Calcium signaling
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Calcium signaling is the use of
calcium ions Calcium ions (Ca2+) contribute to the physiology and biochemistry of organisms' cells. They play an important role in signal transduction pathways, where they act as a second messenger, in neurotransmitter release from neurons, in contractio ...
(Ca2+) to communicate and drive intracellular processes often as a step in signal transduction. Ca2+ is important for
cellular signalling In biology, cell signaling (cell signalling in British English) or cell communication is the ability of a cell to receive, process, and transmit signals with its environment and with itself. Cell signaling is a fundamental property of all cellula ...
, for once it enters the
cytosol The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells ( intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...
of the
cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. ...
it exerts allosteric regulatory effects on many
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
s and
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
s. Ca2+ can act in signal transduction resulting from activation of ion channels or as a second messenger caused by indirect signal transduction pathways such as
G protein-coupled receptors G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
.


Concentration regulation

The resting concentration of Ca2+ in the
cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. ...
is normally maintained around 100 nM. This is 20,000- to 100,000-fold lower than typical extracellular concentration. To maintain this low concentration, Ca2+ is actively pumped from the cytosol to the extracellular space, the endoplasmic reticulum (ER), and sometimes into the mitochondria. Certain proteins of the cytoplasm and organelles act as buffers by binding Ca2+. Signaling occurs when the cell is stimulated to release Ca2+ ions from intracellular stores, and/or when Ca2+ enters the cell through plasma membrane ion channels. Under certain conditions, the intracellular Ca2+ concentration may begin to oscillate at a specific frequency.


Phospholipase C pathway

Specific signals can trigger a sudden increase in the cytoplasmic Ca2+ levels to 500–1,000 nM by opening channels in the ER or the plasma membrane. The most common signaling pathway that increases cytoplasmic calcium concentration is the phospholipase C (PLC) pathway. # Many
cell surface receptor Cell surface receptors (membrane receptors, transmembrane receptors) are receptors that are embedded in the plasma membrane of cells. They act in cell signaling by receiving (binding to) extracellular molecules. They are specialized integral m ...
s, including
G protein-coupled receptors G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
and
receptor tyrosine kinases Receptor tyrosine kinases (RTKs) are the high- affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinas ...
, activate the PLC enzyme. # PLC uses
hydrolysis Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile. Biological hydrolys ...
of the membrane phospholipid PIP2 to form IP3 and
diacylglycerol A diglyceride, or diacylglycerol (DAG), is a glyceride consisting of two fatty acid chains covalently bonded to a glycerol molecule through ester linkages. Two possible forms exist, 1,2-diacylglycerols and 1,3-diacylglycerols. DAGs can act as s ...
(DAG), two classic secondary messengers. # DAG attaches to the plasma membrane and recruits protein kinase C (PKC). # IP3 diffuses to the ER and is bound to the
IP3 receptor Inositol trisphosphate receptor (InsP3R) is a membrane glycoprotein complex acting as a Ca2+ channel activated by inositol trisphosphate (InsP3). InsP3R is very diverse among organisms, and is necessary for the control of cellular and physio ...
. # The IP3 receptor serves as a Ca2+ channel, and releases Ca2+ from the ER. # The Ca2+ bind to PKC and other proteins and activate them.


Depletion from the endoplasmic reticulum

Depletion of Ca2+ from the ER will lead to Ca2+ entry from outside the cell by activation of "Store-Operated Channels" (
SOCs SOCS (suppressor of cytokine signaling proteins) refers to a family of genes involved in inhibiting the JAK-STAT signaling pathway. Genes * CISH * SOCS1 * SOCS2 * SOCS3 * SOCS4 * SOCS5 * SOCS6 * SOCS7 Suppressor of cytokine signaling 7 is a pro ...
). This inflow of Ca2+ is referred to as Ca2+-release-activated Ca2+ current ( ICRAC). The mechanisms through which ICRAC occurs are currently still under investigation. Although Orai1 and
STIM1 Stromal interaction molecule 1 is a protein that in humans is encoded by the ''STIM1'' gene. STIM1 has a single transmembrane domain, and is localized to the endoplasmic reticulum, and to a lesser extent to the plasma membrane. Even though the pro ...
, have been linked by several studies, for a proposed model of store-operated calcium influx. Recent studies have cited the
phospholipase A phospholipase is an enzyme that hydrolyzes phospholipids into fatty acids and other lipophilic substances. Acids trigger the release of bound calcium from cellular stores and the consequent increase in free cytosolic Ca2+, an essential step in ...
A2 beta,
nicotinic acid adenine dinucleotide phosphate Nicotinic acid adenine dinucleotide phosphate, (NAADP), is a Ca2+-mobilizing second messenger synthesised in response to extracellular stimuli. Like its mechanistic cousins, IP3 and cyclic adenosine diphosphoribose (Cyclic ADP-ribose), NAADP bind ...
(NAADP), and the protein STIM 1 as possible mediators of ICRAC.


