AMP-activated protein kinase and nitric oxide regulate the glucose sensitivity of ventromedial hypothalamic glucose-inhibited neurons
AMP-activated protein kinase and nitric oxide regulate the glucose sensitivity of ventromedial hypothalamic glucose-inhibited neurons
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DOI：
10.1152/ajpcell.00127.2009
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发表时间：
2009-09-01
影响因子：
5.5
通讯作者：
Routh, Vanessa H.
中科院分区：
文献类型：
--
作者：
Murphy, Beth Ann;Fakira, Kurt A.;Routh, Vanessa H.
Murphy BA, Fakira KA, Song Z, Beuve A, Routh VH。AMPactivated蛋白激酶和一氧化氮调节下丘脑腹内侧葡萄糖抑制神经元的葡萄糖敏感性。[J] .中国生物医学工程学报，2009,31(2):557 - 557。首次发表于2009年7月1日；doi: 10.1152 / ajpcell.00127.2009。葡萄糖调节下丘脑腹内侧（VMH）葡萄糖抑制（GI）神经元活性的机制在很大程度上是未知的。我们之前的研究表明，amp激活的蛋白激酶（AMPK）增加了VMH GI神经元中一氧化氮（NO）的产生。我们假设ampk介导的NO信号是VMH GI神经元在葡萄糖降低时去极化所必需的。为了支持我们的假设，抑制神经元一氧化氮合酶（nNOS）或NO受体可溶性关酰环化酶（sGC）可阻断GI神经元的去极化，使葡萄糖从2.5 mM降低到0.7 mM或AMPK激活。相反，激活sGC或cGMP的细胞渗透性类似物8-溴鸟苷3′，5′-环单磷酸（8-Br-cGMP）可增强GI神经元对葡萄糖降低的反应，这表明AMPK刺激NO-sGC-cGMP信号通路是GI神经元葡萄糖感知所必需的。有趣的是，AMPK抑制剂化合物C完全阻断了sGC激活或8-Br-cGMP的作用，8-Br-cGMP增加了VMH AMPK α 2的磷酸化。这些数据表明，NO反过来又放大了GI神经元中AMPK的激活。最后，囊性纤维化跨膜调节因子（CFTR） Cl（-）电导的抑制阻断了GI神经元去极化以降低葡萄糖或AMPK激活，而葡萄糖、AMPK激活和8-Br-cGMP的降低则增加了VMH CFTR的磷酸化。我们得出结论，葡萄糖降低触发了以下一系列事件，导致VMH GI神经元的去极化：AMPK激活、nNOS磷酸化、NO产生和sGC-cGMP信号的刺激，这些信号放大了AMPK的激活并导致CFTR的关闭。
Murphy BA, Fakira KA, Song Z, Beuve A, Routh VH. AMPactivated protein kinase and nitric oxide regulate the glucose sensitivity of ventromedial hypothalamic glucose-inhibited neurons. Am J Physiol Cell Physiol 297: C750-C758, 2009. First published July 1, 2009; doi:10.1152/ajpcell.00127.2009.-The mechanisms by which glucose regulates the activity of glucose-inhibited (GI) neurons in the ventromedial hypothalamus (VMH) are largely unknown. We have previously shown that AMP-activated protein kinase (AMPK) increases nitric oxide (NO) production in VMH GI neurons. We hypothesized that AMPK-mediated NO signaling is required for depolarization of VMH GI neurons in response to decreased glucose. In support of our hypothesis, inhibition of neuronal nitric oxide synthase (nNOS) or the NO receptor soluble guanylyl cyclase (sGC) blocked depolarization of GI neurons to decreased glucose from 2.5 to 0.7 mM or to AMPK activation. Conversely, activation of sGC or the cell-permeable analog of cGMP, 8-bromoguanosine 3',5'-cyclic monophosphate (8-Br-cGMP), enhanced the response of GI neurons to decreased glucose, suggesting that stimulation of NO-sGC-cGMP signaling by AMPK is required for glucose sensing in GI neurons. Interestingly, the AMPK inhibitor compound C completely blocked the effect of sGC activation or 8-Br-cGMP, and 8-Br-cGMP increased VMH AMPK alpha 2 phosphorylation. These data suggest that NO, in turn, amplifies AMPK activation in GI neurons. Finally, inhibition of the cystic fibrosis transmembrane regulator (CFTR) Cl(-) conductance blocked depolarization of GI neurons to decreased glucose or AMPK activation, whereas decreased glucose, AMPK activation, and 8-Br-cGMP increased VMH CFTR phosphorylation. We conclude that decreased glucose triggers the following sequence of events leading to depolarization in VMH GI neurons: AMPK activation, nNOS phosphorylation, NO production, and stimulation of sGC-cGMP signaling, which amplifies AMPK activation and leads to closure of the CFTR.