*Institute of Structural and Molecular Biology, Division of Biosciences, University College London, Gower Street, London, WC1E 6BT, U.K.
Biosci Rep. 2012 Apr 1;32(2):197-213. doi: 10.1042/BSR20110076.
In adult rat cardiac myocytes adrenaline decreased AMPK (AMP-activated protein kinase) activity with a half-time of approximately 4 min, decreased phosphorylation of AMPK (α-Thr172) and decreased phosphorylation of ACC (acetyl-CoA carboxylase). Inactivation of AMPK by adrenaline was through both α1- and β-ARs (adrenergic receptors), but did not involve cAMP or calcium signalling, was not blocked by the PKC (protein kinase C) inhibitor BIM I (bisindoylmaleimide I), by the ERK (extracellular-signal-regulated kinase) cascade inhibitor U0126 or by PTX (pertussis toxin). Adrenaline caused no measurable change in LKB1 activity. Adrenaline decreased AMPK activity through a process that was distinct from AMPK inactivation in response to insulin or PMA. Neither adrenaline nor PMA altered the myocyte AMP:ATP ratio although the adrenaline effect was attenuated by oligomycin and by AICAR (5-amino-4-imidazolecarboxamide-1-β-D-ribofuranoside), agents that mimic 'metabolic stress'. Inactivation of AMPK by adrenaline was abolished by 1 μM okadaic acid suggesting that activation of PP2A (phosphoprotein phosphatase 2A) might mediate the adrenaline effect. However, no change in PP2A activity was detected in myocyte extracts. Adrenaline increased phosphorylation of the AMPK β-subunit in vitro but there was no detectable change in vivo in phosphorylation of previously identified AMPK sites (β-Ser24, β-Ser108 or β-Ser182) suggesting that another site(s) is targeted.
在成年大鼠心肌细胞中，肾上腺素使 AMPK（AMP 激活的蛋白激酶）活性降低，半衰期约为 4 分钟，降低 AMPK（α-Thr172）的磷酸化和 ACC（乙酰辅酶 A 羧化酶）的磷酸化。肾上腺素对 AMPK 的失活是通过 α1-和 β-AR（肾上腺素能受体）实现的，但不涉及 cAMP 或钙信号，不能被 PKC（蛋白激酶 C）抑制剂 BIM I（双吲哚马来酰亚胺 I）、ERK（细胞外信号调节激酶）级联抑制剂 U0126 或 PTX（百日咳毒素）阻断。肾上腺素对 LKB1 活性没有可测量的影响。肾上腺素通过一种与胰岛素或 PMA 反应引起的 AMPK 失活不同的过程降低 AMPK 活性。肾上腺素和 PMA 都没有改变心肌细胞的 AMP:ATP 比，尽管肾上腺素的作用被寡霉素和 AICAR（5-氨基-4-咪唑甲酰胺-1-β-D-核糖呋喃糖苷）减弱，这些药物模拟“代谢应激”。1 μM 冈田酸可消除肾上腺素对 AMPK 的失活作用，表明激活 PP2A（磷酸蛋白磷酸酶 2A）可能介导肾上腺素的作用。然而，在心肌细胞提取物中未检测到 PP2A 活性的变化。肾上腺素在体外增加 AMPK β 亚基的磷酸化，但在体内，先前鉴定的 AMPK 位点（β-Ser24、β-Ser108 或 β-Ser182）的磷酸化没有明显变化，表明另一个（或多个）位点是靶标。
