calmodulin, 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 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.[43]

Adaptation edit

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.[44] Other times the calcium level change can actually release guanylyl 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 the T cell receptor[48]
Myocytes
Various Activation of protein 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 edit

Substantial decreases in extracellular Ca2+ ion concentrations may result in a condition known as hypocalcemic tetany, which is marked by spontaneous motor neuron discharge. In addition, severe hypocalcaemia will begin to affect aspects of blood coagulation and signal transduction.

Ca2+ ions can damage cells if they enter in excessive numbers (for example, in the case of excitotoxicity, or over-excitation of neural circuits, which can occur in neurodegenerative diseases, or after insults such as brain trauma or stroke). Excessive entry of calcium into a cell may damage it or even cause it to undergo apoptosis, or death by necrosis. Calcium also acts as one of the primary regulators of osmotic stress (osmotic shock). Chronically elevated plasma calcium (hypercalcemia) is associated with cardiac arrhythmias and decreased neuromuscular excitability. One cause of hypercalcemia is a condition known as hyperparathyroidism.

Invertebrates edit

Some invertebrates use calcium compounds for building their exoskeleton (shells and carapaces) or endoskeleton (echinoderm plates and poriferan calcareous spicules).

Plants edit

Stomata closing edit

When abscisic 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.

Cellular division edit

Calcium is a necessary ion in the formation of the mitotic 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 the phloem because it can bind with other nutrient ions and precipitate out of liquid solutions.

Structural roles edit

Ca2+ ions are an essential component of plant cell walls and cell membranes, and are used as cations to balance organic anions in the plant vacuole.[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 marine coccolithophores, which use Ca2+ to form the calcium carbonate plates, with which they are covered.

Calcium is needed to form the pectin in the middle 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.

Some plants accumulate Ca in their tissues, thus making them more firm. Calcium is stored as Ca-oxalate crystals in plastids.

Cell signaling edit

Ca2+ ions are usually kept at nanomolar levels in the cytosol of plant cells, and act in a number of signal transduction pathways as second messengers.

See also edit

References edit

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  2. ^ a b Brini, 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. ISBN 978-94-007-7499-5. PMID 24470090.
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External links edit

  • United States Department of Agriculture: Vitamin D and Calcium 2020-05-20 at the Wayback Machine
  • National Osteoporosis Foundation: Calcium and vitamin D

