Akt-dependent phosphorylation of endothelial nitric-oxide synthase mediates penile erection
Akt-dependent phosphorylation of endothelial nitric-oxide synthase mediates penile erection
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DOI：
10.1073/pnas.052712499
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发表时间：
2002-03-19
影响因子：
11.1
通讯作者：
Burnett, AL
中科院分区：
文献类型：
--
作者：
Hurt, KJ;Musicki, B;Burnett, AL
在阴茎中，一氧化氮合酶(NO)可由神经元型一氧化氮合酶(NNOS)和内皮型一氧化氮合酶(ENOS)共同生成。内皮型一氧化氮合酶被血管内的粘性阻力/剪切力激活，持续产生一氧化氮，这个过程是由磷脂酰肌醇3-激酶(P13-K)/Akt通路介导的。在这里，我们展示了P13-激酶/Akt在生理上调节勃起。电刺激海绵体神经和海绵体内直接注射血管松弛药罂粟碱都会引起磷酸化(激活)Akt和eNOS的迅速增加。Akt的上游激活剂P13-激酶的抑制剂Wortmannin和LY294002可降低磷酸化程度。这两种药物还可以减少勃起。在靶向删除eNOS的小鼠中，罂粟碱诱导的阴茎勃起显著减少。我们的发现支持一个模型，在该模型中，神经元型一氧化氮合酶的快速、短暂的激活启动了勃起过程，而P13-激酶/Akt依赖的磷酸化和eNOS的激活导致了持续的NO产生和最大的勃起。
In the penis, nitric oxide (NO) can be formed by both neuronal NO synthase and endothelial NOS (eNOS). eNOS is activated by viscous drag/shear stress in blood vessels to produce NO continuously, a process mediated by the phosphatidylinositol 3-kinase (P13-kinase)/Akt pathway. Here we show that P13-kinase/Akt physiologically mediates erection. Both electrical stimulation of the cavernous nerve and direct intracavernosal injection of the vasorelaxant drug papaverine cause rapid increases in phosphorylated (activated) Akt and eNOS. Phosphorylation is diminished by wortmannin and LY294002, inhibitors of P13-kinase, the upstream activator of Akt. The two drugs also reduce erection. Penile erection elicited by papaverine is reduced profoundly in mice with targeted deletion of eNOS. Our findings support a model in which rapid, brief activation of neuronal NOS initiates the erectile process, whereas P13-kinase/Akt-dependent phosphorylation and activation of eNOS leads to sustained NO production and maximal erection.