Calmodulin-dependent protein kinase kinase-β is an alternative upstream kinase for AMP-activated protein kinase
Calmodulin-dependent protein kinase kinase-β is an alternative upstream kinase for AMP-activated protein kinase
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DOI：
10.1016/j.cmet.2005.05.009
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发表时间：
2005-07-01
期刊：
影响因子：
29
通讯作者：
Hardie, DG
中科院分区：
文献类型：
--
作者：
Hawley, SA;Pan, DA;Hardie, DG
AMP激活的蛋白激酶（AMPK）是细胞和全身能量平衡的关键调节因子。已经报道了两种上游激酶在无细胞测定中激活AMPK，即，肿瘤抑制因子LKB 1和钙调蛋白依赖性蛋白激酶激酶。然而，目前仅存在LKB 1的生理相关证据。我们现在报告说，有一个显着的基础活性和磷酸化的AMPK在LIKB 1缺陷的细胞，可以通过Ca 2+离子载体刺激，和研究使用的CaMKK抑制剂STO-609和亚型特异性siRNA表明，CaMKK β是需要这种效果。在无细胞测定中，CaMKK β也比CaMKK α更快地激活AMPK。K+诱导的去极化在大鼠大脑皮层切片，增加细胞内Ca 2+，而不干扰细胞的腺嘌呤核苷酸水平，激活AMPK，这是阻断STO-609。我们的研究结果表明，一个潜在的钙依赖性神经保护途径涉及磷酸化和激活AMPK的CaMKK β。
The AMP-activated protein kinase (AMPK) is a critical regulator of energy balance at both the cellular and whole-body levels. Two upstream kinases have been reported to activate AMPK in cell-free assays, i.e., the tumor suppressor LKB1 and calmodulin-dependent protein kinase kinase. However, evidence that this is physiologically relevant currently only exists for LKB1. We now report that there is a significant basal activity and phosphorylation of AMPK in LIKB1-deficient cells that can be stimulated by Ca2+ ionophores, and studies using the CaMKK inhibitor STO-609 and isoform-specific siRNAs show that CaMKK beta is required for this effect. CaMKK beta also activates AMPK much more rapidly than CaMKK alpha in cell-free assays. K+-induced depolarization in rat cerebrocortical slices, which increases intracellular Ca2+ without disturbing cellular adenine nucleotide levels, activates AMPK, and this is blocked by STO-609. Our results suggest a potential Ca2+-dependent neuroprotective pathway involving phosphorylation and activation of AMPK by CaMKK beta.