Mechanism of Action
In medicine, the most important effect of ciclosporin is to lower the activity of T cells and their immune response.
Ciclosporin binds to the cytosolic protein cyclophilin (immunophilin) of lymphocytes, especially T cells. This complex of ciclosporin and cyclophilin inhibits calcineurin, which, under normal circumstances, is responsible for activating the transcription of interleukin 2. In T-cells, activation of the T-cell receptor normally increases intracellular calcium, which acts via calmodulin to activate calcineurin. Calcineurin then dephosphorylates the transcription factor nuclear factor of activated T-cells (NFATc), which moves to the nucleus of the T-cell and increases the activity of genes coding for IL-2 and related cytokines. Ciclosporin prevents the dephosphorlyation of NF-AT by binding to cyclophilin. It also inhibits lymphokine production and interleukin release and, therefore, leads to a reduced function of effector T-cells. It does not affect cytostatic activity.
Ciclosporin affects mitochondria by preventing the mitochondrial permeability transition pore from opening, thus inhibiting cytochrome c release, a potent apoptotic stimulation factor. This is not the primary mechanism of action for clinical use, but is an important effect for research on apoptosis.
Ciclosporin binds to the cyclophilin D protein (CypD) that constitutes part of the mitochondrial permeability transition pore (MPTP), and by inhibiting the calcineurin phosphatase pathway. The MPTP is found in the mitochondrial membrane of cardiac myocytes (heart muscle cells) and moves calcium ions (Ca2+) into the mitochondria. When open, Ca2+ enters the mitochondria, disrupting transmembrane potential (the electric charge across a membrane). If unregulated, this can contribute to mitochondrial swelling and dysfunction. To allow for normal contraction, intracellular Ca2+ increases, and the MPTP in turn opens, shuttling Ca2+ into the mitochondria. Calcineurin is a Ca2+-activated phosphatase (enzyme that removes a phosphate group from substrate) that regulates cardiac hypertrophy. Regulation occurs through NFAT (nuclear factor of activated T-cells) activation, which, when dephosphorylated, binds to GATA and forms a transcription factor (protein that can bind DNA and alter the expression of DNA) with ability to control the hypertrophic gene (2). Activation of calcineurin causes increases in hypertrophy.
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