Calcineurin

thumb|Crystallographic structure of calcineurin heterodimer composed of the catalytic ([[PPP3CA) and regulatory (PPP3R1) subunits.]]

Calcineurin (CaN) is a calcium and calmodulin dependent serine/threonine 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 the T cell response. Calcineurin is the target of a class of drugs called calcineurin inhibitors, which include ciclosporin, voclosporin, pimecrolimus and tacrolimus.

Calcineurin is a highly conserved protein within eukaryotic life, appearing within organisms from yeasts to mammals.

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. In humans, 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).

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Calcineurin A contains the active site, which is between 57-9 kDa depending on isoform, with larger catalytic subunits found in lower eukaryotes such as Saccharomyces fungus. Calcineurin induces 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.

Calcineurin directly dephosphorylates cytoplasmic subunits of the NFAT1 transcription complex, operating through direct binding through a conserved N terminus. Translocation of the NFAT transcription factors into the nucleus is maintained via the concentration of Ca²⁺ ions due to the integration of Ca²⁺ signaling within mitogen-activated protein kinase in NFAT, the activity of Calmodulin can act as a coincidence detector for Ras signaling pathways. In mice which overexpression of the protein subunit occurs, it is observed that the amount of sleep and as a result wakefulness is increased.

Schizophrenia

Calcineurin is linked to receptors for several brain chemicals including glutamate, 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. 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 and ciclosporin 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<!-- DSCR1 is a former symbol --> and AKAP5.

Viral Inhibition

Inhibition of calcineurin is also found to be performed by encoded proteins in viruses. Notably, the African swine fever virus encodes the A238L protein, which binds to calcineurin and inhibits translocation and function of NFATc.