Enhanced catecholamine release in mice expressing PKB/SGK-resistant GSK3
Enhanced catecholamine release in mice expressing PKB/SGK-resistant GSK3
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表达 PKB/SGK 抗性 GSK3 的小鼠中儿茶酚胺释放增强
DOI：
10.1007/s00424-011-1006-6
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Lang F
中科院分区：
文献类型：
--
作者：
Siraskar B;Völkl J;Ahmed MS;Hierlmeier M;Schmid E;Leibrock C;Föller M;Lang UE;Lang F
糖原合成酶激酶3（GSK 3）在多种功能的调节中起着决定性的作用。GSK 3被磷酸化，其活性被蛋白激酶B（PK B/Akt）以及血清和糖皮质激素诱导型激酶（SGK）亚型抑制，这些亚型又被生长因子通过磷酸肌醇（PI）3激酶信号传导激活。PI 3/PKB/Akt/SGK依赖性抑制GSK 3在基因靶向敲入小鼠中被破坏，这些小鼠具有突变的PKB/SGK抗性GSK 3 α，β（gsk 3 KI），其中PKB/SGK磷酸化位点的丝氨酸已被丙氨酸取代。最近的实验表明，这些小鼠的血压明显高于野生型小鼠（gsk 3 WT）。本研究旨在阐明根本原因。血压测定与尾袖法，心率心电图测量，儿茶酚胺浓度ELISA法，香草扁桃酸高压液相色谱法。结果，sk 3 KI小鼠的血压和心率显著高于sk 3 WT小鼠。α-肾上腺素能受体阻滞剂哌唑嗪（1 μg/g体重，b.w.）和神经节阻滞剂六甲双铵（40 μg/g b.w.）降低血压的程度在sk 3 KI比sk 3 WT小鼠更大，并几乎消除了基因型之间的差异。同样，β-肾上腺素能阻滞剂阿替洛尔（5 μg/g b.w.）使sk 3 KI小鼠心率下降的程度大于sk 3 WT小鼠，并再次消除了基因型间心率的差异。血浆肾上腺素和去甲肾上腺素浓度，以及尿中香草扁桃酸排泄量，在sk 3 KI组显著高于sk 3 WT组。这些观察揭示了PKB/Akt/SGK依赖性GSK 3信号传导的一种全新功能，即，调节儿茶酚胺的释放。
Glycogen synthase kinase 3 (GSK3) plays a decisive role in the regulation of multiple functions. GSK3 is phosphorylated and its activity inhibited by protein kinase B (PKB/Akt) and serum and glucocorticoid inducible kinase (SGK) isoforms, which are in turn activated by growth factors through phosphoinositide (PI) 3 kinase signaling. PI3/PKB/Akt/SGK-dependent inhibition of GSK3 is disrupted in gene-targeted knockin mice with mutated and thus PKB/SGK-resistant GSK3α,ß (gsk3KI) where the serine of the PKB/SGK phosphorylation site has been replaced by alanine. Recent experiments revealed that blood pressure is significantly higher in those mice than in wild type mice (gsk3WT). The present study was performed to elucidate the underlying cause. Blood pressure was determined with the tail cuff method, heart rate by ECG measurements, catecholamine concentrations by ELISA, and vanillylmandelic acid by high pressure liquid chromatography. As a result, blood pressure and heart rate were significantly higher ingsk3KIthan ingsk3WTmice. The α-adrenergic blocker prazosin (1 μg/g body weight, b.w.) and the ganglion blocker hexamethonium (40 μg/g b.w.) decreased blood pressure to a larger extent ingsk3KIthan ingsk3WTmice and virtually abrogated the difference between genotypes. Similarly, the β-adrenergic blocker atenolol (5 μg/g b.w.) decreased the heart rate to a larger extent ingsk3KIthan ingsk3WTmice and again dissipated the difference of heart rate between genotypes. Plasma epinephrine and norepinephrine concentrations, as well as urinary excretion of vanillylmandelic acid, were significantly higher ingsk3KIthan ingsk3WTmice. The observations reveal a completely novel function of PKB/Akt/SGK-dependent GSK3 signaling, i.e., regulation of catecholamine release.
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DOI：
--
发表时间：
1988
期刊：
Progress in clinical and biological research
影响因子：
--
作者：
Randall,WC;Ardell,JL;O'Toole,MF;Wurster,RD
通讯作者：
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影响因子：
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作者：
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通讯作者：
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DOI：
10.1152/ajpheart.01192.2003
发表时间：
2004-10-01
影响因子：
4.8
作者：
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通讯作者：
Smith, TL
影响因子：
16.8
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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