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Cong Zhang - One of the best experts on this subject based on the ideXlab platform.
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new insights of subfertility among transplanted women immunosuppressive drug fk506 leads to calcium leak and oocyte activation before fertilization
Journal of Cellular Biochemistry, 2018Co-Authors: Linli Liu, Ma Yang, Naiqiang Wang, Zijiang Che, Cong ZhangAbstract:FKBP12, known as FK506 binding protein, binds to immunosuppressive drug FK506, which must be taken by patients who received organ transplant. The side effect of FK506 is that women have difficulties in bearing a baby, so it is important to find the reason of their subfertility. This research explored the expression of FKBP12 in pre-implantation embryos and investigated its potential effect on reproduction. The results demonstrate that FKBP12 had good co-localization with endoplasmic reticulum and inositol-1, 4, 5- trisphosphate receptor in pre-implantation stages. Inhibiting FKBP12 by FK506 significantly increased the rate of 1-cell and fragmented embryos, greatly reduced the rate of 2-cell embryos during in vitro fertilization. When the mice received FK506 by gavage for 21 days, the calcium intensity of oocytes was decreased, these mice were subfertile and gave birth to significantly less pups during 6-month breeding period. QPCR demonstrated that Fbxo43 and P27kip, which are related to the release of MII oocyte arrest, and calcium channel partner protein Orai1 were downregulated, while Cdc2 and Ca2+ sensor at ER, stromal interaction molecule 1 (Stim1) were upregulated for a short time after adding FK506. Further exploration discovered that FK506 treatment increased Ca2+ concentration in the cytoplasm and caused pronucleus formation, however, the rate of parthenogenetic activation was lower compared to SrCl2 group. These findings identify the previously unknown role of FKBP12 in female reproduction which contributes to the release of calcium via IP3R channel and might open up new strategies for women who want to bear a baby after transplantation. This article is protected by copyright. All rights reserved
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new insights of subfertility among transplanted women immunosuppressive drug fk506 leads to calcium leak and oocyte activation before fertilization
Journal of Cellular Biochemistry, 2018Co-Authors: Naiqiang Wang, Cong Zhang, Linlin Liu, Man Yang, Zijiang ChenAbstract:FKBP12, known as FK506 binding protein, binds to immunosuppressive drug FK506, which must be taken by patients who received organ transplant. The side effect of FK506 is that women have difficulties in bearing a baby, so it is important to find the reason of their subfertility. This research explored the expression of FKBP12 in pre-implantation embryos and investigated its potential effect on reproduction. The results demonstrate that FKBP12 had good co-localization with endoplasmic reticulum and inositol-1, 4, 5- trisphosphate receptor in pre-implantation stages. Inhibiting FKBP12 by FK506 significantly increased the rate of 1-cell and fragmented embryos, greatly reduced the rate of 2-cell embryos during in vitro fertilization. When the mice received FK506 by gavage for 21 days, the calcium intensity of oocytes was decreased, these mice were subfertile and gave birth to significantly less pups during 6-month breeding period. QPCR demonstrated that Fbxo43 and P27kip, which are related to the release of MII oocyte arrest, and calcium channel partner protein Orai1 were downregulated, while Cdc2 and Ca2+ sensor at ER, stromal interaction molecule 1 (Stim1) were upregulated for a short time after adding FK506. Further exploration discovered that FK506 treatment increased Ca2+ concentration in the cytoplasm and caused pronucleus formation, however, the rate of parthenogenetic activation was lower compared to SrCl2 group. These findings identify the previously unknown role of FKBP12 in female reproduction which contributes to the release of calcium via IP3 R channel and might open up new strategies for women who want to bear a baby after transplantation.
Andrew M. Cameron - One of the best experts on this subject based on the ideXlab platform.
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calcineurin associated with the inositol 1 4 5 trisphosphate receptor fkbp12 complex modulates ca2 flux
Cell, 1995Co-Authors: Andrew M. Cameron, Joseph P. Steiner, Jane A Roskams, Siraj M Ali, Gabriele V Ronnettt, Solomon H SnyderAbstract:The immunosuppressant drug FK506 binds to the immunophilin protein FKBP12 and inhibits its prolyl isomerase activity. Immunosuppressive actions, however, are mediated via an FK506-FKBP12 inhibition of the Ca(2+)-activated phosphatase calcineurin. Physiologic cellular roles for FKBP12 have remained unclear. FKBP12 is physically associated with the RyR and IP3R Ca2+ channels in the absence of FK506, with added FK506 disrupting these complexes. Dissociation of FKBP12 results in alteration of channel Ca2+ conductance in both cases. We now report that calcineurin is physiologically associated with the IP3R-FKBP12 and RyR-FKBP12 receptor complexes and that this interaction can be disrupted by FK506 or rapamycin. Calcineurin anchored to the IP3R via FKBP12 regulates the phosphorylation status of the receptor, resulting in a dynamic Ca(2+)-sensitive regulation of IP3-mediated Ca2+ flux.
