Calcineurin

Calcineurin (CN), also known as PPP3CA, is a calcium and calmodulin dependent serine/threonine phosphatase. It plays a crucial role in various cellular processes, including T-cell activation, neuronal and muscle development, and the regulation of protein synthesis and gene expression. Calcineurin is a target of the immunosuppressive drugs cyclosporin and tacrolimus, which are used to prevent organ transplant rejection.

Structure

Calcineurin is a heterodimer composed of a catalytic A subunit (CnA) and a regulatory B subunit (CnB). The A subunit contains a serine/threonine phosphatase domain, a calmodulin-binding domain, and an autoinhibitory domain that overlaps with the calmodulin-binding domain. The B subunit binds calcium ions and is necessary for the activation of the phosphatase activity of the A subunit.

Function

Calcineurin dephosphorylates various proteins, including members of the nuclear factor of activated T-cells (NFAT) family of transcription factors. Dephosphorylation of NFAT proteins by calcineurin promotes their translocation into the nucleus, where they participate in the transcription of genes involved in T-cell activation. Besides its role in the immune system, calcineurin is involved in the development and function of the nervous system and skeletal muscle, and it has been implicated in the pathophysiology of several neurological and psychiatric disorders, including Alzheimer's disease, Parkinson's disease, and schizophrenia.

Regulation

Calcineurin activity is regulated by calcium and calmodulin. Upon an increase in intracellular calcium levels, calmodulin undergoes a conformational change that allows it to bind to calcineurin and activate its phosphatase activity. The activity of calcineurin is also modulated by its endogenous inhibitors, such as cabin-1, AKAP79, and the RCAN family of proteins, which can bind to calcineurin and inhibit its activity.

Clinical Significance

Due to its critical role in T-cell activation, calcineurin is a key target for immunosuppressive therapy in organ transplantation. Cyclosporin and tacrolimus bind to the immunophilins cyclophilin and FKBP12, respectively, and the resulting complexes inhibit calcineurin, thereby suppressing the immune response and preventing organ rejection. However, the use of calcineurin inhibitors is associated with several side effects, including nephrotoxicity, hypertension, and increased risk of infections and cancer. Research into the development of more selective calcineurin inhibitors or modulators continues, with the aim of reducing these side effects.

See Also

• Immunosuppression
• Phosphatase
• T-cell activation
• Cyclosporin
• Tacrolimus