Calcium release activated channel

Last updated
Calcium release-activated calcium channel protein 1 (olf186-F)
Identifiers
SymbolOrai
Pfam PF07856
InterPro IPR012446
TCDB 1.A.52
OPM superfamily 234
OPM protein 4hkr

Calcium release-activated channels (CRAC) are specialized plasma membrane Ca2+ ion channels. When calcium ions (Ca2+) are depleted from the endoplasmic reticulum (a major store of Ca2+) of mammalian cells, the CRAC channel is activated to slowly replenish the level of calcium in the endoplasmic reticulum. The Ca2+ Release-activated Ca2+ (CRAC) Channel (CRAC-C) Family (TC# 1.A.52) is a member of the Cation Diffusion Facilitator (CDF) Superfamily. These proteins typically have between 4 and 6 transmembrane α-helical spanners (TMSs). The 4 TMS CRAC channels arose by loss of 2TMSs from 6TMS CDF carriers, an example of 'reverse' evolution'. [1]

Contents

Homology

There are several proteins that belong to the CRAC-C family. A list of the currently classified members of the CRAC-C family can be found in the Transporter Classification Database. This classification is based on sequence similarity which also happens to coincide with functional and structural similarities between homologues.

Structure

Almost all CRAC homologues are about 250 residues long, but some are up to 100 residues longer (e.g., the Drosophila melanogaster Olf186-F, TC# 1.A.52.1.5).

The plasma membrane protein "Orai" (ORAI1 and ORAI2 in humans) forms the pore of the CRAC channel. The protein ORAI1 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. [2] When the concentration of Ca2+ inside the ER approaches an upper set point, another protein, SARAF (TMEM66) associates with STIM1 to inactivate the store-operated calcium channel (SOCE). [3]

The crystal structure of Orai from Drosophila melanogaster has been determined at 3.35 angstrom resolution ( PDB: 4HKR ​). [4] The calcium channel is composed of a hexameric assembly of Orai subunits arranged around a central ion pore. The pore traverses the membrane and extends into the cytosol. A ring of glutamate residues on its extracellular side forms the selectivity filter. A basic region near the intracellular side can bind anions that may stabilize the closed state. The architecture of the channel differs markedly from other ion channels and provides insight into the principles of selective calcium permeation and gating. [4]

Function

In electrically non-excitable cells (i.e., blood cells), Ca2+ influx is essential for regulating a host of kinetically distinct processes involving exocytosis, enzyme control, gene regulation, cell growth and proliferation, and apoptosis. Capacitative calcium entry appears to also be a major means of signal transduction. The major Ca2+ entry pathway in these cells is the store-operated one, in which the emptying of intracellular Ca2+ stores activates Ca2+ influx (store-operated Ca2+ entry, or capacitative Ca2+ entry). This is often referred to as the store-operated current or SOC. [5]

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 (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.

STIM Complex

STIM1 is a Ca2+-sensor protein specialized for electrical signaling in the endoplasmic reticulum (ER). [6] It interacts with and mediates store-dependent regulation of both Orai1 and TRPC1 channels. TRPC1+STIM1-dependent SOC requires functional Orai1. [7] STIM1 is the mechanistic 'missing link' between the ER and the plasma membrane. STIM proteins sense the depletion of luminal Ca2+ from the ER and trigger activation of CRAC channels in the surface membrane after Ca2+ store depletion. The process involves oligomerization, then translocation to junctions adjacent to the plasma membrane, by which the CRAC channels become organized into clusters and then open to bring about SOC entry. [8]

Lymphocytes

The primary mechanism of extracellular Ca2+ entry in lymphocytes involves CRAC channels. STIM1 is a crucial component of the CRAC influx mechanism in lymphocytes, acting as a sensor of low Ca2+ concentration in the ER and an activator of the Ca2+ selective channel ORAI1 in the plasma membrane. Yarkoni and Cambier (2011) reported that STIM1 expression differs in murine T and B lymphocytes; mature T cells express about 4 times more STIM1 than mature B cells. Through the physiologic range of expression, STIM1 levels determine the magnitude of Ca2+ influx responses that follow BCR-induced intracellular store depletion. [9]