As a second messenger

Calcium is a ubiquitous second messenger with wide-ranging physiological roles. These include
muscle contraction Muscle contraction is the activation of tension-generating sites within muscle cells. In physiology, muscle contraction does not necessarily mean muscle shortening because muscle tension can be produced without changes in muscle length, such as ...
, neuronal transmission (as in an
excitatory synapse An excitatory synapse is a synapse in which an action potential in a presynaptic neuron increases the probability of an action potential occurring in a postsynaptic cell. Neurons form networks through which nerve impulses travel, each neuron ofte ...
), cellular
motility Motility is the ability of an organism to move independently, using metabolic energy. Definitions Motility, the ability of an organism to move independently, using metabolic energy, can be contrasted with sessility, the state of organisms th ...
(including the movement of flagella and cilia),
fertilization Fertilisation or fertilization (see spelling differences), also known as generative fertilisation, syngamy and impregnation, is the fusion of gametes to give rise to a new individual organism or offspring and initiate its development. Proce ...
, cell growth (proliferation), neurogenesis, learning and memory as with
synaptic plasticity In neuroscience, synaptic plasticity is the ability of synapses to strengthen or weaken over time, in response to increases or decreases in their activity. Since memories are postulated to be represented by vastly interconnected neural circuits ...
, and secretion of saliva. High levels of cytoplasmic Ca2+ can also cause the cell to undergo apoptosis. Other biochemical roles of calcium include regulating
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
activity, permeability of ion channels, activity of
ion pumps An ion pump (also referred to as a sputter ion pump) is a type of vacuum pump which operates by sputtering a metal getter. Under ideal conditions, ion pumps are capable of reaching pressures as low as 10−11 mbar. An ion pump first ionizes ga ...
, and components of the
cytoskeleton The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is com ...
. Many of Ca2+ mediated events occur when the released Ca2+ binds to and activates the regulatory protein calmodulin. Calmodulin may activate the Ca2+-calmodulin-dependent
protein kinase A protein kinase is a kinase which selectively modifies other proteins by covalently adding phosphates to them (phosphorylation) as opposed to kinases which modify lipids, carbohydrates, or other molecules. Phosphorylation usually results in a fu ...
s, or may act directly on other effector proteins. Besides calmodulin, there are many other Ca2+-binding proteins that mediate the biological effects of Ca2+.


In muscle contractions

Contractions of skeletal
muscle fiber A muscle cell is also known as a myocyte when referring to either a cardiac muscle cell (cardiomyocyte), or a smooth muscle cell as these are both small cells. A skeletal muscle cell is long and threadlike with many nuclei and is called a muscl ...
are caused due to electrical stimulation. This process is caused by the
depolarization In biology, depolarization or hypopolarization is a change within a cell, during which the cell undergoes a shift in electric charge distribution, resulting in less negative charge inside the cell compared to the outside. Depolarization is ess ...
of the transverse tubular junctions. Once depolarized the sarcoplasmic reticulum (SR) releases Ca2+ into the myoplasm where it will bind to a number of calcium sensitive buffers. The Ca2+ in the myoplasm will diffuse to Ca2+ regulator sites on the
thin filaments Myofilaments are the three protein filaments of myofibrils in muscle cells. The main proteins involved are myosin, actin, and titin. Myosin and actin are the ''contractile proteins'' and titin is an elastic protein. The myofilaments act together ...
. This leads to the actual contraction of the muscle. Contractions of smooth muscle fiber are dependent on how a Ca2+ influx occurs. When a Ca2+ influx occurs, cross bridges form between myosin and
actin Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of ov ...
leading to the contraction of the muscle fibers. Influxes may occur from extracellular Ca2+ diffusion via ion channels. This can lead to three different results. The first is a uniform increase in the Ca2+ concentration throughout the cell. This is responsible for increases in vascular diameters. The second is a rapid time dependent change in the membrane potential which leads to a very quick and uniform increase of Ca2+. This can cause a spontaneous release of neurotransmitters via sympathetic or parasympathetic nerve channels. The last potential result is a specific and localized subplasmalemmal Ca2+ release. This type of release increases the activation of
protein kinase A protein kinase is a kinase which selectively modifies other proteins by covalently adding phosphates to them (phosphorylation) as opposed to kinases which modify lipids, carbohydrates, or other molecules. Phosphorylation usually results in a fu ...
, and is seen in
cardiac muscle Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle th ...
where it causes excitation-concentration coupling. Ca2+ may also result from internal stores found in the SR. This release may be caused by Ryaodine (RYRs) or IP3 receptors. RYRs Ca2+ release is spontaneous and localized. This has been observed in a number of smooth muscle tissues including
arteries An artery (plural arteries) () is a blood vessel in humans and most animals that takes blood away from the heart to one or more parts of the body (tissues, lungs, brain etc.). Most arteries carry oxygenated blood; the two exceptions are the pu ...
, portal vein,
urinary bladder The urinary bladder, or simply bladder, is a hollow organ in humans and other vertebrates that stores urine from the kidneys before disposal by urination. In humans the bladder is a distensible organ that sits on the pelvic floor. Urine ente ...
,
ureter The ureters are tubes made of smooth muscle that propel urine from the kidneys to the urinary bladder. In a human adult, the ureters are usually long and around in diameter. The ureter is lined by urothelial cells, a type of transitional epit ...
tissues, airway tissues, and
gastrointestinal The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans and ...
tissues. IP3 Ca2+ release is caused by activation of the IP3 receptor on the SR. These influxes are often spontaneous and localized as seen in the colon and portal vein, but may lead to a global Ca2+ wave as observed in many vascular tissues.


