ATP regulation of type 1 inositol 1,4,5-trisphosphate receptor channel gating by allosteric tuning of Ca2+ activation
ATP regulation of type 1 inositol 1,4,5-trisphosphate receptor channel gating by allosteric tuning of Ca2+ activation
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DOI：
10.1074/jbc.274.32.22231
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发表时间：
1999-08-06
影响因子：
4.8
通讯作者：
Foskett, JK
中科院分区：
文献类型：
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作者：
Mak, DOD;McBride, S;Foskett, JK
三磷酸肌醇（InsP（3））通过与其受体（InsP（3）R）结合来动员细胞内Ca 2+，InsP（3）R是一种位于内质网的Ca 2+释放通道。应用膜片钳技术研究了非洲爪蟾卵母细胞核内ATP浓度对内质网膜1型InsP（3）R通道胞浆Ca ~（2+）依赖性的影响。胞质ATP游离酸（[ATP]（i）），而不是MgATP复合物，通过稳定开放通道状态和不稳定关闭状态激活InsP（3）配体InsP（3）R的门控。活化与半最大活化[Ca 2 +]（i）从0 [ATP]（i）中的500 +/- 50 nM降低至9.5 mM [ATP]（i）中的29 +/- 4 nM相关，表观ATP亲和力= 0.27 +/- 0.04 mM，与体内浓度相似。相反，ATP对Ca 2+激活的最大开放概率或Hill系数没有影响。因此，ATP通过对通道的Ca 2+激活位点的Ca 2+敏感性的变构调节来增强InsP（3）R的门控。ATP可能通过调节InsP（3）R的Ca 2+诱导的Ca 2+释放特性，在形成胞质Ca 2+信号中发挥重要作用，可能将细胞代谢状态与重要的Ca 2+依赖性过程联系起来。
Inositol 1,4,5-trisphosphate (InsP(3)) mobilizes intracellular Ca2+ by binding to its receptor (InsP(3)R), an endoplasmic reticulum-localized Ca2+ release channel. Patch clamp electrophysiology of Xenopus oocyte nuclei was used to study the effects of cytoplasmic ATP concentration on the cytoplasmic Ca2+ ([Ca2+](i)) dependence of single type 1 InsP(3)R channels in native endoplasmic reticulum membrane. Cytoplasmic ATP free-acid ([ATP](i)), but not the MgATP complex, activated gating of the InsP(3)-liganded InsP(3)R, by stabilizing open channel state(s) and destabilizing the closed state(s). Activation was associated with a reduction of the half-maximal activating [Ca2+](i) from 500 +/- 50 nM in 0 [ATP](i) to 29 +/- 4 nM in 9.5 mM [ATP](i), with apparent ATP affinity = 0.27 +/- 0.04 mM, similar to in vivo concentrations. In contrast, ATP was without effect on maximum open probability or the Hill coefficient for Ca2+ activation. Thus, ATP enhances gating of the InsP(3)R by allosteric regulation of the Ca2+ sensitivity of the Ca2+ activation sites of the channel. By regulating the Ca2+-induced Ca2+ release properties of the InsP(3)R, ATP may play an important role in shaping cytoplasmic Ca2+ signals, possibly linking cell metabolic state to important Ca2+ dependent processes.