SCID

Antigen stimulation of immune cells triggers Ca2+ entry through tetrameric Ca2+ release-activated Ca2+ (CRAC) channels, promoting the immune response to pathogens by activating the transcription factor NFAT. Cells from patients with one form of hereditary Severe Combined Immune Deficiency (SCID) syndrome are defective in store-operated Ca2+ entry and CRAC channel function. [10] The genetic defect in these patients appears to be in ORAI1 (TM protein 142A; TMEM142a), which contains four putative transmembrane segments. [11] SCID patients are homozygous for a single missense mutation in ORAI1, and expression of wild-type ORAI1 in SCID T cells restores store-operated Ca2+ influx and the CRAC current (ICRAC).

SOCE

Store operated calcium entry (SOCE) is used to regulate basal calcium, refill intracellular Ca2+ stores, and execute a wide range of specialized activities. STIM and Orai are the essential components enabling the reconstitution of Ca2+ release-activated Ca2+ (CRAC) channels that mediate SOCE. Palty et al. (2012) reported the molecular identification of SARAF as a negative regulator of SOCE. It is an endoplasmic reticulum membrane resident protein that associates with STIM to facilitate slow Ca2+-dependent inactivation of SOCE. SARAF plays a key role in shaping cytosolic Ca2+ signals and determining the content of the major intracellular Ca2+ stores, a role that is likely to be important in protecting cells from Ca2+overfilling. [3]

See also

Related Research Articles

Endoplasmic reticulum Irregular network of membranes coterminous with the outer nuclear membrane in eukaryote cytoplasm that form a meshwork of tubular channels, often expanded into cisternae

The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum (RER), and smooth endoplasmic reticulum (SER). The endoplasmic reticulum is found in most eukaryotic cells and forms an interconnected network of flattened, membrane-enclosed sacs known as cisternae, and tubular structures in the SER. The membranes of the ER are continuous with the outer nuclear membrane. The endoplasmic reticulum is not found in red blood cells, or spermatozoa.

Endomembrane system Membranes in the cytoplasm of a eukaryotic cell

The endomembrane system is composed of the different membranes that are suspended in the cytoplasm within a eukaryotic cell. These membranes divide the cell into functional and structural compartments, or organelles. In eukaryotes the organelles of the endomembrane system include: the nuclear membrane, the endoplasmic reticulum, the Golgi apparatus, lysosomes, vesicles, endosomes, and plasma (cell) membrane among others. The system is defined more accurately as the set of membranes that form a single functional and developmental unit, either being connected directly, or exchanging material through vesicle transport. Importantly, the endomembrane system does not include the membranes of chloroplasts or mitochondria, but might have evolved partially and from the actions of the latter.

Inositol trisphosphate or inositol 1,4,5-trisphosphate abbreviated InsP3 or Ins3P or IP3 is an inositol phosphate signaling molecule. It is made by hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2), a phospholipid that is located in the plasma membrane, by phospholipase C (PLC). Together with diacylglycerol (DAG), IP3 is a second messenger molecule used in signal transduction in biological cells. While DAG stays inside the membrane, IP3 is soluble and diffuses through the cell, where it binds to its receptor, which is a calcium channel located in the endoplasmic reticulum. When IP3 binds its receptor, calcium is released into the cytosol, thereby activating various calcium regulated intracellular signals.

Second messengers are intracellular signaling molecules released by the cell in response to exposure to extracellular signaling molecules—the first messengers. Second messengers trigger physiological changes at cellular level such as proliferation, differentiation, migration, survival, apoptosis and depolarization.