In neurons

In
neuron A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. ...
s, concomitant increases in cytosolic and mitochondrial Ca2+ are important for the synchronization of neuronal electrical activity with mitochondrial energy metabolism.
Mitochondrial matrix In the mitochondrion, the matrix is the space within the inner membrane. The word "matrix" stems from the fact that this space is viscous, compared to the relatively aqueous cytoplasm. The mitochondrial matrix contains the mitochondrial DNA, ribo ...
Ca2+ levels can reach the tens of μM levels that are necessary for the activation of
isocitrate dehydrogenase Isocitrate dehydrogenase (IDH) () and () is an enzyme that catalyzes the oxidative decarboxylation of isocitrate, producing alpha-ketoglutarate (α-ketoglutarate) and CO2. This is a two-step process, which involves oxidation of isocitrate (a s ...
, which is one of the key regulatory enzymes of the
Krebs cycle The citric acid cycle (CAC)—also known as the Krebs cycle or the TCA cycle (tricarboxylic acid cycle)—is a series of chemical reactions to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and protein ...
. The ER, in neurons, may serve in a network integrating numerous extracellular and intracellular signals in a binary membrane system with the plasma membrane. Such an association with the plasma membrane creates the relatively new perception of the ER and theme of "a neuron within a neuron." The ER's structural characteristics, ability to act as a Ca2+ sink, and specific Ca2+ releasing proteins, serve to create a system that may produce regenerative waves of Ca2+ release. These may communicate both locally and globally in the cell. These Ca2+ signals integrate extracellular and intracellular fluxes, and have been implicated to play roles in synaptic plasticity, memory, neurotransmitter release, neuronal excitability, and long term changes at the gene transcription level. ER stress is also related to Ca2+ signaling and along with the unfolded protein response, can cause ER associated degradation (ERAD) and autophagy.


In fertilization

Ca2+ influx during fertilization has been observed in many species as a trigger for development of the
oocyte An oocyte (, ), oöcyte, or ovocyte is a female gametocyte or germ cell involved in reproduction. In other words, it is an immature ovum, or egg cell. An oocyte is produced in a female fetus in the ovary during female gametogenesis. The femal ...
. These influxes may occur as a single increase in concentration as seen with fish and
echinoderm An echinoderm () is any member of the phylum Echinodermata (). The adults are recognisable by their (usually five-point) radial symmetry, and include starfish, brittle stars, sea urchins, sand dollars, and sea cucumbers, as well as the s ...
s, or may occur with the concentrations
oscillating Oscillation is the repetitive or periodic variation, typically in time, of some measure about a central value (often a point of equilibrium) or between two or more different states. Familiar examples of oscillation include a swinging pendulum ...
as observed in mammals. The triggers to these Ca2+ influxes may differ. The influx have been observed to occur via membrane Ca2+ conduits and Ca2+ stores in the sperm. It has also been seen that sperm binds to membrane receptors that lead to a release in Ca2+ from the ER. The sperm has also been observed to release a soluble factor that is specific to that species. This prevents cross species fertilization to occur. These soluble factors lead to activation of IP3 which causes a Ca2+ release from the ER via IP3 receptors. It has also been seen that some model systems mix these methods such as seen with mammals. Once the Ca2+ is released from the ER the egg starts the process of forming a fused
pronucleus A pronucleus () is the nucleus of a sperm or egg cell during the process of fertilization. The sperm cell becomes a pronucleus after the sperm enters the ovum, but before the genetic material of the sperm and egg fuse. Contrary to the sperm cell, ...
and the restart of the mitotic cell cycle. Ca2+ release is also responsible for the activation of NAD+ kinase which leads to membrane biosynthesis, and the exocytosis of the oocytes
cortical granules Cortex or cortical may refer to: Biology * Cortex (anatomy), the outermost layer of an organ ** Cerebral cortex, the outer layer of the vertebrate cerebrum, part of which is the ''forebrain'' *** Motor cortex, the regions of the cerebral cortex i ...
which leads to the formation of the hyaline layer allowing for the slow block to
polyspermy In biology, polyspermy describes the fertilization of an egg by more than one sperm. Diploid organisms normally contain two copies of each chromosome, one from each parent. The cell resulting from polyspermy, on the other hand, contains three or ...
.


See also

* Nanodomain * European Calcium Society


References


Further reading

* {{DEFAULTSORT:Calcium Signaling Cell signaling Signal transduction Calcium signaling