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Regulatory Mechanisms of Calcineurin Phosphatase Activity

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Calcineurin (protein phosphatase 3, Cn) is best known for its central position in Ca2+-dependent T-cell signaling. Interest in calcineurin has, however, conserved its momentum as new Ca2+-dependent pathways have been steadily surfacing in several other cell types, such as brain, heart, skin cells and beta pancreatic cells, and Cn appears to serve as a central controller of stress, immune response, and cellular proliferation and differentiation.

Calcineurin is the principal target of the immunosuppressive drugs cyclosporin A (CsA) and tacrolimus (TRL). Therapy based on these immunosuppressants has markedly reduced the incidence of transplant rejection in allograft recipients. In addition, these drugs have proven very useful for patients suffering from chronic inflammatory skin conditions. Unfortunately, their application is somewhat limited by a broad spectrum of toxic side-effects, affecting several organ systems. This calls for enhancements in the design of this class of immunosuppressants.

An intricate constellation of regulatory systems allows for precise modulation and adaptation of calcineurin activity in vivo. The last few years have been very fruitful in elucidating several long-standing issues regarding the binding patterns of substrates and inhibitors to Cn. This new knowledge may enable more precise manipulation of the Ca2+-calcineurin pathway in the near future, preferably targeted towards one specific substrate or cell system. In this review, we will discuss the factors and mechanisms underlying calcineurin activity regulation and their exploitation in recent approaches towards better immunosuppressants.

Keywords: CaM-binding domain; Calcineurin; Cn phosphatase activity; Cyclosporin A; NFAT; RCAN; arachidonic acid; bovine brain; calpain; cardiomyocytes; cyclosporin A (CsA); glycemic control; immunophilin; immunophilin complexes; immunosuppressants; inositol 1,4,5-triphosphate (IP3); lipophilicity; metalloenzyme; phobic CnA; phospholipids; pimecrolimus; polyphenolic aldehyde gossypol; protein phosphatase; tacrolimus; tacrolimus (TRL); thioredoxin; topology

Document Type: Research Article


Publication date: 2011-01-01

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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