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Effects of FK506 on ca release channels (review).

Ozawa T - Perspect Medicin Chem (2008)

Bottom Line: Tacrolimus (FK506), which was isolated from the fermentation broth of Streptomyces tsukubaensis No. 9993, has an immunosuppressive effect.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.Recently, it was found that FK506 itself induces Ca(2+) release through RyRs in some tissues.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.

ABSTRACT
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.

No MeSH data available.


Chemical structure of tacrolimus (FK506).
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Related In: Results  -  Collection

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f1-pmc-2008-051: Chemical structure of tacrolimus (FK506).

Mentions: Tacrolimus (Fig. 1), a 23-membered macrolide lactone, was isolated from the fermentation broth of Streptomyces tsukubaensis No. 9993 in 1984 [1] and is designated by the code number of FK506. The drug is a colorless prism, and the molecular formula is C44H69NO12·H2O (Mw: 804.02). The chemical structure was determined by Tanaka et al. [19]. The drug is soluble in ethanol, methanol and DMSO and is insoluble in water.


Effects of FK506 on ca release channels (review).

Ozawa T - Perspect Medicin Chem (2008)

Chemical structure of tacrolimus (FK506).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2746578&req=5

f1-pmc-2008-051: Chemical structure of tacrolimus (FK506).
Mentions: Tacrolimus (Fig. 1), a 23-membered macrolide lactone, was isolated from the fermentation broth of Streptomyces tsukubaensis No. 9993 in 1984 [1] and is designated by the code number of FK506. The drug is a colorless prism, and the molecular formula is C44H69NO12·H2O (Mw: 804.02). The chemical structure was determined by Tanaka et al. [19]. The drug is soluble in ethanol, methanol and DMSO and is insoluble in water.

Bottom Line: Tacrolimus (FK506), which was isolated from the fermentation broth of Streptomyces tsukubaensis No. 9993, has an immunosuppressive effect.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.Recently, it was found that FK506 itself induces Ca(2+) release through RyRs in some tissues.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.

ABSTRACT
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.

No MeSH data available.