Cell Physiology Laboratory and Biomembrane Plasticity Research Center, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 110-799, Republic of Korea; Department of Physiology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 110-799, Republic of Korea.
Biochem Biophys Res Commun. 2013 Nov 1;440(4):539-44. doi: 10.1016/j.bbrc.2013.09.099. Epub 2013 Oct 5.
Leptin regulates pancreatic β-cell excitability through AMP-activated protein kinase (AMPK)-mediated ATP-sensitive potassium (KATP) channel trafficking. However, the signaling components connecting AMPK to KATP channel trafficking are not identified. In this study, we discovered that AMPK inhibits phosphatase and tensin homologue (PTEN) via glycogen synthase kinase 3β (GSK3β) and this signaling pathway is crucial for KATP channel trafficking in leptin-treated pancreatic β-cells. Pharmacologic or genetic inhibition of AMPK or GSK3β, but not casein kinase 2 (CK2), impaired leptin-induced PTEN inactivation and thereby KATP channel trafficking. The PTEN mutant lacking both protein and lipid phosphatase activity is sufficient to induce KATP channel trafficking without leptin. These results present a novel signaling mechanism that underlies leptin regulation of KATP channel trafficking in pancreatic β-cells. Our findings assist in gaining a broader perspective on the peripheral action of leptin on pancreatic β-cell physiology and glucose homeostasis.
瘦素通过 AMP 激活的蛋白激酶（AMPK）介导的三磷酸腺苷敏感性钾（KATP）通道转运来调节胰腺β细胞的兴奋性。然而，连接 AMPK 与 KATP 通道转运的信号成分尚不清楚。在这项研究中，我们发现 AMPK 通过糖原合成酶激酶 3β（GSK3β）抑制磷酸酶和张力蛋白同源物（PTEN），而这条信号通路对于瘦素处理的胰腺β细胞中 KATP 通道转运至关重要。通过药理学或遗传学抑制 AMPK 或 GSK3β，但不是酪蛋白激酶 2（CK2），可损害瘦素诱导的 PTEN 失活，从而影响 KATP 通道转运。缺乏蛋白和脂质磷酸酶活性的 PTEN 突变体足以在没有瘦素的情况下诱导 KATP 通道转运。这些结果提出了一种新的信号机制，为瘦素调节胰腺β细胞中 KATP 通道转运提供了基础。我们的发现有助于更全面地了解瘦素对胰腺β细胞生理学和葡萄糖稳态的外周作用。
