Rapid Regulation of KATP Channel Activity by 17β-Estradiol in Pancreatic β-Cells Involves the Estrogen Receptor β and the Atrial Natriuretic Peptide Receptor
Rapid Regulation of KATP Channel Activity by 17β-Estradiol in Pancreatic β-Cells Involves the Estrogen Receptor β and the Atrial Natriuretic Peptide Receptor
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DOI：
10.1210/me.2009-0287
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发表时间：
2009-12-01
影响因子：
--
通讯作者：
Nadal, Angel
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文献类型：
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作者：
Soriano, Sergi;Ropero, Ana B.;Nadal, Angel
ATP敏感性钾通道（K-ATP）是葡萄糖刺激胰岛素分泌的关键分子。该通道的活性调节β细胞膜电位、葡萄糖诱导的[Ca 2 +]（i）信号和胰岛素释放。在这项研究中，17 β-雌二醇（E2）的生理浓度对K-ATP通道活性的快速影响进行了研究，在完整的β细胞使用膜片钳技术。当使用野生型（WT）小鼠的细胞时，1 nM E2迅速使K-ATP通道活性降低60%。E2对K-ATP通道的作用在ER α-/-小鼠的β细胞中没有改变，但在ER β-/-小鼠的细胞中显著降低。E2的作用由ER β激动剂2，3-二（4-羟基苯基）-丙腈（DPN）模拟。DPN激活ER β可增强葡萄糖诱导的Ca 2+信号和胰岛素释放。已有证据表明，E2对K-ATP通道活性的急性抑制作用涉及环GMP和环GMP依赖性蛋白激酶。在这项研究中，我们使用来自心房利钠肽（也称为心房利钠肽受体）的膜鸟苷酸环化酶A受体基因消融小鼠（GC-A KO小鼠）的β细胞，以证明该膜受体参与β细胞中触发的快速E2作用。E2迅速抑制K-ATP通道活性，并增强WT小鼠胰岛中的胰岛素释放，但在GC-A KO小鼠胰岛中不存在。此外，DPN降低了WT小鼠β细胞中的K-ATP通道活性，但在GC-A KO小鼠的β细胞中没有。这项工作揭示了ER β作为促胰岛素分子的新作用，可能具有重要的生理和药理学意义。（分子内分泌学23：1973-1982，2009）
The ATP-sensitive potassium (K-ATP) channel is a key molecule involved in glucose-stimulated insulin secretion. The activity of this channel regulates beta-cell membrane potential, glucose-induced [Ca2+](i) signals, and insulin release. In this study, the rapid effect of physiological concentrations of 17 beta-estradiol (E2) on K-ATP channel activity was studied in intact beta-cells by use of the patch-clamp technique. Whencells from wild-type (WT) mice were used, 1 nM E2 rapidly reduced K-ATP channel activity by 60%. The action of E2 on K-ATP channel was not modified in beta-cells from ER alpha-/- mice, yet it was significantly reduced in cells from ER beta-/- mice. The effect of E2 was mimicked by the ER beta agonist 2,3-bis(4hydroxyphenyl)-propionitrile (DPN). Activation of ER beta by DPN enhanced glucose-induced Ca2+ signals and insulin release. Previous evidence indicated that the acute inhibitory effects of E2 on K-ATP channel activity involve cyclic GMP and cyclic GMP-dependent protein kinase. In this study, we used beta-cells from mice with genetic ablation of the membrane guanylate cyclase A receptor for atrial natriuretic peptide (also called the atrial natriuretic peptide receptor) (GC-A KO mice) to demonstrate the involvement of this membrane receptor in the rapid E2 actions triggered in beta-cells. E2 rapidly inhibited K-ATP channel activity and enhanced insulin release in islets from WT mice but not in islets from GC-A KO mice. In addition, DPN reduced K-ATP channel activity in beta-cells from WT mice, but not in beta-cells from GC-A KO mice. This work unveils a new role for ER beta as an insulinotropic molecule that may have important physiological and pharmacological implications. (Molecular Endocrinology 23: 1973-1982, 2009)