The anti-diabetic drugs rosiglitazone and metformin stimulate AMP-activated protein kinase through distinct signaling pathways
The anti-diabetic drugs rosiglitazone and metformin stimulate AMP-activated protein kinase through distinct signaling pathways
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DOI：
10.1074/jbc.m202489200
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发表时间：
2002-07-12
影响因子：
4.8
通讯作者：
Carling, D
中科院分区：
文献类型：
--
作者：
Fryer, LGD;Parbu-Patel, A;Carling, D
AMP活化蛋白激酶（AMPK）在细胞内响应于增加细胞内AMP：ATP比率的多种应激而被活化。在这里，我们表明，孵育的肌肉细胞与噻唑烷二酮，罗格列酮，导致显着增加，这一比例与AMPK的伴随激活。这一发现提高了噻唑烷二酮类药物的许多有益作用可能通过AMPK的激活来介导的可能性。此外，我们表明，除了经典的激活途径，AMPK也可以刺激而不改变腺嘌呤核苷酸的水平。在肌细胞中，高渗应激和抗糖尿病药物二甲双胍在AMP：ATP比率没有任何增加的情况下激活AMPK。然而，尽管活化不再依赖于该比率，但它仍然涉及催化（a）亚基内苏氨酸172的磷酸化增加。AMPK刺激对高渗应激的反应似乎不涉及磷脂酰肌醇3-磷酸激酶、蛋白激酶C、促分裂原活化蛋白（MAP）激酶激酶或p38 MAP激酶α或β。我们的研究结果表明，AMPK可以激活至少两种不同的信号转导机制，并表明它可能发挥更广泛的作用，在细胞应激反应比以前所理解的。
AMP-activated protein kinase (AMPK) is activated within the cell in response to multiple stresses that increase the intracellular AMP:ATP ratio. Here we show that incubation of muscle cells with the thiazolidinedione, rosiglitazone, leads to a dramatic increase in this ratio with the concomitant activation of AMPK. This finding raises the possibility that a number of the beneficial effects of the thiazolidinediones could be mediated via activation of AMPK. Furthermore, we show that in addition to the classical activation pathway, AMPK can also be stimulated without changing the levels of adenine nucleotides. In muscle cells, both hyperosmotic stress and the anti-diabetic agent, metformin, activate AMPK in the absence of any increase in the AMP:ATP ratio. However, although activation is no longer dependent on this ratio, it still involves increased phosphorylation of threonine 172 within the catalytic (a) subunit. AMPK stimulation in response to hyperosmotic stress does not appear to involve phosphatidylinositol 3-phosphate kinase, protein kinase C, mitogen-activated protein (MAP) kinase kinase, or p38 MAP kinase alpha or beta. Our results demonstrate that AMPK can be activated by at least two distinct signaling mechanisms and suggest that it may play a wider role in the cellular stress response than was previously understood.