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immunophilin fk506 binding protein associated with inositol 1 4 5 trisphosphate receptor modulates calcium flux
Proceedings of the National Academy of Sciences of the United States of America, 1995Co-Authors: Andrew M. Cameron, Joseph P. Steiner, Loren D. Walensky, David M Sabatini, Adam I Kaplin, S SnyderAbstract:Abstract The immunophilin FK506 binding protein 12 (FKBP12) is associated with and modulates the ryanodine receptor calcium release channel of skeletal muscle. Ryanodine receptor has amino acid homology and functional similarity with another intracellular Ca2+ release channel, the inositol 1,4,5-trisphosphate receptor (IP3R). In the present study we show that highly purified preparations of IP3R contain FKBP12. The complex of these two proteins is disrupted by the immunosuppressants FK506 and rapamycin, both of which are known to bind FKBP12 with high affinity. Disrupting the IP3R-FKBP12 interaction increases Ca2+ flux through IP3R, an effect that is reversed by added FKBP12. FKBP12 appears to be physiologically linked to IP3R, regulating its Ca2+ conductance.
Joseph P. Steiner - One of the best experts on this subject based on the ideXlab platform.
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the 12 kd fk506 binding protein fkbp12 is released in the male reproductive tract and stimulates sperm motility
Molecular Medicine, 1998Co-Authors: Loren D. Walensky, Joseph P. Steiner, David M Sabatini, Ted M Dawson, Juan D Suarez, Gary R Klinefelter, Solomon H SnyderAbstract:The 12 kD FK506 binding protein FKBP12 is a cytosolic receptor for the immunosuppressant drugs FK506 and rapamycin. In addition to its critical role in drug-induced T-cell immunosuppression, FKBP12 associates physiologically with ryanodine and inositol 1,4,5-trisphosphate (IP3) receptors, regulating their ability to flux calcium. We investigated a role for FKBP12 in male reproductive physiology on the basis of our identification of extremely high levels of [3H]FK506 binding in male reproductive tissues. [3H]FK506 binding studies were performed to identify tissues enriched with FK506 binding sites. The abundant [3H]FK506 binding sites identified in the male reproductive tract were localized by [3H]FK506 autoradiography. FK506 affinity chromatography was employed to purify FKBP from epididymal fluid. Anti-FKBP12 Western analysis was used to confirm the identity of the purified FKBP. The binding of exogenous FKBP12 to sperm was evaluated by [32P]FKBP12 binding studies and [33P]FKBP12 autoradiography. The effect of recombinant FKBP12 on sperm motility was investigated using a Hamilton Thorne motility analyzer. Male reproductive tissues contained high levels of [3H]FK506 binding. The localization of [3H]FK506 binding sites to the tubular epithelium of the caput epididymis and the lumen of the cauda and vas deferens suggested that FKBP is released in the male reproductive tract. FKBP12 was purified from epididymal plasma by FK506 affinity chromatography. Radiolabeled FKBP 12 specifically bound to immature but not mature sperm. In sperm motility studies, FKBP12-treated caput sperm exhibited double the curvilinear velocity of untreated controls. High levels of FKBP12 are released in the male reproductive tract and specifically associate with maturing sperm. Recombinant FKBP12 enhances the curvilinear velocity of immature sperm, suggesting a role for FKBP12 in motility initiation. The highest concentrations of soluble FKBP12 in the male reproductive tract occur in the lumen of the vas deferens, a site of sperm storage and the conduit for ejaculated sperm. Preservation of mammalian sperm for reproductive technologies may be optimized by supplementing incubation or storage media with FKBP12.
