Calcineurin



Calcineurin (CN) is a protein phosphatase also known as protein phosphatase 3, and calcium-dependent serine-threonine phosphatase. It activates the T cells of the immune system and can be blocked by drugs. Calcineurin activates nuclear factor of activated T cell, cytoplasmic (NFATc), a transcription factor, by dephosphorylating it. The activated NFATc is then translocated into the nucleus, where it upregulates the expression of interleukin 2 (IL-2), which, in turn, stimulates the growth and differentiation of T cell response. Calcineurin is the target of a class of drugs called calcineurin inhibitors, which includes cyclosporine, pimecrolimus and tacrolimus.

Structure
Calcineurin is a heterodimer of a 61-kD calmodulin-binding catalytic subunit, calcineurin A and a 19-kD Ca2+-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 interacts with a T cell receptor on T cells, there is an increase in the cytoplasmic level of calcium, which activates calcineurin, by binding a regulatory subunit and activating calmodulin binding. Calcineurin induces different transcription factors (NFATs) 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.

Rheumatic diseases
Adult rheumatoid arthritis (RA) as a single drug [1-5], or in combination with methotrexate [6,7]. The microemulsion formulation is approved by the Federal Drug Administration of the United States for treatment of severely active RA. Psoriatic arthritis [8,9] Psoriasis [10-12] Acute ocular Behçet’s disease [13] Juvenile idiopathic arthritis [14,15] Adult and juvenile polymyositis and dermatomyositis [14-21] Adult and juvenile systemic lupus erythematosus [22-25] Adult lupus membranous nephritis [26] Systemic sclerosis [27-29] Aplastic anemia [30,31] Steroid-resistant nephrotic syndrome (see "Treatment of minimal change disease in adults" and "Treatment of primary focal segmental glomerulosclerosis") Atopic dermatitis (see "Epidemiology, clinical manifestations, and diagnosis of atopic dermatitis (eczema)") Severe, corticosteroid-dependent asthma (see "Alternative and experimental agents for the treatment of asthma") Severe ulcerative colitis [32-34] Pemphigus vulgaris [35] Myasthenia gravis [36] Dry eye disease, with or without Sjögren's syndrome (administered as ophthalmic emulsion) [37]

Schizophrenia
Calcineurin is linked to receptors for several brain chemicals including NMDA, dopamine and GABA. An experiment with genetically-altered mice that could not produce calcineurin showed similar symptoms as in humans with schizophrenia: impairment in working memory, 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.

Calcineurin/Nfat signaling is required for perinatal lung maturation and function.

Interactions
Calcineurin has been shown to interact with DSCR1 and AKAP5.