The α2-5′ AMP-activated protein kinase is a site 2 glycogen synthase kinase in skeletal muscle and is responsive to glucose loading
The α2-5′ AMP-activated protein kinase is a site 2 glycogen synthase kinase in skeletal muscle and is responsive to glucose loading
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DOI：
10.2337/diabetes.53.12.3074
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发表时间：
2004-12-01
期刊：
影响因子：
7.7
通讯作者：
Wojtaszewski, JFP
中科院分区：
文献类型：
--
作者：
Jorgensen, SB;Nielsen, JN;Wojtaszewski, JFP
5‘AMP激活的蛋白激酶(AMPK)是一种潜在的抗糖尿病药物靶点。在这里，我们发现5-氨基咪唑-1-β-4-甲酰胺-呋喃核苷(AICAR)对AMPK的药理激活导致糖原合成酶(GS)失活和GS在Ser7(第2位)的磷酸化。在靶向缺失Alpha2-AMPK基因的小鼠肌肉中，GS第2位的磷酸化在基础条件下降低，而在AICAR处理后没有变化。相比之下，在alpha1-AMPK基因敲除小鼠中，对AICAR的反应是正常的。燃料过剩(葡萄糖负荷)降低了AICAR对AMPK的激活，但下游靶标乙酰辅酶A羧化酶-β和GS的磷酸化正常。分级研究表明，这种对AMPK活性的抑制不是AMPK与膜或糖原结合的直接结果，因为AMPK在膜/糖原部分比在胞浆部分被AICAR更大程度地磷酸化。因此，AMPK对AICAR的下游作用不受葡萄糖负荷的影响，而AMPK上游的作用(通过AMPK磷酸化判断)减少。Alpha2-AMPK是一种GS激酶，可以在激活葡萄糖转运的同时使GS失活，这一事实表明应该对AMPK作为抗糖尿病药物靶点的适宜性采取平衡的观点。
The 5'AMP-activated protein kinase (AMPK) is a potential antidiabetic drug target. Here we show that the pharmacological activation of AMPK by 5-aminoimidazole-1-beta-4-carboxamide ribofuranoside (AICAR) leads to inactivation of glycogen synthase (GS) and phosphorylation of GS at Ser 7 (site 2). In muscle of mice with targeted deletion of the alpha2-AMPK gene, phosphorylation of GS site 2 was decreased under basal conditions and unchanged by AICAR treatment. In contrast, in alpha1-AMPK knockout mice, the response to AICAR was normal. Fuel surplus (glucose loading) decreased AMPK activation by AICAR, but the phosphorylation of the downstream targets acetyl-CoA carboxylase-beta and GS was normal. Fractionation studies suggest that this suppression of AMPK activation was not a direct consequence of AMPK association with membranes or glycogen, because AMPK was phosphorylated to a greater extent in response to AICAR in the membrane/glycogen fraction than in the cytosolic fraction. Thus, the downstream action of AMPK in response to AICAR was unaffected by glucose loading, whereas the action of the kinase upstream of AMPK, as judged by AMPK phosphorylation, was decreased. The fact that alpha2-AMPK is a GS kinase that inactivates GS while simultaneously activating glucose transport suggests that a balanced view on the suitability for AMPK as an antidiabetic drug target should be taken.