Division of Cardiovascular and Diabetes Medicine, Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, UK.
J Bioenerg Biomembr. 2013 Jun;45(3):229-41. doi: 10.1007/s10863-013-9509-9. Epub 2013 Apr 11.
Glucose-sensing (GS) behaviour in pancreatic β-cells is dependent on ATP-sensitive K(+) channel (KATP) activity, which is controlled by the relative levels of the KATP ligands ATP and ADP, responsible for closing and opening KATP, respectively. However, the mechanism by which β-cells transfer energy status from mitochondria to KATP, and hence to altered electrical excitability and insulin secretion, is presently unclear. Recent work has demonstrated a critical role for AMP-activated protein kinase (AMPK) in GS behaviour of cells. Electrophysiological recordings, coupled with measurements of gene and protein expression were made from rat insulinoma cells to investigate whether AMPK activity regulates this energy transfer process. Using the whole-cell recording configuration with sufficient intracellular ATP to keep KATP closed, raised AMPK activity induced GS electrical behaviour. This effect was prevented by the AMPK inhibitor, compound C and required a phosphotransfer process. Indeed, high levels of intracellular phosphocreatine or the presence of the adenylate kinase (AK) inhibitor AP5A blocked this action of AMPK. Using conditions that maximised AMPK-induced KATP opening, there was a significant increase in AK1, AK2 and UCP2 mRNA expression. Thus we propose that KATP opening in response to lowered glucose concentration requires AMPK activity, perhaps in concert with increased AK and UCP2 to enable mitochondrial-derived ADP signals to be transferred to plasma membrane KATP by phosphotransfer cascades.
葡萄糖感应（GS）在胰腺β细胞中的行为取决于 ATP 敏感性钾（KATP）通道的活性，而 KATP 的活性又受到 KATP 的配体 ATP 和 ADP 的相对水平的控制，它们分别负责 KATP 的关闭和打开。然而，β细胞将能量状态从线粒体传递到 KATP，从而改变电兴奋性和胰岛素分泌的机制目前尚不清楚。最近的研究表明，AMP 激活的蛋白激酶（AMPK）在细胞的 GS 行为中起着关键作用。通过从大鼠胰岛素瘤细胞中进行电生理学记录，结合基因和蛋白表达的测量，研究 AMPK 活性是否调节这种能量传递过程。使用全细胞记录配置，细胞内有足够的 ATP 使 KATP 保持关闭，增加的 AMPK 活性诱导 GS 电行为。该效应被 AMPK 抑制剂化合物 C 阻止，并需要磷酸转移过程。事实上，细胞内磷酸肌酸的高水平或存在腺苷酸激酶（AK）抑制剂 AP5A 会阻止 AMPK 的这种作用。在最大程度地增加 AMPK 诱导的 KATP 打开的条件下，AK1、AK2 和 UCP2 的 mRNA 表达显著增加。因此，我们提出，响应降低的葡萄糖浓度而打开的 KATP 需要 AMPK 活性，也许与增加的 AK 和 UCP2 一起，通过磷酸转移级联将线粒体衍生的 ADP 信号传递到质膜 KATP。
