Direct effects of caffeine and theophylline on p110δ and other phosphoinositide 3-kinases -: Differential effects on lipid kinase and protein kinase activities
Direct effects of caffeine and theophylline on p110δ and other phosphoinositide 3-kinases -: Differential effects on lipid kinase and protein kinase activities
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DOI：
10.1074/jbc.m202101200
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发表时间：
2002-10-04
影响因子：
4.8
通讯作者：
Shepherd, PR
中科院分区：
文献类型：
--
作者：
Foukas, LC;Daniele, N;Shepherd, PR
我们研究了甲基黄嘌呤对磷酸肌肽3激酶（PI3Ks）酶活性的影响。我们发现咖啡因抑制I类PI3Ks的体外脂质激酶（p110delta的IC(50) = 75 muM， p110alpha和p110beta的IC为400 muM， p110gamma的IC为1 mM），茶碱具有类似的作用（p110delta的IC(50) = 75 muM， p110alpha的IC为300 muM， p110beta和p110gamma的IC为800 muM），并且也抑制α亚型。II类PI3K (PI3K- c2alpha) （IC（50）接近400 muM）。然而，其他四种黄嘌呤衍生物（3-异丁基-1-甲基黄嘌呤，3-丙基黄嘌呤，alloxazine和PD116948（8-环戊基-1,3-二丙基黄嘌呤））的有效性要低一个数量级。令人惊讶的是，三唑喹啉CGS15943（9-氯-2-（2-呋喃基）（1,2,d）三唑（1,5-c）喹唑啉-5-胺）也选择性抑制P110delta （IC(50) < 10 μ M）。咖啡因和茶碱也抑制IA类pi3k和dna依赖性蛋白激酶的内在蛋白激酶活性，尽管其效力远低于脂质激酶（IC(50)， p110 α约为10 mM， p110 β为3 mM， dna依赖性蛋白激酶为10 mM）。在CHO-IR细胞和大鼠比目鱼肌中，茶碱和咖啡因阻断胰岛素用IC刺激蛋白激酶B的能力（50）。与抑制PI3K活性的值相似，而胰岛素对ERK1或ERK2的刺激在浓度高达10 mm时不被抑制。茶碱和咖啡因也阻断胰岛素对CHO-IR细胞中葡萄糖运输的刺激。这些结果表明，这些甲基黄嘌呤是PI3K脂质激酶活性的直接抑制剂，但对丝氨酸激酶活性的抑制作用明显较弱，因此可能在解剖这两种不同的激酶活性方面具有潜在的用途。茶碱、咖啡因和CGS15943可能在解剖p110 δ脂质激酶的特定作用中特别有用。最后，我们得出结论，抑制PI3K（特别是p110 δ）可能解释了咖啡因和茶碱的一些生理和药理学特性。
We investigated the effects of methylxanthines on enzymatic activity of phosphoinositide 3-kinases (PI3Ks). We found that caffeine inhibits the in vitro lipid kinase of class I PI3Ks (IC(50) = 75 muM for p110delta, 400 muM for p110alpha and p110beta, and 1 mM for p110gamma), and theophylline has similar effects (IC(50) = 75 muM for p110delta, 300 muM for p110alpha, and 800 muM for p110beta and p110gamma) and also inhibits the alpha isoform. of class II PI3K (PI3K-C2alpha) (IC(50) approximate to 400 muM). However, four other xanthine derivatives tested (3-isobutyl-1-methylxanthine, 3-propylxanthine, alloxazine, and PD116948 (8-cyclopentyl-1,3-dipropylxanthine)) were an order of magnitude less effective. Surprisingly the triazoloquinazoline CGS15943 (9-chloro-2-(2-furyl)(1,2,d)triazolo(1,5-c)quinazolin-5-amine) also selectively inhibits P110delta (IC(50) < 10 mu M). Caffeine and theophylline also inhibit the intrinsic protein kinase activity of the class IA PI3Ks and DNA-dependent protein kinase, although with a much lower potency than that for the lipid kinase (IC(50) approximate to 10 mM for p110 alpha, 3 mM for p110 beta, and 10 mM for DNA-dependent protein kinase). In CHO-IR cells and rat soleus muscle, theophylline and caffeine block the ability of insulin to stimulate protein kinase B with IC(50). values similar to those for inhibition of PI3K activity, whereas insulin stimulation of ERK1 or ERK2 was not inhibited at concentrations up to 10 mm. Theophylline and caffeine also blocked insulin stimulation of glucose transport in CHO-IR cells. These results demonstrate that these methylxanthines are direct inhibitors of PI3K lipid kinase activity but are distinctly less effective against serine kinase activity and thus could be of potential use in dissecting these two distinct kinase activities. Theophylline, caffeine, and CGS15943 may be of particular use in dissecting the specific role of the p110 delta lipid kinase. Finally, we conclude that inhibition of PI3K (p110 delta in particular) is likely explain some of the physiological and pharmacological properties of caffeine and theophylline.