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Calcium ions Ca2 contribute to the physiology and biochemistry of organisms cells They play an important role in signal transduction pathways 2 3 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 Calcium is used in many nerves in the voltage gated calcium channel which is slightly slower than the voltage gated potassium channel It is most notably used in the cardiac action potential 1 Plasma calcium levels in mammals are tightly regulated 2 3 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 4 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 5 Contents 1 Humans 1 1 Dietary recommendations 1 1 1 Labeling 1 2 Health claims 1 3 Food sources 1 4 Measurement in blood 1 4 1 Corrected calcium 2 Other animals 2 1 Vertebrates 2 1 1 Effects 2 1 2 Adaptation 2 1 3 Negative effects and pathology 2 2 Invertebrates 3 Plants 3 1 Stomata closing 3 2 Cellular division 3 3 Structural roles 3 4 Cell signaling 4 See also 5 References 6 External linksHumans editAge adjusted daily calcium recommendations from U S Institute of Medicine RDAs 6 Age Calcium mg day 1 3 years 7004 8 years 10009 18 years 130019 50 years 1000 gt 51 years 1000Pregnancy 1000Lactation 1000 nbsp Global dietary calcium intake among adults mg day 7 lt 400 400 500 500 600 600 700 700 800 800 900 900 1000 gt 1000In 2021 calcium was the 243rd most commonly prescribed medication in the United States with more than 1 million prescriptions 8 9 Dietary recommendations edit The U S Institute of Medicine IOM established Recommended 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 gt 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 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 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 edit 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 at Reference Daily Intake Health claims edit 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 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 The European 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 edit 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 23 24 Food calcium per 100 gramsparmesan cheese 1140 mgmilk powder 909 mggoat hard cheese 895 mgCheddar cheese 720 mgtahini paste 427 mgmolasses 273 mgsardines 240 mgalmonds 234 mgcollard greens 232 mgkale 150 mggoat milk 134 mgsesame seeds unhulled 125 mgnonfat cow milk 122 mgplain whole milk yogurt 121 mg Food calcium per 100 gramshazelnuts 114 mgtofu soft 114 mgbeet greens 114 mgspinach 99 mgricottas skimmed milk cheese 90 mglentils 79 mgchickpeas 53 mgrolled oats 52 mg 25 eggs boiled 50 mgorange 40 mghuman milk 33 mgrice white long grain 19 mgbeef 12 mgcod 11 mg Measurement in blood edit The amount of calcium in blood more specifically in blood plasma can be measured as total 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 termed hypercalcemia and an abnormally low level is termed hypocalcemia with abnormal generally referring to levels outside the reference range Reference ranges for blood tests for calcium Target Lower limit Upper limit UnitIonized calcium 1 03 26 1 10 27 1 23 26 1 30 27 mmol L4 1 28 4 4 28 4 9 28 5 2 28 mg dLTotal calcium 2 1 29 30 2 2 27 2 5 27 30 2 6 30 2 8 29 mmol L8 4 29 8 5 31 10 2 29 10 5 31 mg dLThe main methods to measure serum calcium are 32 O Cresolphalein Complexone Method A disadvantage of this method is that the volatile nature of the 2 amino 2 methyl 1 propanol used 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 the arsenic in the reagent is a health hazard 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 calcium edit 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 serum albumin 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 the anion gap 35 36 Other animals editVertebrates edit Main article Calcium metabolism In vertebrates 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 human plasma 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 as albumin as well as anions including bicarbonate citrate phosphate and sulfate 37 nbsp Calcium regulation in the human body 38 Different tissues contain calcium in different concentrations For instance Ca2 mostly calcium phosphate and some calcium sulfate is the most important and specific element of bone and calcified cartilage 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 of bone resorption in which calcium is liberated into the bloodstream through the action of bone osteoclasts 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 membrane calcium pumps that utilize ATP for energy as well as a sizable storage within intracellular compartments In electrically 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 levels in situ during neuronal activity 40 Effects edit 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 widespread second messengers used in signal transduction They make their entrance into the cytoplasm either from outside the cell through the cell membrane via calcium channels such as calcium binding proteins or voltage gated calcium channels or from some internal calcium storages such as the endoplasmic reticulum 4 and mitochondria Levels of intracellular calcium are regulated by transport proteins that remove it from the cell For example the sodium calcium exchanger uses energy from the electrochemical 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 the plasma membrane Ca2 ATPase PMCA obtains energy to pump calcium out of the cell by hydrolysing adenosine triphosphate ATP In neurons voltage dependent calcium selective ion channels are important for synaptic transmission through the release of neurotransmitters