
Calcineurin (CaN) is a
calcium
Calcium is a chemical element; it has symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to it ...
and
calmodulin
Calmodulin (CaM) (an abbreviation for calcium-modulated protein) is a multifunctional intermediate calcium-binding messenger protein expressed in all Eukaryote, eukaryotic cells. It is an intracellular target of the Second messenger system, sec ...
dependent
serine/threonine protein phosphatase (also known as
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
phosphatase 3, and calcium-dependent serine-threonine phosphatase).
It activates the
T cells
T cells (also known as T lymphocytes) are an important part of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their ce ...
of the immune system and can be blocked by drugs. Calcineurin activates nuclear factor of activated T cell cytoplasmic (
NFATc), a
transcription factor
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription (genetics), transcription of genetics, genetic information from DNA to messenger RNA, by binding t ...
, by
dephosphorylating it. The activated NFATc is then
translocated into the nucleus, where it upregulates the expression of
interleukin 2
Interleukin-2 (IL-2) is an interleukin, which is a type of cytokine signaling molecule forming part of the immune system. It is a 15.5–16 Dalton (unit), kDa protein that regulates the activities of white blood cells (leukocytes, often ...
(IL-2), which, in turn, stimulates the growth and differentiation of the
T cell response. Calcineurin is the target of a class of drugs called
calcineurin inhibitors
Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications, are drugs that inhibit or prevent the activity of the immune system.
Classification
Immunosuppressive drugs can be classified ...
, which include
ciclosporin
Ciclosporin, also spelled cyclosporine and cyclosporin, is a calcineurin inhibitor, used as an immunosuppressant medication. It is taken Oral administration, orally or intravenously for rheumatoid arthritis, psoriasis, Crohn's disease, nephr ...
,
voclosporin,
pimecrolimus and
tacrolimus
Tacrolimus, sold under the brand name Prograf among others, is an immunosuppressive drug. After Allotransplantation, allogenic organ transplant, the risk of organ Transplant rejection, rejection is moderate. To lower the risk of organ rejectio ...
.
Structure
Calcineurin is a heterodimer of a 61-kD calmodulin-binding catalytic subunit, calcineurin A and a 19-kD Ca
2+-binding regulatory subunit, calcineurin B. There are three isozymes of the catalytic subunit, each encoded by a separate gene (
PPP3CA,
PPP3CB, and
PPP3CC) and two isoforms of the regulatory, also encoded by separate genes (
PPP3R1,
PPP3R2).
Mechanism of action
When an
antigen-presenting cell
An antigen-presenting cell (APC) or accessory cell is a Cell (biology), cell that displays an antigen bound by major histocompatibility complex (MHC) proteins on its surface; this process is known as antigen presentation. T cells may recognize the ...
interacts with a
T cell receptor
The T-cell receptor (TCR) is a protein complex, located on the surface of T cells (also called T lymphocytes). They are responsible for recognizing fragments of antigen as peptides bound to major histocompatibility complex (MHC) molecules. ...
on
T cell
T cells (also known as T lymphocytes) are an important part of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell ...
s, there is an increase in the cytoplasmic level of calcium, which activates calcineurin by binding a regulatory subunit and activating
calmodulin
Calmodulin (CaM) (an abbreviation for calcium-modulated protein) is a multifunctional intermediate calcium-binding messenger protein expressed in all Eukaryote, eukaryotic cells. It is an intracellular target of the Second messenger system, sec ...
binding.
Calcineurin induces transcription factors (
NFAT
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 developme ...
s) that are important in the transcription of IL-2 genes. IL-2 activates T-helper lymphocytes and induces the production of other cytokines. In this way, it governs the action of
cytotoxic lymphocytes. The amount of IL-2 being produced by the T-helper cells is believed to influence the extent of the immune response significantly.
Clinical relevance
Rheumatic diseases
Calcineurin inhibitors are prescribed for adult
rheumatoid arthritis
Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects synovial joint, joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and h ...
(RA) as a single drug or in combination with
methotrexate
Methotrexate, formerly known as amethopterin, is a chemotherapy agent and immunosuppressive drug, immune-system suppressant. It is used to treat cancer, autoimmune diseases, and ectopic pregnancy, ectopic pregnancies. Types of cancers it is u ...
. The microemulsion formulation is approved by the U.S.
Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...
for treatment of severely active RA. It is also prescribed for:
psoriatic arthritis
Psoriatic arthritis (PsA) is a long-term inflammatory arthritis that may occur in some people affected by the autoimmune disease psoriasis. The classic features of psoriatic arthritis include dactylitis (sausage-like swelling of the fingers ...
,
psoriasis
Psoriasis is a long-lasting, noncontagious autoimmune disease characterized by patches of abnormal skin. These areas are red, pink, or purple, dry, itchy, and scaly. Psoriasis varies in severity from small localized patches to complete b ...
