Emanuela Barbero
Chiara Bona
DEFINITION
Calcineurin (CN), also known as protein phosphatase 3, is a calcium-dependent serine-threonine phosphatase.
Calcineurin is a heterodimer composed by:
* Calcineurin A, a 61-kD calmodulin-binding catalytic subunit
* Calcineurin B a 19-kD Ca2+-binding regulatory subunit
There are three isozymes of the catalytic subunit, each encoded by a separate gene (PPP3CA, PPP3CB, and PPP3CC) and two isoforms of the the regulatory, also encoded by separate genes (PPP3R1, PPP3R2).
http://en.wikipedia.org/wiki/Calcineurin
CHEMICAL STRUCTURE AND IMAGES
The catalytic subunit calcineurin A is colored in gray, the calcineurin B subunit is yellow, FKBP is green, and the immunosuppressant drug FK506 is shown in ball-and-stick fashion in gray. The four Ca2+ of the B subunit are represented as blue spheres.
http://www.ncbi.nlm.nih.gov/Structure/mmdb/mmdbsrv.cgi?uid=46344
http://www.ncbi.nlm.nih.gov/gene/5530
BIOLOGICAL FUNCTIONS
Calcineurin is involved in development of immunitary cells.
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 then 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.
It also triggers the differentiation of CD4 T cells in Th2, as it upregulates the expression of JAK3; JAK3 is bound to IL4-R, and its upregulation led to a major effect of STAT5, that acts as a nuclear factor and stimulates transcription of genes involved in cell proliferation and differentiation.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2213529/?tool=pubmed
CALCINEURIN AND IMMUNODEFICIENCY
Physiologically, there is a calcineurin binding protein named Cabin-1 that inhibits calcineurin-mediated signal transduction. In fact, overexpression of Cabin-1 inhibits the transcriptional activation of calcineurin respondive elements in IL-2 promoter and blocks dephosphorylation of NF-AT.
http://www.ncbi.nlm.nih.gov/pubmed/9655484
Concerning drugs, several inhibitors of calcineurin are used in immunosuppressive therapies; calcineurin inhibitors are thought to be the most efficient drugs in post-transplant immunosuppressive therapy (especially kidney transplants), as they inhibit IL-2 they prevent activation of T-cells, so they are also used in case of immuno-mediated diseases. Examples of inhibitors of calcineurin are cyclosporine and tacrolimus (FK506), that bind to FKBP12 and form a complex of FKBP-12, calcium, calmodulin e calcineurin, inhibiting phosphatase activity of calcineurin.
An high number of patients with renal transplantation, treated with inhibitors of calcineurin, develops hypertension that is commonly associated with non-anion gap (mild) metabolic acidosis and hyperkalaemia.
This fact could be related to an interaction between calcineurin inhibitors and Na–Cl cotransporters (NCC); NCC must be dephosphorylated in order to be inactivated and removed from the plasma membrane. Conceivably, the process is calcineurin dependent and therefore inhibited by tacrolimus.
Physiologically, NCC is involved in sodium retention, so an NCC hyperactivation causes hypervolumetric hypertension.
http://www.nature.com/nm/journal/v17/n10/full/nm.2497.html
http://ndt.oxfordjournals.org.offcampus.dam.unito.it/content/early/2011/12/14/ndt.gfr679.long#ref-1
Cyclosporine also causes hypertension because it downregulates NOS expression and and increases ET-1 receptors.
NOS produce NO only if it is in dimeric form, and it requires BH4 to dimerize. In its monomeric form NOS produces ROS, that causes endothelial damage and stimulates ET-1 production. This contributes causing hypertension.
http://www.sciencedirect.com.offcampus.dam.unito.it/science/article/pii/S1053249810004882
Furthermore, cyclosporine induces hypertension because it attenuates NO production through a calcineurin-sensitive pathway regulating eNOS dephosphorylation.
http://www.ncbi.nlm.nih.gov/pubmed/12050171
