Calcium signaling
Encyclopedia
Calcium is a common signaling mechanism, as once it enters the cytoplasm it exerts allosteric regulatory effects on many enzymes and proteins. Calcium can act in signal transduction
after influx resulting from activation of ion channels or as a second messenger caused by indirect signal transduction pathways such as G protein-coupled receptors.
, neuronal transmission as in an excitatory synapse
, cellular motility
(including the movement of flagella and cilia), fertilisation
, cell growth
or proliferation, learning and memory as with synaptic plasticity
, and secretion of saliva
. Other biochemical roles of calcium include regulating enzyme
activity, permeability of ion channels, activity of ion pumps
, and components of the cytoskeleton
.
The resting concentration of Ca2+ in the cytoplasm
is normally maintained in the range of 10–100 nM. To maintain this low concentration, Ca2+ is actively pumped from the cytosol to the extracellular space and into the endoplasmic reticulum
(ER), and sometimes in the mitochondria. Certain proteins of the cytoplasm and organelles act as buffers by binding Ca2+. Signaling occurs when the cell is stimulated to release calcium ions (Ca2+) from intracellular stores, and/or when calcium enters the cell through plasma membrane ion channels.
Specific signals can trigger a sudden increase in the cytoplasmic Ca2+ level up to 500–1,000 nM by opening channels in the endoplasmic reticulum
or the plasma membrane. The most common signaling pathway that increases cytoplasmic calcium concentration is the phospholipase C
pathway. Many cell surface receptors, including G protein-coupled receptors and receptor tyrosine kinase
s activate the phospholipase C
(PLC) enzyme. PLC hydrolyses the membrane phospholipid PIP2 to form IP3 and diacylglycerol (DAG), two classical second messengers. DAG activates the protein kinase C
enzyme, while IP3 diffuses to the endoplasmic reticulum, binds to its receptor (IP3 receptor), which is a Ca2+ channel, and thus releases Ca2+ from the endoplasmic reticulum
.
Depletion of calcium from the endoplasmic reticulum
will lead to Ca2+ entry from outside the cell by activation of "Store-Operated Channels" (SOCs
). This inflowing calcium current that results after stored calcium reserves have been released is referred to as Ca2+-release-activated Ca2+ current (ICRAC
). The mechanisms through which ICRAC occurs are currently still under investigation, although two candidate molecules, Orai1
and STIM1
, have been linked by several studies, and a model of store-operated calcium influx, involving these molecules, has been proposed. Recent studies have cited the phospholipase
A2 beta, nicotinic acid adenine dinucleotide phosphate (NAADP), and the protein STIM 1 as possible mediators of ICRAC.
Many of Ca2+-mediated events occur when the released Ca2+ binds to and activates the regulatory protein calmodulin
. Calmodulin may activate calcium-calmodulin-dependent protein kinase
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+.
Signal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
after influx resulting from activation of ion channels or as a second messenger caused by indirect signal transduction pathways such as G protein-coupled receptors.
Calcium signaling through ion channels
Movement of calcium ions from the extracellular compartment to the intracellular compartment alters membrane depolarisation. This is seen in the heart, during the plateau phase of ventricular contraction. In this example, calcium acts to maintain depolarisation of the heart.Calcium as a secondary messenger
Important physiological roles for calcium signaling range widely. These include muscle contractionMuscle contraction
Muscle fiber generates tension through the action of actin and myosin cross-bridge cycling. While under tension, the muscle may lengthen, shorten, or remain the same...
, neuronal transmission as in an excitatory synapse
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 often making numerous connections with other cells...
, cellular motility
Motility
Motility is a biological term which refers to the ability to move spontaneously and actively, consuming energy in the process. Most animals are motile but the term applies to single-celled and simple multicellular organisms, as well as to some mechanisms of fluid flow in multicellular organs, in...
(including the movement of flagella and cilia), fertilisation
Fertilisation
Fertilisation is the fusion of gametes to produce a new organism. In animals, the process involves the fusion of an ovum with a sperm, which eventually leads to the development of an embryo...
, cell growth
Cell growth
The term cell growth is used in the contexts of cell development and cell division . When used in the context of cell division, it refers to growth of cell populations, where one cell grows and divides to produce two "daughter cells"...
or proliferation, learning and memory as with synaptic plasticity
Synaptic plasticity
In neuroscience, synaptic plasticity is the ability of the connection, or synapse, between two neurons to change in strength in response to either use or disuse of transmission over synaptic pathways. Plastic change also results from the alteration of the number of receptors located on a synapse...
, and secretion of saliva
Saliva
Saliva , referred to in various contexts as spit, spittle, drivel, drool, or slobber, is the watery substance produced in the mouths of humans and most other animals. Saliva is a component of oral fluid. In mammals, saliva is produced in and secreted from the three pairs of major salivary glands,...