, acute ocular
Behçet's disease,
juvenile idiopathic arthritis
Juvenile idiopathic arthritis (JIA), formerly known as juvenile rheumatoid arthritis (JRA), is the most common chronic rheumatic disease of childhood, affecting approximately 3.8 to 400 out of 100,000 children. ''Juvenile'', in this context, ref ...
, adult and juvenile
polymyositis
Polymyositis (PM) is a type of chronic inflammation of the muscles ( inflammatory myopathy) related to dermatomyositis and inclusion body myositis. Its name is derived . The inflammation of polymyositis is mainly found in the endomysial layer ...
and
dermatomyositis
Dermatomyositis (DM) is a Chronic condition, long-term inflammatory disorder, inflammatory Autoimmune disease, autoimmune disorder which affects the skin and the muscles. Its symptoms are generally a skin rash and worsening muscle weakness over ...
, adult and juvenile
systemic lupus erythematosus
Lupus, formally called systemic lupus erythematosus (SLE), is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue in many parts of the body. Symptoms vary among people and may be mild to severe. Common ...
, adult lupus
membranous nephritis,
systemic sclerosis
Systemic scleroderma, or systemic sclerosis, is an autoimmune rheumatic disease characterised by excessive production and accumulation of collagen, called fibrosis, in the skin and internal organs and by injuries to small arteries. There are tw ...
,
aplastic anemia, steroid-resistant
nephrotic syndrome
Nephrotic syndrome is a collection of symptoms due to kidney damage. This includes proteinuria, protein in the urine, hypoalbuminemia, low blood albumin levels, hyperlipidemia, high blood lipids, and significant edema, swelling. Other symptoms ...
,
atopic dermatitis
Atopic dermatitis (AD), also known as atopic eczema, is a long-term type of inflammation of the skin. Atopic dermatitis is also often called simply eczema but the same term is also used to refer to dermatitis, the larger group of skin conditi ...
, severe corticosteroid-dependent
asthma
Asthma is a common long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wh ...
, severe
ulcerative colitis
Ulcerative colitis (UC) is one of the two types of inflammatory bowel disease (IBD), with the other type being Crohn's disease. It is a long-term condition that results in inflammation and ulcers of the colon and rectum. The primary sympto ...
,
pemphigus vulgaris
Pemphigus vulgaris is a rare chronic blistering skin disease and the most common form of pemphigus. Pemphigus was derived from the Greek word ''pemphix'', meaning blister. It is classified as a type II hypersensitivity reaction in which antibody, ...
,
myasthenia gravis
Myasthenia gravis (MG) is a long-term neuromuscular junction disease that leads to varying degrees of skeletal muscle weakness. The most commonly affected muscles are those of the eyes, face, and swallowing. It can result in double vision, ...
, and
dry eye disease, with or without
Sjögren's syndrome (administered as ophthalmic emulsion).
Schizophrenia
Calcineurin is linked to receptors for several brain chemicals including
glutamate
Glutamic acid (symbol Glu or E; known as glutamate in its anionic form) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a Essential amino acid, non-essential nutrient for humans, meaning that ...
,
dopamine
Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...
and
GABA
GABA (gamma-aminobutyric acid, γ-aminobutyric acid) is the chief inhibitory neurotransmitter in the developmentally mature mammalian central nervous system. Its principal role is reducing neuronal excitability throughout the nervous system.
GA ...
. An experiment with genetically-altered mice that could not produce calcineurin showed similar symptoms as in humans with
schizophrenia
Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...
: impairment in
working memory
Working memory is a cognitive system with a limited capacity that can Memory, hold information temporarily. It is important for reasoning and the guidance of decision-making and behavior. Working memory is often used synonymously with short-term m ...
, attention deficits, aberrant social behavior, and several other abnormalities characteristic of schizophrenia.
Diabetes
Calcineurin along with NFAT, may improve the function of diabetics'
pancreatic beta cells.
Thus tacrolimus contributes to the frequent development of new diabetes following renal transplantation.
Calcineurin/NFAT signaling is required for perinatal lung maturation and function.
Organ transplantation
Calcineurin inhibitors such as
tacrolimus
Tacrolimus, sold under the brand name Prograf among others, is an immunosuppressive drug. After Allotransplantation, allogenic organ transplant, the risk of organ Transplant rejection, rejection is moderate. To lower the risk of organ rejectio ...
and
ciclosporin
Ciclosporin, also spelled cyclosporine and cyclosporin, is a calcineurin inhibitor, used as an immunosuppressant medication. It is taken Oral administration, orally or intravenously for rheumatoid arthritis, psoriasis, Crohn's disease, nephr ...
are used to suppress the immune system in organ
allotransplant recipients to prevent rejection of the transplanted tissue.
Interactions
Calcineurin has been shown to
interact with
RCAN1 and
AKAP5.
References
Further reading
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External links
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Signal transduction
EC 3.1.3