into the synaptic cleft by vesicle fusion of synaptic vesicles Calcium s function in muscle 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 with cAMP they are called synarchic messengers Calcium can bind to several different calcium modulated proteins such as troponin C the first one to be identified and calmodulin 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 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 43 Adaptation edit 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 44 Other times the calcium level change can actually release guanylyl 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 EffectEndothelial cells VasodilationSecretory cells mostly Secretion vesicle fusion Juxtaglomerular cell Secretion 47 Parathyroid chief cells Secretion 47 Neurons Transmission vesicle fusion neural adaptationT cells Activation in response to antigen presentation to the T cell receptor 48 Myocytes Contraction Activation of protein kinase CVarious Activation of protein kinase C Further reading Function of protein kinase C nbsp Reference ranges for blood tests showing calcium levels in purple at rightNegative effects and pathology edit Substantial decreases in extracellular Ca2 ion concentrations may result in a condition known as hypocalcemic tetany which is marked by spontaneous motor neuron discharge In addition severe hypocalcaemia will begin to affect aspects of blood coagulation and signal transduction Ca2 ions can damage cells if they enter in excessive numbers for example in the case of excitotoxicity or over excitation of neural circuits which can occur in neurodegenerative diseases or after insults such as brain trauma or stroke Excessive entry of calcium into a cell may damage it or even cause it to undergo apoptosis or death by necrosis Calcium also acts as one of the primary regulators of osmotic stress osmotic shock Chronically elevated plasma calcium hypercalcemia is associated with cardiac arrhythmias and decreased neuromuscular excitability One cause of hypercalcemia is a condition known as hyperparathyroidism Invertebrates edit Some invertebrates use calcium compounds for building their exoskeleton shells and carapaces or endoskeleton echinoderm plates and poriferan calcareous spicules Plants editStomata closing edit When abscisic 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 Cellular division edit Calcium is a necessary ion in the formation of the mitotic 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 the phloem because it can bind with other nutrient ions and precipitate out of liquid solutions Structural roles edit Ca2 ions are an essential component of plant cell walls and cell membranes and are used as cations to balance organic anions in the plant vacuole 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 marine coccolithophores which use Ca2 to form the calcium carbonate plates with which they are covered Calcium is needed to form the pectin in the middle 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 Some plants accumulate Ca in their tissues thus making them more firm Calcium is stored as Ca oxalate crystals in plastids Cell signaling edit Ca2 ions are usually kept at nanomolar levels in the cytosol of plant cells and act in a number of signal transduction pathways as second messengers See also editBiology and pharmacology of chemical elements Iodine in biology Use of Iodine by organisms Magnesium in biology Use of Magnesium by organisms Osteoporosis Skeletal disorder Potassium in biology Use of Potassium by organisms Selenium in biology Use of Selenium by organisms Sodium in biology Use of Sodium by organisms Vitamin D Group of fat soluble secosteroidsReferences edit Kleber Andre G Rudy Yoram 2004 04 01 Basic Mechanisms of Cardiac Impulse Propagation and Associated Arrhythmias Physiological Reviews 84 2 431 488 doi 10 1152 physrev 00025 2003 ISSN 0031 9333 PMID 15044680 a b Brini Marisa Ottolini Denis Cali 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 ISBN 978 94 007 7499 5 PMID 24470090 a b Brini 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 ISBN 978 94 007 5560 4 PMID 23595672 electronic book ISBN 978 94 007 5561 1 ISSN 1559 0836 electronic ISSN 1868 0402 a b Wilson C H Ali E S Scrimgeour N Martin A M Hua J Tallis G A Rychkov G Y Barritt G J 2015 Steatosis inhibits liver cell store operated Ca 2 entry and reduces ER Ca 2 through a protein kinase C dependent mechanism Biochem J 466 2 379 90 doi 10 1042 bj20140881 PMID 25422863 Milo Ron Philips Rob Cell Biology by the Numbers What are the concentrations of different ions in cells book bionumbers org Retrieved 24 March 2017 a b Institute of Medicine US Committee to Review Dietary Reference Intakes for Vitamin D Calcium Ross A C Taylor C L Yaktine A L Del Valle H B 2011 Dietary Reference Intakes for Calcium and Vitamin D Chapter 5 Dietary Reference Intakes pages 345 402 Washington D C National Academies Press doi 10 17226 13050 ISBN 978 0 309 16394 1 PMID 21796828 S2CID 58721779 Balk EM Adam GP Langberg VN Earley A Clark P Ebeling PR Mithal A Rizzoli R Zerbini CA Pierroz DD Dawson Hughes B December 2017 Global dietary calcium intake among adults a systematic review Osteoporosis International 28 12 3315 24 doi 10 1007 s00198 017 4230 x PMC 5684325 PMID 29026938 The Top 300 of 2021 ClinCalc Archived from the original on 15 January 2024 Retrieved 14 January 2024 Calcium Drug Usage Statistics ClinCalc Retrieved 14 January 2024 Overview on Dietary Reference Values for the EU population as derived by the EFSA Panel on Dietetic Products Nutrition and Allergies PDF 2017 Institute of Medicine US Committee