Interactions of ATP, oestradiol, genistein and the anti-olestrogens, faslodex (ICI 182780) and tamoxifen, with the human erythrocyte glucose transporter, GLUT1
Interactions of ATP, oestradiol, genistein and the anti-olestrogens, faslodex (ICI 182780) and tamoxifen, with the human erythrocyte glucose transporter, GLUT1
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DOI：
10.1042/bj20011624
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发表时间：
2002-08-01
影响因子：
4.1
通讯作者：
Naftalin, RJ
中科院分区：
文献类型：
--
作者：
Afzal, I;Cunningham, P;Naftalin, RJ
17β-雌二醇（K 下标为 ED）和植物雌激素异黄酮染料木黄酮 (GEN) 抑制人红细胞和红细胞血影中的葡萄糖转运。选择性雌激素受体调节剂或抗雌激素，faslodex (ICI 182780) (FAS) 和他莫昔芬 (TAM)，竞争性拮抗雌二醇对红细胞葡萄糖排出的抑制作用 (K-i(ED/FAS) = 2.84 +/- 0.16 muM 和 K-i(ED/TAM) = 100 +/- 2 nM）。 Faslodex 对葡萄糖排出没有显着的抑制作用，但他莫昔芬单独抑制葡萄糖排出 (K-i(TAM) = 300 +/- 100 nM）。在鬼魂中，ATP (1-4 mM) 竞争性拮抗雌二醇、金雀异黄素和细胞松弛素 B (CB) 依赖性葡萄糖排出抑制，(K-i(ATP/ED) = 2.5 +/- 0.23 mM、K-i(ATP/GEN) = 0.99 +/- 0.17 mM 和 K-i(ATP/CB) = 0.76 +/- 0.08毫米）。 Tamoxifen 和 faslodex 可逆转雌二醇依赖性葡萄糖出口抑制，ATP > 1 mM（K-i(ED/TAM) = 130 +/- 5 nM 和 K-i(ED/FAS) = 2.7 +/- 0.9 muM）。葡萄糖转运蛋白 (GLUT)1 的细胞质表面包含四个与人雌激素受体 β (hesr-2) 配体结合域中的序列具有密切同源性的序列。一个同源性与连接跨膜螺旋 6 和 7 的大胞质片段中的 Walker ATP 结合基序 II（GLUT1，残基 225-229）相邻；另一个 GLUT（残基 421-423）包含 Walker ATP 结合基序 III。将这些区域映射到 GLUT 的三维模板上表明，可能的雌激素结合位点位于跨越 GLUT 的亲水孔的细胞质入口处的 His(337)、Arg(349) 和 Glu(249) 之间，其与 hesr-2 中的 His(475)、Glu(305) 和 Arg(346) 具有相似的拓扑结构，这些结构锚定了 GLUT 的头部和尾部羟基。雌二醇和染料木黄酮，因此被适当地放置以提供可以调节葡萄糖输出的ATP敏感的雌激素结合位点。
17beta-Oestradiol (ED when subscript to K) and the phytoestrogen isoflavone genistein (GEN) inhibit glucose transport in human erythrocytes and erythrocyte ghosts. The selective oestrogen receptor modulators or anti-oestrogens, faslodex (ICI 182780) (FAS) and tamoxifen (TAM), competitively antagonize oestradiol inhibition of glucose exit from erythrocytes (K-i(ED/FAS) = 2.84 +/- 0.16 muM and K-i(ED/TAM) = 100 +/- 2 nM). Faslodex has no significant inhibitory effect on glucose exit, but tamoxifen alone inhibits glucose exit (K-i(TAM) = 300 +/- 100 nM). In ghosts, ATP (1-4 mM) competitively antagonizes oestradiol, genistein and cytochalasin B (CB)-dependent inhibitions of glucose exit, (K-i(ATP/ED) = 2.5 +/- 0.23 mM, K-i(ATP/GEN) = 0.99 +/- 0.17 mM and K-i(ATP/CB) = 0.76 +/- 0.08 mM). Tamoxifen and faslodex reverse oestradiol-dependent inhibition of glucose exit with ATP > 1 mM (K-i(ED/TAM) = 130 +/- 5 nM and K-i(ED/FAS) = 2.7 +/- 0.9 muM). The cytoplasmic surface of the glucose transporter (GLUT)l contains four sequences with close homologies to sequences in the ligand-binding domain of human oestrogen receptor beta (hesr-2). One homology is adjacent to the Walker ATP-binding motif II (GLUT1, residues 225-229) in the large cytoplasmic segment linking transmembrane helices 6 and 7; another GLUT (residues 421-423) contains the Walker ATP-binding motif III. Mapping of these regions on to a three-dimensional template of GLUT indicates that a possible oestrogen-binding site lies between His(337), Arg(349) and Glu(249) at the cytoplasmic entrance to the hydrophilic pore spanning GLUT, which have a similar topology to His(475), Glu(305) and Arg(346) in hesr-2 that anchor the head and tail hydroxy groups of oestradiol and genistein, and thus are suitably placed to provide an ATP-sensitive oestrogen binding site that could modulate glucose export.