STABILIZATION OF CALCIUM-RELEASE CHANNEL (RYANODINE RECEPTOR) FUNCTION BY FK506-BINDING PROTEIN
STABILIZATION OF CALCIUM-RELEASE CHANNEL (RYANODINE RECEPTOR) FUNCTION BY FK506-BINDING PROTEIN
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DOI：
10.1016/0092-8674(94)90214-3
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发表时间：
1994-05-20
期刊：
影响因子：
64.5
通讯作者：
MARKS, AR
中科院分区：
文献类型：
--
作者：
BRILLANTES, AMB;ONDRIAS, K;MARKS, AR
FK506结合蛋白(FKBP12)最初被鉴定为免疫抑制剂FK506和雷帕霉素的胞浆受体。FKBP12是一种普遍表达的12,000道尔顿脯氨酸异构酶，其细胞功能尚不清楚。FKBP12与565,000道尔顿兰尼定受体(RyR)结合，其中4个形成肌浆和内质网的细胞内钙释放通道。通过在昆虫细胞中共表达RyR和FKBP12，我们已经证明FKBP12通过增加全电导水平的通道(增加了400%)、降低咖啡因激活后的开放概率(从0.63+/-0.09降低到0.04+/-0.02)以及延长平均开放时间(从4.4+/-0.6ms增加到75+/-41ms)来调节通道门控。FK506或雷帕霉素，FKBP12异构酶活性的抑制剂，逆转了这些稳定作用。这些结果首次提供了FKBP12的天然细胞功能，并证实了功能性的钙释放通道复合体包括FKBP12。
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 Ca2+ 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 Ca2+ release channel complex includes FKBP12.