Calcium signaling

Calcium signaling is the use of calcium ions (Ca2+) to communicate and drive intracellular processes often as a step in signal transduction. Ca2+ is important for cellular signalling, for once it enters the cytosol of the cytoplasm it exerts allosteric regulatory effects on many enzymes and proteins. 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.

The sodium-calcium exchanger (often denoted Na+/Ca2+ exchanger, exchange protein, or NCX) is an antiporter membrane protein that removes calcium from cells. It uses the energy that is stored in the electrochemical gradient of sodium (Na+) by allowing Na+ to flow down its gradient across the plasma membrane in exchange for the countertransport of calcium ions (Ca2+). A single calcium ion is exported for the import of three sodium ions. The exchanger exists in many different cell types and animal species. The NCX is considered one of the most important cellular mechanisms for removing Ca2+.

Calcium ATPase

Ca2+ ATPase is a form of P-ATPase that transfers calcium after a muscle has contracted. The two kinds of calcium ATPase are:

Nuclear factor of activated T-cells (NFAT) is a family of transcription factors shown to be important in immune response. One or more members of the NFAT family is expressed in most cells of the immune system. NFAT is also involved in the development of cardiac, skeletal muscle, and nervous systems. NFAT was first discovered as an activator for the transcription of IL-2 in T cells but has since been found to play an important role in regulating many more body systems. NFAT transcription factors are involved in many normal body processes as well as in development of several diseases, such as inflammatory bowel diseases and several types of cancer. NFAT is also being investigated as a drug target for several different disorders.

TRPC is a family of transient receptor potential cation channels in animals.

Store-operated channels (SOCs) are ion channels located in the plasma membrane of 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. Calcium SOCs are especially important for the cell because they are the major source of intracellular calcium; and calcium itself is involved in a wide array of vital cellular functions. SOCs are so called because they are activated by intracellular calcium stores depletion by both physiological or pharmacological processes.

TRPC1

Transient receptor potential canonical 1 (TRPC1) is a protein that in humans is encoded by the TRPC1 gene.

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.

ORAI1

Calcium release-activated calcium channel protein 1 is a calcium selective ion channel that in humans is encoded by the ORAI1 gene. Orai channels play an important role in the activation of T-lymphocytes. The loss of function mutation of Orai1 causes severe combined immunodeficiency (SCID) in humans The mammalian orai family has two additional homologs, Orai2 and Orai3. Orai proteins share no homology with any other ion channel family of any other known proteins. They have 4 transmembrane domains and form hexamers.

STIM2

Stromal interaction molecule 2 (STIM2) is a protein that in humans is encoded by the STIM2 gene.

TMEM66

SARAF is a protein that in humans is encoded by the SARAF gene, formerly known as TMEM66.

Membrane contact sites (MCS) are close appositions between two organelles. Ultrastructural studies typically reveal an intermembrane distance in the order of the size of a single protein, as small as 10 nm or wider, with no clear upper limit. These zones of apposition are highly conserved in evolution. These sites are thought to be important to facilitate signalling, and they promote the passage of small molecules, including ions, lipids and reactive oxygen species. MCS are important in the function of the endoplasmic reticulum (ER), since this is the major site of lipid synthesis within cells. The ER makes close contact with many organelles, including mitochondria, Golgi, endosomes, lysosomes, peroxisomes, chloroplasts and the plasma membrane. Both mitochondria and sorting endosomes undergo major rearrangements leading to fission where they contact the ER. Sites of close apposition can also form between most of these organelles most pairwise combinations. First mentions of these contact sites can be found in papers published in the late 1950s mainly visualized using electron microscopy (EM) techniques. Copeland and Dalton described them as “highly specialized tubular form of endoplasmic reticulum in association with the mitochondria and apparently in turn, with the vascular border of the cell”.

