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Effects of FK506 on Ca(2+) Release Channels (Review)
Tacrolimus (FK506), which was isolated from the fermentation broth of Streptomyces tsukubaensis No. 9993, has an immunosuppressive effect. In T-lymphocytes, FK506 binds to the intracellular receptor, a 12-kDa FK506-binding protein (FKBP12). The FK506-FKBP12 complex binds to the phosphatase calcineur...
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Formato: | Texto |
Lenguaje: | English |
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Libertas Academica
2008
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2746578/ https://www.ncbi.nlm.nih.gov/pubmed/19787097 |
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author | Ozawa, Terutaka |
author_facet | Ozawa, Terutaka |
author_sort | Ozawa, Terutaka |
collection | PubMed |
description | Tacrolimus (FK506), which was isolated from the fermentation broth of Streptomyces tsukubaensis No. 9993, has an immunosuppressive effect. In T-lymphocytes, FK506 binds to the intracellular receptor, a 12-kDa FK506-binding protein (FKBP12). The FK506-FKBP12 complex binds to the phosphatase calcineurin (CN) and inhibits the activity of CN. By inhibition of the activity of CN, dephosphorylation of a nuclear factor of activated T-cells (NFAT) is inhibited, and translocation of the NFAT to the nucleus is suppressed. Thereby, the production of T-cell-derived mediators such as interleukin 2 (IL-2) is inhibited, and the proliferation of cytotoxic T-cells is suppressed. In muscle cells, FKBP12 and FKBP12.6 are associated with ryanodine-sensitive Ca(2+) release channels (ryanodine receptors: RyRs) on the skeletal and cardiac muscle sarcoplasmic reticulum (SR), respectively. FK506 modulates the RyR by dissociating FKBP12 or FKBP12.6 from the RyR complex. FKBP12 is also associated with inositol 1,4,5-trisphosphate (IP(3))-sensitive Ca(2+) release channels (IP(3) receptors: IP(3)Rs) on the endoplasmic reticulum (ER) of non-muscle cells. The IP(3)R-FKBP12 complex binds to CN, which dephosphorylates the protein kinase C (PKC) phosphorylation site on the receptor. When FKBP12 is dissociated from the IP(3)R complex by FK506, CN is also dissociated from the IP(3)R. Thereby, the IP(3)R is phosphorylated by PKC, and the receptor is modulated. Recently, it was found that FK506 itself induces Ca(2+) release through RyRs in some tissues. |
format | Text |
id | pubmed-2746578 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2008 |
publisher | Libertas Academica |
record_format | MEDLINE/PubMed |
spelling | pubmed-27465782009-09-28 Effects of FK506 on Ca(2+) Release Channels (Review) Ozawa, Terutaka Perspect Medicin Chem Perspective Tacrolimus (FK506), which was isolated from the fermentation broth of Streptomyces tsukubaensis No. 9993, has an immunosuppressive effect. In T-lymphocytes, FK506 binds to the intracellular receptor, a 12-kDa FK506-binding protein (FKBP12). The FK506-FKBP12 complex binds to the phosphatase calcineurin (CN) and inhibits the activity of CN. By inhibition of the activity of CN, dephosphorylation of a nuclear factor of activated T-cells (NFAT) is inhibited, and translocation of the NFAT to the nucleus is suppressed. Thereby, the production of T-cell-derived mediators such as interleukin 2 (IL-2) is inhibited, and the proliferation of cytotoxic T-cells is suppressed. In muscle cells, FKBP12 and FKBP12.6 are associated with ryanodine-sensitive Ca(2+) release channels (ryanodine receptors: RyRs) on the skeletal and cardiac muscle sarcoplasmic reticulum (SR), respectively. FK506 modulates the RyR by dissociating FKBP12 or FKBP12.6 from the RyR complex. FKBP12 is also associated with inositol 1,4,5-trisphosphate (IP(3))-sensitive Ca(2+) release channels (IP(3) receptors: IP(3)Rs) on the endoplasmic reticulum (ER) of non-muscle cells. The IP(3)R-FKBP12 complex binds to CN, which dephosphorylates the protein kinase C (PKC) phosphorylation site on the receptor. When FKBP12 is dissociated from the IP(3)R complex by FK506, CN is also dissociated from the IP(3)R. Thereby, the IP(3)R is phosphorylated by PKC, and the receptor is modulated. Recently, it was found that FK506 itself induces Ca(2+) release through RyRs in some tissues. Libertas Academica 2008-03-18 /pmc/articles/PMC2746578/ /pubmed/19787097 Text en © 2009 The authors. http://creativecommons.org/licenses/by/3.0 This article is published under the Creative Commons Attribution By licence. For further information go to: http://creativecommons.org/licenses/by/3.0. (http://creativecommons.org/licenses/by/3.0) |
spellingShingle | Perspective Ozawa, Terutaka Effects of FK506 on Ca(2+) Release Channels (Review) |
title | Effects of FK506 on Ca(2+) Release Channels (Review) |
title_full | Effects of FK506 on Ca(2+) Release Channels (Review) |
title_fullStr | Effects of FK506 on Ca(2+) Release Channels (Review) |
title_full_unstemmed | Effects of FK506 on Ca(2+) Release Channels (Review) |
title_short | Effects of FK506 on Ca(2+) Release Channels (Review) |
title_sort | effects of fk506 on ca(2+) release channels (review) |
topic | Perspective |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2746578/ https://www.ncbi.nlm.nih.gov/pubmed/19787097 |
work_keys_str_mv | AT ozawaterutaka effectsoffk506onca2releasechannelsreview |