ICRAC
Encyclopedia
ICRAC stands for Calcium-Release Activated Calcium Current. When calcium
ions (Ca2+) are depleted from the endoplasmic reticulum
(a major store of Ca2+) of mammal
ian cells, a special plasma membrane
Ca2+ channel, the CRAC channel, is activated to slowly replenish the level of calcium in the endoplasmic reticulum.
is a structural component of the CRAC calcium channel
. ORAI1 interacts with the STIM1
protein. STIM1 is a transmembrane protein
of the endoplasmic reticulum (ER). STIM1 can sense the concentration
of Ca2+ inside the ER. When the concentration of Ca2+ inside the ER becomes low, STIM1 proteins aggregate and interact with ORAI1 located in the cell surface membrane.
(agonist) to its plasma-membrane receptors.
Such signals can arise either from the release of stored calcium or the calcium influx across the plasma membrane, but more characteristically, from both routes. A common mechanism by which such cytoplasmic calcium signals are generated involves receptors that are coupled to the activation of phospholipase C. Phospholipase C generates inositol 1,4,5-trisphosphate (IP3), which in turn mediates the discharge of Ca2+ from intracellular stores (most commonly components of the endoplasmic reticulum), allowing calcium to be released into the cytosol. In most of the cell, the fall in Ca2+ concentration within the lumen of the Ca2+-storing organelles subsequently activates plasma membrane Ca2+ channels. This calcium influx across the plasma membrane has been called “capacitative calcium entry,” or “store-operated calcium entry”.
In non-excitable cells such as blood cell
s, capacitative calcium entry appears to be the major means of regulated influx of Ca2+ and signal transduction
. As a second messenger capacitative calcium entry can induce short term cellular responses, such as proteins-protein interactions, granule secretion…but can also initiate longer-term cellular control mechanisms
such as genes transcription that support cell growth
, apoptosis, differentiation or activation. In in vitro
studies, the effect of this necessary calcium signal for activation of genes transcription factor
can be induce by the action of calcium ionophores such as ionomycin.
Activation of T lymphocytes
is an essential event for the efficient response of the immune system
. Disregulation of this phenomenon can lead to immunological disorder such as autoimmune disease
or inflammation. This activation requires the involvement of the T cell receptor
antigen as well as costimulatory molecules such as CD28. Engagement of this receptor complex will result in a series of signaling cascade, which lead to the production of several cytokines. IL-2 gene transcription
, a key event in T cell activation and proliferation, is dependent on the rapid and sustain increase in intracellular Ca2+. Targeting the very early events of cascade signaling pathway, by inhibiting the capacitative calcium entry is an efficient way to prevent T cell activation.
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
ions (Ca2+) are depleted 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...
(a major store of Ca2+) of mammal
Mammal
Mammals are members of a class of air-breathing vertebrate animals characterised by the possession of endothermy, hair, three middle ear bones, and mammary glands functional in mothers with young...
ian cells, a special plasma membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
Ca2+ channel, the CRAC channel, is activated to slowly replenish the level of calcium in the endoplasmic reticulum.
Structure
The protein ORAI1ORAI1
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...
is a structural component of the CRAC calcium channel
Calcium channel
A Calcium channel is an ion channel which displays selective permeability to calcium ions. It is sometimes synonymous as voltage-dependent calcium channel, although there are also ligand-gated calcium channels.-Comparison tables:...
. ORAI1 interacts with the 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....
protein. STIM1 is a transmembrane protein
Transmembrane protein
A transmembrane protein is a protein that goes from one side of a membrane through to the other side of the membrane. Many TPs function as gateways or "loading docks" to deny or permit the transport of specific substances across the biological membrane, to get into the cell, or out of the cell as...
of the endoplasmic reticulum (ER). STIM1 can sense the concentration
Concentration
In chemistry, concentration is defined as the abundance of a constituent divided by the total volume of a mixture. Four types can be distinguished: mass concentration, molar concentration, number concentration, and volume concentration...
of Ca2+ inside the ER. When the concentration of Ca2+ inside the ER becomes low, STIM1 proteins aggregate and interact with ORAI1 located in the cell surface membrane.
Function
Changes in the cytoplasmic free Ca2+ concentration ([Ca2+]c) constitute one of the main pathways by which information is transferred from extracellular signals received by animal cells to intracellular sites. The intracellular Ca2+ signal is conveyed by the magnitude, location and duration of the changes in [Ca2+]c. Increases in [Ca2+]c in a given region of the cytoplasmic space are usually initiated by the binding of an extracellular signaling moleculeSignaling molecule
A signaling molecule is a chemical involved in transmitting information between cells. Such molecules are released from the cell sending the signal, cross over the gap between cells by diffusion, and interact with specific receptors in another cell, triggering a response in that cell by activating...
(agonist) to its plasma-membrane receptors.
Such signals can arise either from the release of stored calcium or the calcium influx across the plasma membrane, but more characteristically, from both routes. A common mechanism by which such cytoplasmic calcium signals are generated involves receptors that are coupled to the activation of phospholipase C. Phospholipase C generates inositol 1,4,5-trisphosphate (IP3), which in turn mediates the discharge of Ca2+ from intracellular stores (most commonly components of the endoplasmic reticulum), allowing calcium to be released into the cytosol. In most of the cell, the fall in Ca2+ concentration within the lumen of the Ca2+-storing organelles subsequently activates plasma membrane Ca2+ channels. This calcium influx across the plasma membrane has been called “capacitative calcium entry,” or “store-operated calcium entry”.
In non-excitable cells such as blood cell
Blood cell
A blood cell, also called a hematocyte, is a cell normally found in blood. In mammals, these fall into three general categories:* red blood cells — Erythrocytes* white blood cells — Leukocytes* platelets — Thrombocytes...
s, capacitative calcium entry appears to be the major means of regulated influx of Ca2+ and signal transduction
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...
. As a second messenger capacitative calcium entry can induce short term cellular responses, such as proteins-protein interactions, granule secretion…but can also initiate longer-term cellular control mechanisms
Control system
A control system is a device, or set of devices to manage, command, direct or regulate the behavior of other devices or system.There are two common classes of control systems, with many variations and combinations: logic or sequential controls, and feedback or linear controls...
such as genes transcription that support 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"...
, apoptosis, differentiation or activation. In in vitro
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
studies, the effect of this necessary calcium signal for activation of genes transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
can be induce by the action of calcium ionophores such as ionomycin.
Activation of T lymphocytes
T cell
T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...
is an essential event for the efficient response of the immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
. Disregulation of this phenomenon can lead to immunological disorder such as autoimmune disease
Autoimmunity
Autoimmunity is the failure of an organism to recognize its own constituent parts as self, which allows an immune response against its own cells and tissues. Any disease that results from such an aberrant immune response is termed an autoimmune disease...
or inflammation. This activation requires the involvement of the T cell receptor
T cell receptor
The T cell receptor or TCR is a molecule found on the surface of T lymphocytes that is responsible for recognizing antigens bound to major histocompatibility complex molecules...
antigen as well as costimulatory molecules such as CD28. Engagement of this receptor complex will result in a series of signaling cascade, which lead to the production of several cytokines. IL-2 gene transcription
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
, a key event in T cell activation and proliferation, is dependent on the rapid and sustain increase in intracellular Ca2+. Targeting the very early events of cascade signaling pathway, by inhibiting the capacitative calcium entry is an efficient way to prevent T cell activation.