Mitochondria associated membranes Cellular structure

Mitochondria-associated membranes (MAM) represent a region of the endoplasmic reticulum (ER) which is reversibly tethered to mitochondria. These membranes are involved in import of certain lipids from the ER to mitochondria and in regulation of calcium homeostasis, mitochondrial function, autophagy and apoptosis. They also play a role in development of neurodegenerative diseases and glucose homeostasis.

Gram domain-containing 2A

GRAM domain-containing 2A protein is a protein encoded by the GRAMD2A gene. Like GRAMD2B, the protein consists of a GRAM domain and a transmembrane domain that anchors it to the endoplasmic reticulum.

References

  1. ↑ Matias MG, Gomolplitinant KM, Tamang DG, Saier MH (June 2010). "Animal Ca2+ release-activated Ca2+ (CRAC) channels appear to be homologous to and derived from the ubiquitous cation diffusion facilitators". BMC Research Notes. 3: 158. doi:10.1186/1756-0500-3-158. PMC   2894845 . PMID   20525303.
  2. ↑ Feske S (July 2010). "CRAC channelopathies". Pflügers Archiv. 460 (2): 417–35. doi:10.1007/s00424-009-0777-5. PMC   2885504 . PMID   20111871.
  3. 1 2 Palty R, Raveh A, Kaminsky I, Meller R, Reuveny E (April 2012). "SARAF inactivates the store operated calcium entry machinery to prevent excess calcium refilling". Cell. 149 (2): 425–38. doi: 10.1016/j.cell.2012.01.055 . PMID   22464749.
  4. 1 2 Hou X, Pedi L, Diver MM, Long SB (December 2012). "Crystal structure of the calcium release-activated calcium channel Orai". Science. 338 (6112): 1308–13. Bibcode:2012Sci...338.1308H. doi:10.1126/science.1228757. PMC   3695727 . PMID   23180775.
  5. ↑ Parekh AB, Putney JW (April 2005). "Store-operated calcium channels". Physiological Reviews. 85 (2): 757–810. doi:10.1152/physrev.00057.2003. PMID   15788710.
  6. ↑ Bird GS, Hwang SY, Smyth JT, Fukushima M, Boyles RR, Putney JW (November 2009). "STIM1 is a calcium sensor specialized for digital signaling". Current Biology. 19 (20): 1724–9. doi:10.1016/j.cub.2009.08.022. PMC   3552312 . PMID   19765994.
  7. ↑ Cheng KT, Liu X, Ong HL, Ambudkar IS (May 2008). "Functional requirement for Orai1 in store-operated TRPC1-STIM1 channels". The Journal of Biological Chemistry. 283 (19): 12935–40. doi: 10.1074/jbc.C800008200 . PMC   2442339 . PMID   18326500.
  8. ↑ Cahalan MD (June 2009). "STIMulating store-operated Ca(2+) entry". Nature Cell Biology. 11 (6): 669–77. doi:10.1038/ncb0609-669. PMC   2721799 . PMID   19488056.
  9. ↑ Yarkoni Y, Cambier JC (September 2011). "Differential STIM1 expression in T and B cell subsets suggests a role in determining antigen receptor signal amplitude". Molecular Immunology. 48 (15–16): 1851–8. doi:10.1016/j.molimm.2011.05.006. PMC   3163766 . PMID   21663969.
  10. ↑ Zhou Y, Ramachandran S, Oh-Hora M, Rao A, Hogan PG (March 2010). "Pore architecture of the ORAI1 store-operated calcium channel". Proceedings of the National Academy of Sciences of the United States of America. 107 (11): 4896–901. Bibcode:2010PNAS..107.4896Z. doi: 10.1073/pnas.1001169107 . PMC   2841875 . PMID   20194792.
  11. ↑ Hogan PG, Rao A (May 2007). "Dissecting ICRAC, a store-operated calcium current". Trends in Biochemical Sciences. 32 (5): 235–45. doi:10.1016/j.tibs.2007.03.009. PMID   17434311.
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