to Review Dietary Reference Intakes for Vitamin D Calcium Ross A C Taylor C L Yaktine A L Del Valle H B 2011 Dietary Reference Intakes for Calcium and Vitamin D Chapter 6 Tolerable Upper Intake Levels pages 403 56 Washington D C National Academies Press doi 10 17226 13050 ISBN 978 0 309 16394 1 PMID 21796828 S2CID 58721779 Tolerable Upper Intake Levels For Vitamins And Minerals PDF European Food Safety Authority 2006 Federal Register May 27 2016 Food Labeling Revision of the Nutrition and Supplement Facts Labels FR page 33982 PDF Daily Value Reference of the Dietary Supplement Label Database DSLD Dietary Supplement Label Database DSLD Archived from the original on 7 April 2020 Retrieved 16 May 2020 Food Labeling Health Claims Calcium and Osteoporosis and Calcium Vitamin D and Osteoporosis U S Food and Drug Administration 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 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 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 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 Calcium and contribution to the normal development of bones evaluation of a health claim Archived 2019 12 20 at the Wayback Machine European Food Safety Authority 2016 Scientific Opinion on the substantiation of health claims related to calcium and potassium and maintenance of normal acid base balance Archived 2019 09 01 at the Wayback Machine European Food Safety Authority 2011 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 Archived 2019 09 01 at the Wayback Machine EFSA Journal 2010 8 10 1725 Food Composition Databases Show Nutrients List USDA Food Composition Databases United States Department of Agriculture Agricultural Research Service Retrieved November 29 2017 dead link SR Legacy Nutrient Search usda gov Retrieved April 7 2020 FoodData Central a b Larsson L Ohman S November 1978 Serum ionized calcium and corrected total calcium in borderline hyperparathyroidism Clin Chem 24 11 1962 65 doi 10 1093 clinchem 24 11 1962 PMID 709830 Archived from the original on 2019 12 12 Retrieved 2011 10 21 a b c d Reference range list from Uppsala University Hospital Laborationslista Artnr 40284 Sj74a Issued on April 22 2008 a b c d Derived from molar values using molar mass of 40 08 g mol 1 a b c d Last page of Deepak A Rao Le Tao Bhushan Vikas 2007 First Aid for the USMLE Step 1 2008 First Aid for the Usmle Step 1 McGraw Hill Medical ISBN 978 0 07 149868 5 a b c Derived from mass values using molar mass of 40 08 g mol 1 a b Blood Test Results Normal Ranges Archived 2012 11 02 at the Wayback Machine Bloodbook Com Clin Chem 1992 Jun 38 6 904 08 Single stable reagent Arsenazo III for optically robust measurement of calcium in serum and plasma Leary NO Pembroke A Duggan PF Minisola S Pepe J Piemonte S Cipriani C 2 June 2015 The diagnosis and management of hypercalcaemia BMJ Clinical Research Ed 350 h2723 doi 10 1136 bmj h2723 PMID 26037642 S2CID 28462200 Thomas Lynn K Othersen Jennifer Bohnstadt 2016 Nutrition Therapy for Chronic Kidney Disease CRC Press p 116 ISBN 978 1 4398 4950 7 Yap E Roche Recinos A Goldwasser P 30 December 2019 Predicting Ionized Hypocalcemia in Critical Care An Improved Method Based on the Anion Gap The Journal of Applied Laboratory Medicine 5 1 4 14 doi 10 1373 jalm 2019 029314 PMID 32445343 Yap E Ouyang J Puri I Melaku Y Goldwasser P 1 June 2022 Novel methods of predicting ionized calcium status from routine data in critical care External validation in MIMIC III Clinica Chimica Acta 531 375 381 doi 10 1016 j cca 2022 05 003 PMID 35526587 S2CID 248568849 Brini Marisa Ottolini Denis Cali 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 81 138 doi 10 1007 978 94 007 7500 8 4 ISBN 978 94 007 7499 5 PMID 24470090 Boron Walter F Boulpaep Emile L 2003 The Parathyroid Glands and Vitamin D Medical Physiology A Cellular And Molecular Approach Elsevier Saunders p 1094 ISBN 978 1 4160 2328 9 Clapham David E 2007 Calcium Signaling Cell 131 6 1047 1058 doi 10 1016 j cell 2007 11 028 PMID 18083096 S2CID 15087548 Ivannikov M et al 2013 Mitochondrial Free Ca2 Levels and Their Effects on Energy Metabolism in Drosophila Motor Nerve Terminals Biophys J 104 11 2353 61 Bibcode 2013BpJ 104 2353I doi 10 1016 j bpj 2013 03 064 PMC 3672877 PMID 23746507 Christopher J Garland C Robin Hiley Kim A Dora EDHF spreading the influence of the endothelium British Journal of Pharmacology 164 3 839 52 2011 Hua Cai David G Harrison Endothelial Dysfunction in Cardiovascular Diseases The Role of Oxidant Stress Circulation Research 87 840 44 2000 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 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 Bibcode 2005PNAS 10210415D doi 10 1073 pnas 0504099102 PMC 1180786 PMID 16027364 Pugh E N Jr 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 S2CID 22506803 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 a b Boron Walter F Boulpaep Emile L 2003 Medical Physiology A Cellular And Molecular Approach Elsevier Saunders p 867 ISBN 978 1 4160 2328 9 Levinson Warren 2008 Review of medical microbiology and immunology McGraw Hill Medical p 414 ISBN 978 0 07 149620 9 White Philip J Martin R Broadley 2003 Calcium in Plants Annals of Botany 92 4 487 511 doi 10 1093 aob mcg164 PMC 4243668 PMID 12933363 External links editUnited States Department of Agriculture Vitamin D and Calcium Archived 2020 05 20 at the Wayback Machine National Osteoporosis Foundation Calcium and vitamin D Retrieved from https en wikipedia org w index php title Calcium in biology amp oldid 1204654363, wikipedia, wiki, book, books, library,

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