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calcineurin associated with the inositol 1 4 5 trisphosphate receptor fkbp12 complex modulates ca2 flux
Cell, 1995Co-Authors: Andrew M. Cameron, Joseph P. Steiner, Jane A Roskams, Siraj M Ali, Gabriele V Ronnettt, Solomon H SnyderAbstract:The immunosuppressant drug FK506 binds to the immunophilin protein FKBP12 and inhibits its prolyl isomerase activity. Immunosuppressive actions, however, are mediated via an FK506-FKBP12 inhibition of the Ca(2+)-activated phosphatase calcineurin. Physiologic cellular roles for FKBP12 have remained unclear. FKBP12 is physically associated with the RyR and IP3R Ca2+ channels in the absence of FK506, with added FK506 disrupting these complexes. Dissociation of FKBP12 results in alteration of channel Ca2+ conductance in both cases. We now report that calcineurin is physiologically associated with the IP3R-FKBP12 and RyR-FKBP12 receptor complexes and that this interaction can be disrupted by FK506 or rapamycin. Calcineurin anchored to the IP3R via FKBP12 regulates the phosphorylation status of the receptor, resulting in a dynamic Ca(2+)-sensitive regulation of IP3-mediated Ca2+ flux.
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immunophilin fk506 binding protein associated with inositol 1 4 5 trisphosphate receptor modulates calcium flux
Proceedings of the National Academy of Sciences of the United States of America, 1995Co-Authors: Andrew M. Cameron, Joseph P. Steiner, Loren D. Walensky, David M Sabatini, Adam I Kaplin, S SnyderAbstract:Abstract The immunophilin FK506 binding protein 12 (FKBP12) is associated with and modulates the ryanodine receptor calcium release channel of skeletal muscle. Ryanodine receptor has amino acid homology and functional similarity with another intracellular Ca2+ release channel, the inositol 1,4,5-trisphosphate receptor (IP3R). In the present study we show that highly purified preparations of IP3R contain FKBP12. The complex of these two proteins is disrupted by the immunosuppressants FK506 and rapamycin, both of which are known to bind FKBP12 with high affinity. Disrupting the IP3R-FKBP12 interaction increases Ca2+ flux through IP3R, an effect that is reversed by added FKBP12. FKBP12 appears to be physiologically linked to IP3R, regulating its Ca2+ conductance.
Solomon H Snyder - One of the best experts on this subject based on the ideXlab platform.
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the 12 kd fk506 binding protein fkbp12 is released in the male reproductive tract and stimulates sperm motility
Molecular Medicine, 1998Co-Authors: Loren D. Walensky, Joseph P. Steiner, David M Sabatini, Ted M Dawson, Juan D Suarez, Gary R Klinefelter, Solomon H SnyderAbstract:The 12 kD FK506 binding protein FKBP12 is a cytosolic receptor for the immunosuppressant drugs FK506 and rapamycin. In addition to its critical role in drug-induced T-cell immunosuppression, FKBP12 associates physiologically with ryanodine and inositol 1,4,5-trisphosphate (IP3) receptors, regulating their ability to flux calcium. We investigated a role for FKBP12 in male reproductive physiology on the basis of our identification of extremely high levels of [3H]FK506 binding in male reproductive tissues. [3H]FK506 binding studies were performed to identify tissues enriched with FK506 binding sites. The abundant [3H]FK506 binding sites identified in the male reproductive tract were localized by [3H]FK506 autoradiography. FK506 affinity chromatography was employed to purify FKBP from epididymal fluid. Anti-FKBP12 Western analysis was used to confirm the identity of the purified FKBP. The binding of exogenous FKBP12 to sperm was evaluated by [32P]FKBP12 binding studies and [33P]FKBP12 autoradiography. The effect of recombinant FKBP12 on sperm motility was investigated using a Hamilton Thorne motility analyzer. Male reproductive tissues contained high levels of [3H]FK506 binding. The localization of [3H]FK506 binding sites to the tubular epithelium of the caput epididymis and the lumen of the cauda and vas deferens suggested that FKBP is released in the male reproductive tract. FKBP12 was purified from epididymal plasma by FK506 affinity chromatography. Radiolabeled FKBP 12 specifically bound to immature but not mature sperm. In sperm motility studies, FKBP12-treated caput sperm exhibited double the curvilinear velocity of untreated controls. High levels of FKBP12 are released in the male reproductive tract and specifically associate with maturing sperm. Recombinant FKBP12 enhances the curvilinear velocity of immature sperm, suggesting a role for FKBP12 in motility initiation. The highest concentrations of soluble FKBP12 in the male reproductive tract occur in the lumen of the vas deferens, a site of sperm storage and the conduit for ejaculated sperm. Preservation of mammalian sperm for reproductive technologies may be optimized by supplementing incubation or storage media with FKBP12.