. Other biochemical roles of calcium include regulating enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
activity, permeability of ion channels, activity of ion pumps
Ion pump (biology)
In biology, an ion transporter, also called an ion pump, is a transmembrane protein that moves ions across a plasma membrane against their concentration gradient, in contrast to ion channels, where ions go through passive transport...
, and components of the cytoskeleton
Cytoskeleton
The cytoskeleton is a cellular "scaffolding" or "skeleton" contained within a cell's cytoplasm and is made out of protein. The cytoskeleton is present in all cells; it was once thought to be unique to eukaryotes, but recent research has identified the prokaryotic cytoskeleton...
.
The resting concentration of Ca2+ in the cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
is normally maintained in the range of 10–100 nM. To maintain this low concentration, Ca2+ is actively pumped from the cytosol to the extracellular space and into the endoplasmic reticulum
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
(ER), and sometimes in the mitochondria. Certain proteins of the cytoplasm and organelles act as buffers by binding Ca2+. Signaling occurs when the cell is stimulated to release calcium ions (Ca2+) from intracellular stores, and/or when calcium enters the cell through plasma membrane ion channels.
Specific signals can trigger a sudden increase in the cytoplasmic Ca2+ level up to 500–1,000 nM by opening channels in the endoplasmic reticulum
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
or the plasma membrane. The most common signaling pathway that increases cytoplasmic calcium concentration is the phospholipase C
Phospholipase C
Phosphoinositide phospholipase C is a family of eukaryotic intracellular enzymes that play an important role in signal transduction processes. In general, this enzyme is denoted as Phospholipase C, although three other families of phospholipase C enzymes have been identified in bacteria and in...
pathway. Many cell surface receptors, including G protein-coupled receptors and receptor tyrosine kinase
Receptor tyrosine kinase
Receptor tyrosine kinases s 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 kinase proteins....
s activate the phospholipase C
Phospholipase C
Phosphoinositide phospholipase C is a family of eukaryotic intracellular enzymes that play an important role in signal transduction processes. In general, this enzyme is denoted as Phospholipase C, although three other families of phospholipase C enzymes have been identified in bacteria and in...
(PLC) enzyme. PLC hydrolyses the membrane phospholipid PIP2 to form IP3 and diacylglycerol (DAG), two classical second messengers. DAG activates the protein kinase C
Protein kinase C
Protein kinase C also known as PKC is a family of enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and threonine amino acid residues on these proteins. PKC enzymes in turn are activated by signals such as increases in...
enzyme, while IP3 diffuses to the endoplasmic reticulum, binds to its receptor (IP3 receptor), which is a Ca2+ channel, and thus releases Ca2+ from the endoplasmic reticulum
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
.
Depletion of calcium from the endoplasmic reticulum
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
will lead to Ca2+ entry from outside the cell by activation of "Store-Operated Channels" (SOCs
SOC channels
Store-operated channels are ion channels located in the plasma membrane of all non-excitable cells . These channels are most studied in regard to their role in calcium entry into the cytoplasm from extracellular milieu. There are other SOC channels selective to other ions...
). This inflowing calcium current that results after stored calcium reserves have been released is referred to as Ca2+-release-activated Ca2+ current (ICRAC
ICRAC
ICRAC stands for Calcium-Release Activated Calcium Current. When calcium ions are depleted from the endoplasmic reticulum of mammalian cells, a special plasma membrane Ca2+ channel, the CRAC channel, is activated to slowly replenish the level of calcium in the endoplasmic reticulum.-Structure:The...
). The mechanisms through which ICRAC occurs are currently still under investigation, although two candidate molecules, Orai1
ORAI1
Calcium release-activated calcium channel protein 1 is a calcium selective ion channel that in humans is encoded by the ORAI1 gene. Orai1 channels play important role in the activation of T-lymphocytes. The loss of function mutation of Orai1 causes severe combined immunodeficiency in humans The...
and STIM1
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....
, have been linked by several studies, and a model of store-operated calcium influx, involving these molecules, has been proposed. Recent studies have cited the phospholipase
Phospholipase
A phospholipase is an enzyme that hydrolyzes phospholipids into fatty acids and other lipophilic substances. There are four major classes, termed A, B, C and D, distinguished by the type of reaction which they catalyze:*Phospholipase A...
A2 beta, nicotinic acid adenine dinucleotide phosphate (NAADP), and the protein STIM 1 as possible mediators of ICRAC.
Many of Ca2+-mediated events occur when the released Ca2+ binds to and activates the regulatory protein calmodulin
Calmodulin
Calmodulin is a calcium-binding protein expressed in all eukaryotic cells...
. Calmodulin may activate calcium-calmodulin-dependent protein kinase
Protein kinase
A protein kinase is a kinase enzyme that modifies other proteins by chemically adding phosphate groups to them . Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins...
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+.