Polyamines Transduce the Nongenomic, Androgen-Induced Calcium Sensitization in Intestinal Smooth Muscle
Polyamines Transduce the Nongenomic, Androgen-Induced Calcium Sensitization in Intestinal Smooth Muscle
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DOI：
10.1210/me.2013-1201
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发表时间：
2013-10-01
影响因子：
--
通讯作者：
Diaz, Mario
中科院分区：
文献类型：
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作者：
Gonzalez-Montelongo, Maria C.;Marin, Raquel;Diaz, Mario
雄激素通过多种遗传机制调节身体发育和分化，主要是在生殖器官。近年来，性激素活动出现了一个不同的场景：肠道肌肉。因此，虽然雌激素松弛肠道肌肉，但雄激素是机械增强的强大诱导剂。雄激素的这种作用是耐人寻味的，因为它是在生理浓度下观察到的，由非基因组机制介导，并涉及一种钙敏化收缩机械的现象，通过刺激Rho相关激酶对20 kDa肌球蛋白轻链的磷酸化来实现。在这里，我们破译了男性肠道肌肉中雄激素钙增敏和机械增强的分子机制，以及它与多胺代谢的密切关系。因此，雄激素刺激多胺合成，抑制多胺合成可消除雄激素诱导的钙敏化和20 kDa肌球蛋白轻链磷酸化。我们证明，钙敏化诱导的第一个分子步骤是接头蛋白RhoA的非常规激活，该激活由转谷氨酰胺酶催化的RhoA多胺化触发，然后被靶向到膜上激活Rho相关激酶。总之，这些结果表明，雄激素的生理水平通过多胺代谢的调节和RhoA的翻译后修饰，激活了肠平滑肌中一条新的信号转导途径，从而诱导了钙增敏。此外，除了雄激素为数不多的生理上相关的非基因组效应外，这些结果可能是众所周知的肠道运输性别差异的基础，从而扩大了自然界对性激素影响的清单。
Androgens regulate body development and differentiation through a variety of genotropic mechanisms, mostly in reproductive organs. In recent years a different scenario for sex hormone actions has emerged: the intestinal muscle. Thus, although estrogens relax intestinal muscle, androgens are powerful inducers of mechanical potentiation. This effect of androgens was intriguing because it is observed at physiological concentrations, is mediated by nongenomic mechanisms, and involves a phenomenon of calcium sensitization of contractile machinery by stimulating phosphorylation of 20 kDa myosin light chain by Rho-associated kinase. Here we have deciphered the molecular mechanisms underlying calcium sensitization and mechanical potentiation by androgens in male intestinal muscle as well as its tight relationship to polyamine metabolism. Thus, androgens stimulate polyamine synthesis, and the inhibition of polyamine synthesis abolishes androgen-induced calcium sensitization and 20 kDa myosin light chain phosphorylation. We demonstrate that the first molecular step in the induction of calcium sensitization is a nonconventional activation of the adaptor protein RhoA, triggered by a transglutaminase-catalyzed polyamination of RhoA, which is then targeted to the membrane to activate Rho-associated kinase. Altogether, these results demonstrate that the physiological levels of androgens, through the modulation of polyamine metabolism and posttanslational modification of RhoA, activate a new signal transduction pathway in the intestinal smooth muscle to induce calcium sensitization. Furthermore, apart from being one of the few physiologically relevant nongenomic effects of androgens, these results might underlie the well-known gender differences in intestinal transits, thus expanding the nature's inventory of sex hormones effects.