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calcineurin associated with the inositol 1 4 5 trisphosphate receptor fkbp12 complex modulates ca2 flux
Cell, 1995Co-Authors: Andrew M. Cameron, Joseph P. Steiner, Jane A Roskams, Siraj M Ali, Gabriele V Ronnettt, Solomon H SnyderAbstract:The immunosuppressant drug FK506 binds to the immunophilin protein FKBP12 and inhibits its prolyl isomerase activity. Immunosuppressive actions, however, are mediated via an FK506-FKBP12 inhibition of the Ca(2+)-activated phosphatase calcineurin. Physiologic cellular roles for FKBP12 have remained unclear. FKBP12 is physically associated with the RyR and IP3R Ca2+ channels in the absence of FK506, with added FK506 disrupting these complexes. Dissociation of FKBP12 results in alteration of channel Ca2+ conductance in both cases. We now report that calcineurin is physiologically associated with the IP3R-FKBP12 and RyR-FKBP12 receptor complexes and that this interaction can be disrupted by FK506 or rapamycin. Calcineurin anchored to the IP3R via FKBP12 regulates the phosphorylation status of the receptor, resulting in a dynamic Ca(2+)-sensitive regulation of IP3-mediated Ca2+ flux.
Anne Marie B Brillantes - One of the best experts on this subject based on the ideXlab platform.
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stabilization of calcium release channel ryanodine receptor function by fk506 binding protein
Cell, 1994Co-Authors: Anne Marie B Brillantes, Evgeny Kobrinsky, Elena Ondriasova, Andrew Scott, Karol Ondrias, Maria C MoschellaAbstract:Abstract FK506-binding protein (FKBP12) was originally identified as the cytosolic receptor for the immunosuppressant drugs FK506 and rapamycin. The cellular function of FKBP12, a ubiquitously expressed 12,000-dalton proline isomerase, has been unknown. FKBP12 copurifies with the 565,000-dalton ryanodine receptor (RyR), four of which form intracellular Ca 2+ release channels of the sarcoplasmic and endoplasmic reticula. By coexpressing the RyR and FKBP12 in insect cells, we have demonstrated that FKBP12 modulates channel gating by increasing channels with full conductance levels (by >400%), decreasing open probability after caffeine activation (from 0.63 ± 0.09 to 0.04 ± 0.02), and increasing mean open time (from 4.4 ± 0.6 ms to 75 ± 41 ms). FK506 or rapamycin, inhibitors of FKBP12 isomerase activity, reverse these stabilizing effects. These results provide the first natural cellular function for FKBP12, and establish that the functional Ca 2+ release channel complex includes FKBP12.
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fk506 binding protein associated with the calcium release channel ryanodine receptor
Journal of Biological Chemistry, 1992Co-Authors: Thottala Jayaraman, Anne Marie B Brillantes, A P Timerman, Hediye Erdjumentbromage, Paul Tempst, Sidney Fleischer, Andrew R. MarksAbstract:Abstract The calcium release channel (CRC)/ryanodine receptor (RyRec) has been identified as the foot structure of the sarcoplasmic reticulum (SR) and provides the pathway for calcium efflux required for excitation-contraction coupling in skeletal muscle. The CRC has previously been reported to consist of four identical 565-kDa protomers. We now report the identification of a 12-kDa protein which is tightly associated with highly purified RyRec from rabbit skeletal muscle SR. N-terminal amino acid sequencing and cDNA cloning demonstrates that the 12-kDa protein from fast twitch skeletal muscle is the binding protein for the immunosuppressant drug FK506. In humans, FK506 binds to the 12-kDa FK506-binding protein (FKBP12) and blocks calcium-dependent T cell activation. We find that FKBP12 and the RyRec are tightly associated in skeletal muscle SR on the basis of: 1) co-purification through sequential heparin-agarose, hydroxylapatite, and size exclusion chromatography columns; 2) coimmunoprecipitation of the RyRec and FKBP12 with anti-FKBP12 antibodies; and 3) subcellular localization of both proteins to the terminal cisternae of the SR, and not in the longitudinal tubules of SR, in fast twitch skeletal muscle. The molar ratio of FKBP12 to RyRec in highly purified RyRec preparations is approximately 1:4, indicating that one FKBP12 molecule is associated with each calcium release channel/foot structure.